Qinzhuliangxue mixture ameliorates psoriasis by restraining apoptosis in psoriasis via downregulating the MDA-5 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is characterized by hyperkeratosis that produces the classic silvery scales, and the pathogenesis of psoriasis involves abnormal proliferation of keratinocytes. Emerging evidence supports that apoptosis regulates keratinocyte proliferation and formation of stratum corneum, which maintains the homeostasis of the skin. Qinzhuliangxue mixture (QZLX) is a representative formula for the treatment of psoriasis, which was earliest recorded in the classic Chinese medicine book Xia's Surgery. In our previous clinical studies, QZLX demonstrated 83.33% efficacy with few side effects in the treatment of psoriasis. Furthermore, our published basic research has also proved that the QZLX mixture effectively inhibits the hyperproliferation of keratinocytes, thus exerting therapeutic effects on psoriasis. However, whether QZLX mixture can regulate keratinocytes apoptosis requires further clarification. OBJECTIVE OF THE STUDY: To investigate the mechanism of QZLX in the treatment of psoriasis from the perspective of keratinocyte apoptosis. MATERIALS AND METHODS: First, psoriasis-like mice with imiquimod (IMQ)-induced were given QZLX intragastric administration and Psoriasis Area Severity Index (PASI) scores were recored for 11 consecutive days to appraise the efficacy. Then, tissue samples were collected for transcriptome analysis. The DEseq2 method detected significantly differentially expressed genes (DEGs), Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway databases were used to analyze the functions and pathway enrichment of DEGs. After that, the therapeutic mechanisms of QZLX in intervening with psoriasis were explored using TUNEL, immunohistochemical staining, and western blotting. RESULTS: QZLX ameliorated the symptoms and pathological characteristics of IMQ-induced psoriasis in mice. The epidermal cell hyperplasia in the skin was inhibited, in accordance with the suppressed expression of PCNA and Ki67 after treatment. Transcriptome sequencing showed that melanoma differentiation associated gene-5 (MDA-5) was downregulated. GO and KEGG enrichment analysis of the signaling pathways indicated that the differentially expressed genes were significantly enriched in apoptosis pathways. Besides, QZLX treatment decreased the apoptosis of keratinocyte as shown by reduced TUNEL-positive cells. As MDA-5 protein levels decreased, so did the expression of the downstream protein Caspase-8, which indicates that the apoptotic pathway was triggered. Furthermore, QZLX therapy might also help to balance the apoptotic Bcl-2 family expression. CONCLUSION: QZLX restrains the apoptosis of keratinocyte in psoriasis-like mice by downregulating the MDA-5 pathway. The restoration of the balance between cell apoptosis and proliferation in the skin may lead to considerable psoriasis relief. Our study reveals the possible molecular processes behind the effects of QZLX therapy on the skin lesions of psoriasis, and lends support to its clinical efficacy.

Phosphate deficiency modifies lipid composition and seed oil production in camelina.

Camelina (Camelina sativa) is an emerging industrial oilseed crop because of its potential for double cropping, fallow year production, growth on marginal lands, and multiple uses of seed oils and meals. To realize the potential for sustainable production of camelina, a better understanding of how camelina seed oil production and composition respond to low input environments is desired. Phosphorus (P) is one of the least available essential macronutrients to plants with finite worldwide supply. This study investigated seed oil production and lipid composition of camelina in field settings and under greenhouse conditions in response to P deficiency. Lipidomic profiling reveals that P deficiency in field settings triggered extensive leaf lipid remodeling that decreased the ratio of phospholipids to non-P-containing galactolipids from 30% to 5% under P sufficient to deficient conditions. P deficiency increased seed oil content per seed weight by approximately 25% and 20% in field and greenhouse settings, respectively. In addition, P deficiency altered seed fatty acid composition, with increases in monounsaturated 18:1 and 20:1 and decreases in polyunsaturated 18:3. Total seed production was decreased by 10- to 15-fold under P deficiency and the decrease resulted from reduced seed numbers without affecting seed weight. The results from field and greenhouse conditions indicate that P deficiency increases seed oil content, alters fatty acid composition, and decreases greatly seed production, suggesting that achieving a high yield and quality of camelina seed oil is positively linked to P status of soil.

Elongation factor eEF2 kinase and autophagy jointly promote survival of cancer cells.

Cells within solid tumours can become deprived of nutrients; in order to survive, they need to invoke mechanisms to conserve these resources. Using cancer cells in culture in the absence of key nutrients, we have explored the roles of two potential survival mechanisms, autophagy and elongation factor 2 kinase (eEF2K), which, when activated, inhibits the resource-intensive elongation stage of protein synthesis. Both processes are regulated through the nutrient-sensitive AMP-activated protein kinase and mechanistic target of rapamycin complex 1 signalling pathways. We find that disabling both autophagy and eEF2K strongly compromises the survival of nutrient-deprived lung and breast cancer cells, whereas, for example, knocking out eEF2K alone has little effect. Contrary to some earlier reports, we find no evidence that eEF2K regulates autophagy. Unexpectedly, eEF2K does not facilitate survival of prostate cancer PC3 cells. Thus, eEF2K and autophagy enable survival of certain cell-types in a mutually complementary manner. To explore this further, we generated, by selection, cells which were able to survive nutrient starvation even when autophagy and eEF2K were disabled. Proteome profiling using mass spectrometry revealed that these 'resistant' cells showed lower levels of diverse proteins which are required for energy-consuming processes such as protein and fatty acid synthesis, although different clones of 'resistant cells' appear to adapt in dissimilar ways. Our data provide further information of the ways that human cells cope with nutrient limitation and to understanding of the utility of eEF2K as a potential target in oncology.

A target-oriented algorithm for maintaining serum calcium stability automatically in regional citrate anticoagulation.

BACKGROUND: Regional citrate anticoagulation (RCA) for renal replacement therapy is widely practiced in critically ill patients. However, concern exists regarding its labor-intensiveness for monitoring and the associated hypocalcemia. In this study, we provided an algorithm for prescribing RCA and evaluated its safety in patients. METHODS: During 18 hemofiltration treatments with calcium-free replacement solution, participants were randomized to receive algorithm-based or trial-and-error RCA protocol. The effluent volume, post-filter and in vivo ionized calcium (iCa), and calcium in the sera and effluents were periodically measured at an interval of 1 to 2 h. RESULTS: For patients received algorithm-based RCA protocol, no one had a serum iCa less than 0.9 mmol/L, and none needed calcium supplement adjustment to maintain serum calcium stability. For patients accepted trial-and-error protocol, all patients had a serum iCa below 0.9 mmol/L, their serum iCa and calcium levels fluctuated dramatically, and all patients need additional calcium supplement adjustment during RCA. None of the participants showed a post-filter iCa > 0.4 mmol/L. CONCLUSION: We provided a safe algorithm for calculating calcium supplementation doses that could maintain serum calcium stability without additional adjustment during RCA.

Genome- and transcriptome-wide association studies provide insights into the genetic basis of natural variation of seed oil content in Brassica napus.

Seed oil content (SOC) is a highly important and complex trait in oil crops. Here, we decipher the genetic basis of natural variation in SOC of Brassica napus by genome- and transcriptome-wide association studies using 505 inbred lines. We mapped reliable quantitative trait loci (QTLs) that control SOC in eight environments, evaluated the effect of each QTL on SOC, and analyzed selection in QTL regions during breeding. Six-hundred and ninety-two genes and four gene modules significantly associated with SOC were identified by analyzing population transcriptomes from seeds. A gene prioritization framework, POCKET (prioritizing the candidate genes by incorporating information on knowledge-based gene sets, effects of variants, genome-wide association studies, and transcriptome-wide association studies), was implemented to determine the causal genes in the QTL regions based on multi-omic datasets. A pair of homologous genes, BnPMT6s, in two QTLs were identified and experimentally demonstrated to negatively regulate SOC. This study provides rich genetic resources for improving SOC and valuable insights toward understanding the complex machinery that directs oil accumulation in the seeds of B. napus and other oil crops.

Molybdenum induces alterations in the glycerolipidome that confer drought tolerance in wheat.

Molybdenum (Mo), which is an essential microelement for plant growth, plays important roles in multiple metabolic and physiological processes, including responses to drought and cold stress in wheat. Lipids also have crucial roles in plant adaptions to abiotic stresses. The aim of this study was to use glycerolipidomic and transcriptomic analyses to determine the changes in lipids induced by Mo that are associated with Mo-enhanced drought tolerance in wheat. Mo treatments increased the transcript levels of genes involved in fatty acid and glycerolipid biosynthesis and desaturation, but suppressed the expression of genes involved in oxylipin production. Wheat plants supplemented with Mo displayed higher contents of monogalactosyldiacyglycerol (MGDG), digalactosyldoacylglycerol (DGDG), phosphatidylglycerol (PG), phosphatidylethanolamine (PE), and phosphatidylcholine (PC) with increased levels of unsaturation. The levels of MGDG, DGDG, PG, and PC increased under PEG-simulated drought (PSD), and the magnitude of the responses varied in the presence and absence of Mo. Mo increased the accumulation of the most abundant glycerolipid species of C36:6, C34:4, and C34:3 by increasing the expression of genes related to desaturation under PSD, and this contributed to maintaining the fluidity of membranes. In addition, Mo attenuated the decreases in the ratios of DGDG/MGDG and PC/PE that were observed under PSD. These changes in lipids in Mo-treated wheat would contribute to maintaining the integrity of membranes and to protecting the photosynthetic apparatus, thus acting together to enhance drought tolerance.

Nonspecific phospholipase C6 increases seed oil production in oilseed Brassicaceae plants.

Plant oils are valuable commodities for food, feed, renewable industrial feedstocks and biofuels. To increase vegetable oil production, here we show that the nonspecific phospholipase C6 (NPC6) promotes seed oil production in the Brassicaceae seed oil species Arabidopsis, Camelina and oilseed rape. Overexpression of NPC6 increased seed oil content, seed weight and oil yield both in Arabidopsis and Camelina, whereas knockout of NPC6 decreased seed oil content and seed size. NPC6 is associated with the chloroplasts and microsomal membranes, and hydrolyzes phosphatidylcholine and galactolipids to produce diacylglycerol. Knockout and overexpression of NPC6 decreased and increased, respectively, the flux of fatty acids from phospholipids and galactolipids into triacylglycerol production. Candidate-gene association study in oilseed rape indicates that only BnNPC6.C01 of the four homeologues NPC6s is associated with seed oil content and yield. Haplotypic analysis indicates that the BnNPC6.C01 favorable haplotype can increase both seed oil content and seed yield. These results indicate that NPC6 promotes membrane glycerolipid turnover to accumulate TAG production in oil seeds and that NPC6 has a great application potential for oil yield improvement.

Dual Activities of Plant cGMP-Dependent Protein Kinase and Its Roles in Gibberellin Signaling and Salt Stress.

Cyclic GMP (cGMP) is an important regulator in eukaryotes, and cGMP-dependent protein kinase (PKG) plays a key role in perceiving cellular cGMP in diverse physiological processes in animals. However, the molecular identity, property, and function of PKG in plants remain elusive. In this study, we have identified PKG from plants and characterized its role in mediating the gibberellin (GA) response in rice (Oryza sativa). PKGs from plants are structurally unique with an additional type 2C protein phosphatase domain. Rice PKG possesses both protein kinase and phosphatase activities, and cGMP stimulates its kinase activity but inhibits its phosphatase activity. One of PKG's targets is GAMYB, a transcription factor in GA signaling, and the dual activities of PKG catalyze the reversible phosphorylation of GAMYB at Ser6 and modulate the nucleocytoplasmic distribution of GAMYB in response to GA. Loss of PKG impeded the nuclear localization of GAMYB and abolished GAMYB function in the GA response, leading to defects in GA-induced seed germination, internode elongation, and pollen viability. In addition to GAMYB, PKG has multiple potential targets and thus has broad effects, particularly in the salt stress response.

Ectopic expression of tea MYB genes alter spatial flavonoid accumulation in alfalfa (Medicago sativa).

Flavonoids are one of the largest secondary metabolite groups, which are widely present in plants. Flavonoids include anthocyanins, proanthocyanidins, flavonols and isoflavones. In particular, proanthocyanidins possess beneficial effects for ruminant animals in preventing lethal pasture bloat. As a major legume forage, alfalfa (Medicago sativa) contains little proanthocyanidins in foliage to combat bloat. In an attempt to improve proanthocyanidin content in alfalfa foliage, we over-expressed two MYB transcription factors (CsMYB5-1 and CsMYB5-2) from tea plant that is rich in proanthocyanidins. We showed that, via targeted metabolite and transcript analyses, the transgenic alfalfa plants accumulated higher levels of flavonoids in stems/leaves than the control, in particular anthocyanins and proanthocyanidins. Over-expression of CsMYB5-1 and CsMYB5-2 induced the expression levels of genes involved in flavonoid pathway, especially anthocyanin/proanthocyanidin-specific pathway genes DFR, ANS and ANR in stems/leaves. Both anthocyanin/proanthocyanidin content and the expression levels of several genes were conversely decreased in flowers of the transgenic lines than in control. Our results indicated that CsMYB5-1 and CsMYB5-2 differently regulate anthocyanins/proanthocyanidins in stems/leaves and flowers. Our study provides a guide for increasing anthocyanin/proanthocyanidin accumulation in foliage of legume forage corps by genetic engineering. These results also suggest that it is feasible to cultivate new varieties for forage production to potentially solve pasture bloat, by introducing transcription factors from typical plants with high proanthocyanidin level.

Phosphatidylinositol-hydrolyzing phospholipase C4 modulates rice response to salt and drought.

Phosphatidylinositol-specific phospholipase C (PI-PLC) is involved in stress signalling but its signalling function remains largely unknown in crop plants. Here, we report that the PI-PLC4 from rice (Oryza sativa cv), OsPLC4, plays a positive role in osmotic stress response. Two independent knockout mutants, plc4-1 and plc4-2, exhibited decreased seedling growth and survival rate whereas overexpression of OsPLC4 improved survival rate under high salinity and water deficiency, compared with wild type (WT). OsPLC4 hydrolyses PI, phosphatidylinositol 4-phosphate (PI4P), and phosphatidylinositol-4,5-bisphosphate (PIP2 ) to generate diacylglycerol (DAG) in vitro. Knockout of OsPLC4 attenuated salt-induced increase of phosphatidic acid (PA) whereas overexpression of OsPLC4 decreased the level of PI4P and PIP2 under salt treatment. Applications of DAG or PA restored the growth defect of plc4-1 to WT but DAG kinase inhibitor 1 blocked the complementary effect of DAG in plc4-1 under salt stress. In addition, the loss of OsPLC4 compromised the increase of inositol triphosphate and free cytoplasmic Ca2+ ([Ca2+ ]cyt ) and inhibited the induction of genes involved in Ca2+ sensor and osmotic stress response to salt stress. The results indicate that OsPLC4 modulates the activity of two signalling pathways, PA and Ca2+ , to affect rice seedling response to osmotic stress.

Genistein-Specific G6DT Gene for the Inducible Production of Wighteone in Lotus japonicus.

Prenylated isoflavonoids have been found in several legume plants, and they possess various biological activities that play important roles in both plant defense and human health. However, it is still unknown whether prenylated isoflavonoids are present in the model legume plant Lotus japonicus. In the present study, we found that the prenylated isoflavonoid wighteone was produced in L. japonicus when leaf was supplemented with genistein. Furthermore, a novel prenyltransferase gene, LjG6DT, was identified, which shared high similarity with and was closely related to several known prenyltransferase genes involved in isoflavonoid biosynthesis. The recombinant LjG6DT protein expressed in yeast exhibited prenylation activity toward genistein as an exclusive substrate, which produced wighteone, a prenylated genistein at the C-6 position that occurs normally in legume plants. The LjG6DT-green fluorescent protein (GFP) fusion protein is targeted to plastids. The transcript level of LjG6DT is induced by glutathione, methyl jasmonate and salicylic acid, implying that LjG6DT is involved in stress response. Overexpression of LjG6DT in L. japonicus hairy roots led to increased accumulation of wighteone when genistein was supplied, indicating that LjG6DT is functional in vivo. Feeding assays with the upstream intermediate naringenin revealed that accumulation of wighteone in L. japonicus was dependent on genistein supplementation, and accumulation of wighteone is competed by genistein methylation. This study demonstrated that phytoalexin wighteone is inducibly produced in L. japonicus, and it provides new insight into the biosynthesis and accumulation of prenylated isoflavonoids in legume plants.

In situ adjuvant therapy using a responsive doxorubicin-loaded fibrous scaffold after tumor resection.

As tumor microenvironment becoming more and more important in tumor study, the acid pH around or in solid tumors drew lots of attentions. And the progress of drug delivery systems made the responsive-release possible. This time, we fabricated a new-type composite electrospun poly (L-lactide) (PLLA) fibrous scaffolds, that blent with the mesoporous silica particles (MSNs). Further more, we used sodium bicarbonate (SB) as acid sensitive agent which was wrapped inside the MSNs. And doxorubicin (DOX) was also wrapped into MSNs in order to achieve a sustained release to inhibit tumors in mice, which mimicked the remnant breast cancer with surgery. In vitro experiments proved the characteristic of pH-responsive release of the composite fibrous scaffold. In vivo results showed that these composite fibers could induce obvious apoptosis and necrosis over 10 weeks. Further, the cancer-kill effects were also confirmed by the decreased level of Bcl-2 and TNF-α, while increased Bax and caspase-3 expression levels. Altogether, the results indicated that the composite drug delivery system as a local implantable scaffold could effectively kill cancer cells in a long term with pH-sensitivity after the tumor resection.

Membrane glycerolipidome of soybean root hairs and its response to nitrogen and phosphate availability.

Root hairs are tubular extensions of specific root epidermal cells important in plant nutrition and water absorption. To determine membrane glycerolipids in root hairs and roots may differ, as well as their respective response to nutrient availability, this study analyzed the membrane glycerolipid species in soybean root hairs and in roots stripped of root hairs, and their response to nitrogen (N) and phosphate (Pi) supplementation. The ratio of phospholipids to galactolipids was 1.5 fold higher in root hairs than in stripped roots. Under Pi deficiency, the ratio of phospholipids to galactolipids in stripped roots decreased with the greatest decrease found in the level of phosphatidylethanolamine (PE) in root hairs and stripped roots, and root hairs had an increased level of phosphatidic acid (PA). When seedlings were not supplied with N, the level of the N-containing lipids PE and phosphatidylserine in root hairs decreased whereas the level of non-N-containing lipids galactolipids and PA increased compared to N-supplied conditions. In stripped roots, the level of major membrane lipids was not different between N-sufficient and -deficient conditions. The results indicate that the membrane glycerolipidomes in root hairs are more responsive to nutrient availability than are the rest of roots.

NEAT1 upregulates EGCG-induced CTR1 to enhance cisplatin sensitivity in lung cancer cells.

Platinum-based drugs are the firstline of treatment for non-small cell lung cancer (NSCLC), but resistance to these drugs is a major obstacle to effective chemotherapy. Our previous study revealed that the green tea polyphenol, EGCG, induced cisplatin transporter CTR1 (copper transporter 1) and enhanced cisplatin sensitivity in ovarian cancer. In this study, we found that EGCG upregulated CTR1 and increased platinum accumulation in NSCLC (A549, H460 and H1299) cells, cDDP-resistant A549 cells and a nude mouse xenograft model. Cisplatin-induced inhibition of cell growth was enhanced by EGCG treatment in vitro and in vivo. MicroRNA hsa-mir-98-5p appears to suppress CTR1 gene expression, while long non-coding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) appears to enhance it. Bioinformatics analysis showed that hsa-mir-98-5p has specific complementary binding sites for NEAT1. In addition, hsa-mir-98-5p was predicted to be a putative CTR1 target. NEAT1 may act as a competing endogenous lncRNA to upregulate EGCG-induced CTR1 by sponging hsa-mir-98-5p in NSCLC. Our findings reveal a novel mechanism how NEAT1 upregulates EGCG-induced CTR1 and enhances cisplatin sensitivity in vitro and in vivo, and suggest EGCG could serve as an effective adjuvant chemotherapeutic in lung cancer treatment.

Ingestion of bioactive collagen hydrolysates enhance facial skin moisture and elasticity and reduce facial ageing signs in a randomised double-blind placebo-controlled clinical study.

BACKGROUND: Several human studies have demonstrated occurrence of two major collagen peptides, prolyl-hydroxyproline (Pro-Hyp) and hydroxyprolyl-glycine (Hyp-Gly), in human peripheral blood. Some in vitro studies have demonstrated that Pro-Hyp and Hyp-Gly exert chemotaxis on dermal fibroblasts and enhance cell proliferation. Additionally, Pro-Hyp enhances the production of hyaluronic acid by dermal fibroblasts. These findings suggest that the amounts of Pro-Hyp and Hyp-Gly in blood are important factors to show the efficacy of collagen hydrolysates on skin health. RESULTS: We conducted a randomised double-blind placebo-controlled clinical trial of ingestion of two types of collagen hydrolysates, which are composed of different amounts of the bioactive dipeptides Pro-Hyp and Hyp-Gly, to investigate their effects on the improvement of skin conditions. Improvement in skin conditions, such as skin moisture, elasticity, wrinkles, and roughness, were compared with a placebo group at baseline, and 4 and 8 weeks after the start of the trial. In addition, the safety of dietary supplementation with these peptides was evaluated by blood test. Collagen hydrolysate with a higher content of bioactive collagen peptides (H-CP) showed significant and more improvement than the collagen hydrolysate with a lower content of bioactive collagen peptides (L-CP) and the placebo, in facial skin moisture, elasticity (R2), wrinkles and roughness, compared with the placebo group. In addition, there were no adverse events during the trial. CONCLUSION: This study demonstrated that the use of the collagen hydrolysate with a higher content of Pro-Hyp and Hyp-Gly led to more improvement in facial skin conditions, including facial skin moisture, elasticity, wrinkles and roughness. © 2016 Society of Chemical Industry.

Phospholipase Dε enhances Braasca napus growth and seed production in response to nitrogen availability.

Phospholipase D (PLD), which hydrolyses phospholipids to produce phosphatidic acid, has been implicated in plant response to macronutrient availability in Arabidopsis. This study investigated the effect of increased PLDε expression on nitrogen utilization in Brassica napus to explore the application of PLDε manipulation to crop improvement. In addition, changes in membrane lipid species in response to nitrogen availability were determined in the oil seed crop. Multiple PLDε over expression (PLDε-OE) lines displayed enhanced biomass accumulation under nitrogen-deficient and nitrogen-replete conditions. PLDε-OE plants in the field produced more seeds than wild-type plants but have no impact on seed oil content. Compared with wild-type plants, PLDε-OE plants were enhanced in nitrate transporter expression, uptake and reduction, whereas the activity of nitrite reductase was higher under nitrogen-depleted, but not at nitrogen-replete conditions. The level of nitrogen altered membrane glycerolipid metabolism, with greater impacts on young than mature leaves. The data indicate increased expression of PLDε has the potential to improve crop plant growth and production under nitrogen-depleted and nitrogen-replete conditions.

Role of aminoalcoholphosphotransferases 1 and 2 in phospholipid homeostasis in Arabidopsis.

Aminoalcoholphosphotransferase (AAPT) catalyzes the synthesis of phosphatidylcholine (PC) and phosphotidylethanolamine (PE), which are the most prevalent membrane phospholipids in all eukaryotic cells. Here, we show that suppression of AAPTs results in extensive membrane phospholipid remodeling in Arabidopsis thaliana. Double knockout (KO) mutants that are hemizygous for either aapt1 or aapt2 display impaired pollen and seed development, leading to embryotic lethality of the double KO plants, whereas aapt1 or aapt2 single KO plants show no overt phenotypic alterations. The growth rate and seed yield of AAPT RNA interference (RNAi) plants are greatly reduced. Lipid profiling shows decreased total galactolipid and phospholipid content in aapt1-containing mutants, including aapt1, aapt1/aapt1 aapt2/AAPT2, aapt1/AAPT1 aapt2/aapt2, and AAPT RNAi plants. The level of PC in leaves was unchanged, whereas that of PE was reduced in all AAPT-deficient plants, except aapt2 KO. However, the acyl species of PC was altered, with increased levels of C34 species and decreased C36 species. Conversely, the levels of PE and phosphatidylinositol were decreased in C34 species. In seeds, all AAPT-deficient plants, including aapt2 KO, displayed a decrease in PE. The data show that AAPT1 and AAPT2 are essential to plant vegetative growth and reproduction and have overlapping functions but that AAPT1 contributes more than AAPT2 to PC production in vegetative tissues. The opposite changes in molecular species between PC and PE and unchanged PC level indicate the existence of additional pathways that maintain homeostatic levels of PC, which are crucial for the survival and proper development of plants.

EGCG Enhances Cisplatin Sensitivity by Regulating Expression of the Copper and Cisplatin Influx Transporter CTR1 in Ovary Cancer.

Cisplatin is one of the first-line platinum-based chemotherapeutic agents for treatment of many types of cancer, including ovary cancer. CTR1 (copper transporter 1), a transmembrane solute carrier transporter, has previously been shown to increase the cellular uptake and sensitivity of cisplatin. It is hypothesized that increased CTR1 expression would enhance the sensitivity of cancer cells to cisplatin (cDDP). The present study demonstrates for the first time that (-)-epigallocatechin-3-gallate (EGCG), a major polyphenol from green tea, can enhance CTR1 mRNA and protein expression in ovarian cancer cells and xenograft mice. EGCG inhibits the rapid degradation of CTR1 induced by cDDP. The combination of EGCG and cDDP increases the accumulation of cDDP and DNA-Pt adducts, and subsequently enhances the sensitivity of ovarian cancer SKOV3 and OVCAR3 cells to the chemotherapeutic agent. In the OVCAR3 ovarian cancer xenograft nude mice model, the combination of the lower concentration of cDDP and EGCG strongly repressed the tumor growth and exhibited protective effect on the nephrotoxicity induced by cisplatin. Overall, these findings uncover a novel chemotherapy mechanism of EGCG as an adjuvant for the treatment of ovarian cancer.

Curcumin Reactivates Silenced Tumor Suppressor Gene RARß by Reducing DNA Methylation.

Reactivation of tumor suppressor genes by nontoxic bioactive food component represents a promising strategy for cancer chemoprevention. Retinoic acid receptor ß (RARß), one member of the RAR receptor family, is considered as a tumor suppressor. Reduced expression of RARß has been reported in lung cancer and other solid tumors. DNA hypermethylation of the promoter region of RARß is a major mechanism for its silencing in tumors. Recently, curcumin has been considered as a potential DNA methyltransferase inhibitor. Herein, we demonstrated that curcumin significantly elevate RARß expression at the mRNA and protein levels in tested cancer cells. Additionally, curcumin decreased RARß promoter methylation in lung cancer A549 and H460 cells. Mechanistic study demonstrated that curcumin was able to downregulate the mRNA levels of DNMT3b. In a lung cancer xenograft node mice model, curcumin exhibited protective effect against weight loss because of tumor burden. Tumor growth was strongly repressed by curcumin treatment. As the results from in vitro, RARß mRNA were increased and DNMT3b mRNA were decreased by curcumin treatment compared with the mice in control group. Altogether, this study reveals a novel molecular mechanism of curcumin as a chemo-preventive agent for lung cancer through reactivation of RARß.

Hybrids from Farnesylthiosalicylic Acid and Hydroxamic Acid as Dual Ras-Related Signaling and Histone Deacetylase (HDAC) Inhibitors: Design, Synthesis and Biological Evaluation.

A novel series of hybrids was designed and synthesized by combining key elements from farnesylthiosalicylic acid (FTS) and hydroxamic acid. Several 3,7,11-trimethyldodeca-2,6,10-trien-1-yl) thio)benzamide derivatives, particularly those with branched and linear aliphatic linkers between the hydroxamic zinc binding group (ZBG) and the benzamide core, not only displayed significant antitumor activities against six human cancer cells but also exhibited histone deacetylase (HDAC) inhibitory effects in vitro. Among them, N-(4-(hydroxyamino)-4-oxobutyl)-2-(((2E,6E)-3,7,11-trimethyldodeca-2,6, 10-trien-1-yl)thio)benzamide (8 d) was the most potent, with IC50 values of 4.9-7.6 µM; these activities are eight- to sixteen-fold more potent than FTS and comparable to that of suberoylanilide hydroxamic acid (SAHA). Derivative 8 d induced cell cycle arrest in the G0/G1 phase, inhibited the acetylation of histone H3 and α-tubulin, and blocked Ras-related signaling pathways in a dose-dependent manner. The improved tumor growth inhibition and cell-cycle arrest in vitro might result from the dual inhibition. These findings suggest dual inhibitors of Ras-related signaling pathway and HDAC hold promise as therapeutic agents for the treatment of cancer.