Milestones in understanding transport, sensing, and signaling of the plant nutrient phosphorus.

As an essential nutrient element, phosphorus (P) is primarily acquired and translocated as inorganic phosphate (Pi) by plant roots. Pi is often sequestered in the soil and becomes limited for plant growth. Plants have developed a sophisticated array of adaptive responses, termed P starvation responses, to cope with P deficiency by improving its external acquisition and internal utilization. Over the past 2 to 3 decades, remarkable progress has been made toward understanding how plants sense and respond to changing environmental P. This review provides an overview of the molecular mechanisms that regulate or coordinate P starvation responses, emphasizing P transport, sensing, and signaling. We present the major players and regulators responsible for Pi uptake and translocation. We then introduce how P is perceived at the root tip, how systemic P signaling is operated, and the mechanisms by which the intracellular P status is sensed and conveyed. Additionally, the recent exciting findings about the influence of P on plant-microbe interactions are highlighted. Finally, the challenges and prospects concerning the interplay between P and other nutrients and strategies to enhance P utilization efficiency are discussed. Insights obtained from this knowledge may guide future research endeavors in sustainable agriculture.

Association of Chinese herbal medicine use with the depression risk among the long-term breast cancer survivors: A longitudinal follow-up study.

Background: Breast cancer patients are at elevated risk of depression during treatment, thus provoking the chance of poor clinical outcomes. This retrospective cohort study aimed to investigate whether integrating Chinese herbal medicines citation(CHM) into conventional cancer therapy could decrease the risk of depression in the long-term breast cancer survivors. Methods: A cohort of patients aged 20-70 years and with newly diagnosed breast cancer during 2000-2008 was identified from a nationwide claims database. In this study, we focused solely on survivors of breast cancer at least1 year after diagnosis. After one-to-one matching for age, sex, and baseline comorbidities, breast cancer patients who received (n = 1,450) and did not receive (n = 1,450) CHM treatment were enrolled. The incidence rate and hazard ratio citation(HR) for depression between the two groups was estimated at the end of 2012. A Cox proportional hazard model was constructed to examine the impact of the CHM use on the risk of depression. Results: During the study period, the incidence rate of depression was significantly lower in the treated cohort than in the untreated cohort [8.57 compared with 11.01 per 1,000 person-years citation(PYs)], and the adjusted HR remained significant at 0.74 (95% CI 0.58-0.94) in a Cox proportional hazards regression model. The corresponding risk further decreasing to 43% among those using CHM for more than 1 year. Conclusion: Finding from this investigation indicated that the lower risk of depression observed in breast cancer patients treated with CHM, suggesting that CHM treatment should be considered for disease management toward breast cancer. Yet, the optimal administered dose should be determined in further clinical trials.

Arbuscular mycorrhizal symbiosis enhances tomato lateral root formation by modulating CEP2 peptide expression.

Plant lateral root (LR) growth usually is stimulated by arbuscular mycorrhizal (AM) symbiosis. However, the molecular mechanism is still unclear. We used gene expression analysis, peptide treatment and virus-induced gene alteration assays to demonstrate that C-terminally encoded peptide (CEP2) expression in tomato was downregulated during AM symbiosis to mitigate its negative effect on LR formation through an auxin-related pathway. We showed that enhanced LR density and downregulated CEP2 expression were observed during mycorrhizal symbiosis. Synthetic CEP2 peptide treatment reduced LR density and impaired the expression of genes involved in indole-3-butyric acid (IBA, the precursor of IAA) to IAA conversion, auxin polar transport and the LR-related signaling pathway; however, application of IBA or synthetic auxin 1-naphthaleneacetic acid (NAA) to the roots may rescue both defective LR formation and reduced gene expression. CEP receptor 1 (CEPR1) might be the receptor of CEP2 because its knockdown plants did not respond to CEP2 treatment. Most importantly, the LR density of CEP2 overexpression or knockdown plants could not be further increased by AM inoculation, suggesting that CEP2 was critical for AM-induced LR formation. These results indicated that AM symbiosis may regulate root development by modulating CEP2, which affects the auxin-related pathway.

PCDHB15 as a potential tumor suppressor and epigenetic biomarker for breast cancer.

Breast cancer is among the most frequently diagnosed cancer types and the leading cause of cancer-related death in women. The mortality rate of patients with breast cancer is currently increasing, perhaps due to a lack of early screening tools. In the present study, using The Cancer Genome Atlas (TCGA) breast cancer dataset (n=883), it was determined that methylation of the protocadherin ß15 (PCDHB15) promoter was higher in breast cancer samples than that in normal tissues. A negative association between promoter methylation and expression of PCDHB15 was observed in the TCGA dataset and breast cancer cell lines. In TCGA cohort, lower PCDHB15 expression was associated with shorter relapse-free survival times. Treatment with the DNA methyltransferase inhibitor restored PCDHB15 expression in a breast cancer cell line; however, overexpression of PCDHB15 was shown to suppress colony formation. PCDHB15 methylation detected in circulating cell-free DNA (cfDNA) isolated from serum samples was higher in patients with breast cancer (40.8%) compared with that in patients with benign tumors (22.4%). PCDHB15 methylation was not correlated with any clinical parameters. Taken together, PCDHB15 is a potential tumor suppressor in cases of breast cancer, which can be epigenetically silenced via promoter methylation. PCDHB15 methylation using cfDNA is a novel minimally invasive epigenetic biomarker for the diagnosis and prognosis of breast cancer.

Transcriptome analysis reveals the mechanisms for mycorrhiza-enhanced salt tolerance in rice.

More than half of the global population relies on rice as a staple food, but salinization of soil presents a great threat to rice cultivation. Although previous studies have addressed the possible benefits of arbuscular mycorrhizal (AM) symbiosis for rice under salinity stress, the underlying molecular mechanisms are still unclear. In this study, we found that mycorrhizal rice had better shoot and reproductive growth and a significantly higher K+/Na+ ratio in the shoot. The reactive oxygen species (ROS) scavenging capacity in rice shoots was also improved by AM symbiosis. To elucidate the molecular mechanisms required for AM-improved salt tolerance, transcriptome analysis revealing the differentially expressed genes (DEGs) based on the response to AM symbiosis, salinity or specific tissue was performed. Thirteen percent of DEGs showed tissue-preferred responses to both AM symbiosis and salt stress and might be the key genes contributing to AM-enhanced salt tolerance. Gene Ontology (GO) enrichment analysis identified GO terms specifically appearing in this category, including cell wall, oxidoreductase activity, reproduction and ester-related terms. Interestingly, GO terms related to phosphate (Pi) homeostasis were also found, suggesting the possible role of the Pi-related signaling pathway involved in AM-enhanced salt tolerance. Intriguingly, under nonsaline conditions, AM symbiosis influenced the expression of these genes in a similar way as salinity, especially in the shoots. Overall, our results indicate that AM symbiosis may possibly use a multipronged approach to influence gene expression in a way similar to salinity, and this modification could help plants be prepared for salt stress.

A terahertz time-domain super-resolution imaging method using a local-pixel graph neural network for biological products.

The low image acquisition speed of terahertz (THz) time-domain imaging systems limits their application in biological products analysis. In the current study, a local pixel graph neural network was built for THz time-domain imaging super-resolution. The method could be applied to the analysis of any heterogeneous biological products as it only required a small number of sample images for training and particularly it focused on THz feature frequencies. The graph network applied the Fourier transform to graphs extracted from low-resolution (LR) images bringing an invariance of rotation and flip for local pixels, and the network then learnt the relationship between the state of graphs and the corresponding pixels to be reconstructed. With wood cores and seeds as examples, the images of these samples were captured by a THz time-domain imaging system for training and analysed by the method, achieving the root mean square error (RMSE) of pixels of 0.0957 and 0.1061 for the wood core and seed images, respectively. In addition, the reconstructed high-resolution (HR) images, LR images and true HR images at several feature frequencies were also compared in the current study. Results indicated that the method could not only reconstruct the spatial details and the useful signals from high noise signals at high feature frequencies but could also operate super-resolution in both spatial and spectral aspects.

Influence of three different anesthesia protocols on aged rat brain: a resting-state functional magnetic resonance imaging study.

BACKGROUND: Resting-state functional magnetic resonance imaging (rs-fMRI) is a promising method for the study of brain function. Typically, rs-fMRI is performed on anesthetized animals. Although different functional connectivity (FC) in various anesthetics on whole brain have been studied, few studies have focused on different FC in the aged brain. Here, we measured FC under three commonly used anesthesia methods and analyzed data to determine if the FC in whole brain analysis were similar among groups. METHODS: Twenty-four male aged Wistar rats were randomly divided into three groups (n = 8 in each group). Anesthesia was performed under either isoflurane (ISO), combined ISO + dexmedetomidine (DEX) or α-chloralose (AC) according to the groups. Data of rs-fMRI was analyzed by FC in a voxel-wise way. Differences in the FC maps between the groups were analyzed by one-way analysis of variance and post hoc two-sample t tests. RESULTS: Compared with ISO + DEX anesthesia, ISO anesthesia caused increased FC in posterior brain and decreased FC in the middle brain of the aged rat. AC anesthesia caused global suppression as no increase in FC was observed. CONCLUSION: ISO could be used as a substitute for ISO + DEX in rat default mode network studies if the left temporal association cortex is not considered important.

Decreased risk of colorectal cancer among patients with type 2 diabetes receiving Chinese herbal medicine: a population-based cohort study.

OBJECTIVES: Patients with type 2 diabetes have a higher risk of colorectal cancer (CRC), but whether Chinese herbal medicines (CHMs) can reduce this risk is unknown. This study investigated the effect that CHMs have on CRC risk in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study used the Taiwanese National Health Insurance Research Database to identify 54 744 patients, newly diagnosed with type 2 diabetes, aged 20-70 years, who were receiving treatment between 1998 and 2007. From this sample, we randomly selected 14 940 CHMs users and 14 940 non-CHMs users, using propensity scores matching. All were followed through 2012 to record CRC incidence. Cox proportional hazards regression was used to compute the hazard ratio (HR) of CRC by CHMs use. RESULTS: During follow-up, 235 CHMs users and 375 non-CHMs users developed CRC, incidence rates of 1.73% and 2.47% per 1000 person-years, respectively. CHM users had a significantly reduced risk of CRC compared with non-CHM users (adjusted HR=0.71; 95% CI 0.60 to 0.84). The greatest effect was in those receiving CHMs for more than 1 year. Huang-Qin, Xue-Fu-Zhu-Yu-Tang, Shu-Jing-Huo-Xue-Tang, Liu-Wei-Di-Huang-Wan, Ji-Sheng-Shen-Qi-Wan, Gan-Lu-Yin, Shao-Yao-Gan-Cao-Tang and Ban-Xia-Xie-Xin-Tang were significantly associated with lower risk of CRC. CONCLUSION: Integrating CHMs into the clinical management of patients with type 2 diabetes may be beneficial in reducing the risk of CRC.

High birth weight and its interaction with physical activity influence the risk of obesity in early school-aged children.

BACKGROUND: High birth weight (HBW) is associated with childhood obesity, but with inconsistent results. This study investigated the relationship between HBW and childhood obesity, and further explored the interaction of HBW with behavioral and socio-economic determinants of obesity. METHODS: This cross-sectional study enrolled 1906 grade-two children of Guangzhou, China, from June to November, 2016. Overweight/obesity corresponded to a body mass index higher than the sex-age-specific criteria. Abdominal obesity was assessed using the sex-specific waist-height ratio cutoffs. The association of HBW with obesity was evaluated in multivariable logistic regression model. The relative excess risk due to interaction (RERI) and the attributable proportion of interaction (AP) indices were used to measure additive interaction, while applying the interaction of OR index for multiplicative interaction assessment. RESULTS: Children with HBW had an increased risk of overweight/obesity [odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.56-3.76] compared with those without HBW. Significant additive interaction of HBW with physical activity was found for overweight/obesity [relative excess risk due to interaction (RERI) = 2.69, 95% CI = 0.62-4.75; attributable proportion of interaction (AP) = 0.72, 95% CI = 0.42-1.02]. The HBW children with insufficient activity had higher odds of overweight/obesity compared to the non-HBW children with sufficient activity (OR = 3.75, 95% CI = 2.06-6.83). In addition, we identified a significant interaction of HBW with household income for abdominal obesity (RERI = 1.20, 95% CI = 0.02-2.37; AP = 0.76, 95% CI = 0.16-1.36). CONCLUSIONS: HBW confers an increased risk for childhood overweight/obesity. Physical activity attenuates the effect of HBW on overweight/obesity, and HBW possibly synergistically interacts with high household income to promote abdominal obesity in childhood.

Upstream Open Reading Frame and Phosphate-Regulated Expression of Rice OsNLA1 Controls Phosphate Transport and Reproduction.

Rice (Oryza sativa) OsNLA1 has been proposed to play a crucial role in regulating phosphate (Pi) acquisition in roots, similar to that of Arabidopsis (Arabidopsis thaliana) AtNLA. However, unlike AtNLA, OsNLA1 is not a target of miR827, a Pi starvation-induced microRNA. It is, therefore, of interest to know whether the expression of OsNLA1 depends on Pi supply and how it is regulated. In this study, we provide evidence that OsNLA1 controls Pi acquisition by directing the degradation of several OsPHT1 Pi transporters (i.e. OsPT1/2/4/7/8/12). We further show that OsNLA1 has an additional function in reproduction and uncover the mechanism of its expression regulation. Analysis of mRNA levels, promoter-GUS activity, and protoplast transient expression showed that the expression of OsNLA1.1, the most abundant transcript variant, is up-regulated in response to increasing Pi supply. The OsNLA1 promoter region was found to contain an upstream open reading frame that is required for Pi-responsive expression regulation. OsNLA1 promoter activity was observed in roots, ligules, leaves, sheaths, pollen grains, and surrounding the vascular tissues of anthers, suggesting that OsNLA1 is important throughout the development of rice. Disruption of OsNLA1 resulted in increased Pi uptake from roots as well as impaired pollen development and reduced grain production. In summary, our study reveals that Pi-induced OsNLA1 expression regulated by a unique mechanism functions in Pi acquisition, Pi translocation, and reproductive success.

A rice Serine/Threonine receptor-like kinase regulates arbuscular mycorrhizal symbiosis at the peri-arbuscular membrane.

In terrestrial ecosystems most plant species live in mutualistic symbioses with nutrient-delivering arbuscular mycorrhizal (AM) fungi. Establishment of AM symbioses includes transient, intracellular formation of fungal feeding structures, the arbuscules. A plant-derived peri-arbuscular membrane (PAM) surrounds the arbuscules, mediating reciprocal nutrient exchange. Signaling at the PAM must be well coordinated to achieve this dynamic cellular intimacy. Here, we identify the PAM-specific Arbuscular Receptor-like Kinase 1 (ARK1) from maize and rice to condition sustained AM symbiosis. Mutation of rice ARK1 causes a significant reduction in vesicles, the fungal storage structures, and a concomitant reduction in overall root colonization by the AM fungus Rhizophagus irregularis. Arbuscules, although less frequent in the ark1 mutant, are morphologically normal. Co-cultivation with wild-type plants restores vesicle and spore formation, suggesting ARK1 function is required for the completion of the fungal life-cycle, thereby defining a functional stage, post arbuscule development.

Role of vacuoles in phosphorus storage and remobilization.

Vacuoles play a fundamental role in storage and remobilization of various nutrients, including phosphorus (P), an essential element for cell growth and development. Cells acquire P primarily in the form of inorganic orthophosphate (Pi). However, the form of P stored in vacuoles varies by organism and tissue. Algae and yeast store polyphosphates (polyPs), whereas plants store Pi and inositol phosphates (InsPs) in vegetative tissues and seeds, respectively. In this review, we summarize how vacuolar P molecules are stored and reallocated and how these processes are regulated and co-ordinated. The roles of SYG1/PHO81/XPR1 (SPX)-domain-containing membrane proteins in allocating vacuolar P are outlined. We also highlight the importance of vacuolar P in buffering the cytoplasmic Pi concentration to maintain cellular homeostasis when the external P supply fluctuates, and present additional roles for vacuolar polyP and InsP besides being a P reserve. Furthermore, we discuss the possibility of alternative pathways to recycle Pi from other P metabolites in vacuoles. Finally, future perspectives for researching this topic and its potential application in agriculture are proposed.

Diphenhydramine induces melanoma cell apoptosis by suppressing STAT3/MCL-1 survival signaling and retards B16-F10 melanoma growth in vivo.

Melanoma is the most aggressive skin malignancy with a high rate of mortality and is frequently refractory to many therapeutics, thus demanding the discovery of novel effective anti-melanoma agents. Diphenhydramine (DPH) is an H1 histamine receptor antagonist and a relatively safe drug. Previous studies have revealed the in vitro cytotoxicity of DPH against melanoma cells, but the mechanisms involved concerning its cytotoxicity and the in vivo anti-melanoma effect remain unknown. We herein present the first evidence supporting that DPH is selectively proapoptotic for a panel of melanoma cell lines irrespective of BRAFV600E status while sparing normal melanocytes. Of note, DPH effectively suppressed tumor growth and prolonged the length of survival of mice bearing B16-F10 melanoma. Mechanistic investigation further revealed that DPH downregulated antiapoptotic MCL-1, whereas MCL-1 overexpression impeded the proapoptotic action of DPH. Moreover, DPH attenuated STAT3 activation, as evidenced by the reduced levels of tyrosine 705-phosphorylated STAT3. Notably, ectopic expression of constitutively active STAT3 mutant reduced DPH-induced apoptosis but also protected MCL-1 from downregulation by DPH, illustrating that DPH impairs STAT3 activation to block STAT3-mediated induction of MCL-1 in eliciting apoptosis. Collectively, we for the first time validate the in vivo anti­melanoma effect of DPH and also establish DPH as a drug targeting STAT3/MCL-1 survival signaling pathway to induce apoptosis. Our discovery therefore suggests the potential to repurpose DPH as an anti-melanoma therapeutic agent.

Identification of plant vacuolar transporters mediating phosphate storage.

Plant vacuoles serve as the primary intracellular compartments for inorganic phosphate (Pi) storage. Passage of Pi across vacuolar membranes plays a critical role in buffering the cytoplasmic Pi level against fluctuations of external Pi and metabolic activities. Here we demonstrate that the SPX-MFS proteins, designated as PHOSPHATE TRANSPORTER 5 family (PHT5), also named Vacuolar Phosphate Transporter (VPT), function as vacuolar Pi transporters. Based on (31)P-magnetic resonance spectroscopy analysis, Arabidopsis pht5;1 loss-of-function mutants accumulate less Pi and exhibit a lower vacuolar-to-cytoplasmic Pi ratio than controls. Conversely, overexpression of PHT5 leads to massive Pi sequestration into vacuoles and altered regulation of Pi starvation-responsive genes. Furthermore, we show that heterologous expression of the rice homologue OsSPX-MFS1 mediates Pi influx to yeast vacuoles. Our findings show that a group of Pi transporters in vacuolar membranes regulate cytoplasmic Pi homeostasis and are required for fitness and plant growth.

Rice perception of symbiotic arbuscular mycorrhizal fungi requires the karrikin receptor complex.

In terrestrial ecosystems, plants take up phosphate predominantly via association with arbuscular mycorrhizal fungi (AMF). We identified loss of responsiveness to AMF in the rice (Oryza sativa) mutant hebiba, reflected by the absence of physical contact and of characteristic transcriptional responses to fungal signals. Among the 26 genes deleted in hebiba, DWARF 14 LIKE is, the one responsible for loss of symbiosis . It encodes an alpha/beta-fold hydrolase, that is a component of an intracellular receptor complex involved in the detection of the smoke compound karrikin. Our finding reveals an unexpected plant recognition strategy for AMF and a previously unknown signaling link between symbiosis and plant development.

Promoter-based identification of novel non-coding RNAs reveals the presence of dicistronic snoRNA-miRNA genes in Arabidopsis thaliana.

BACKGROUND: In the past few decades, non-coding RNAs (ncRNAs) have emerged as important regulators of gene expression in eukaryotes. Most studies of ncRNAs in plants have focused on the identification of silencing microRNAs (miRNAs) and small interfering RNAs (siRNAs). Another important family of ncRNAs that has been well characterized in plants is the small nucleolar RNAs (snoRNAs) and the related small Cajal body-specific RNAs (scaRNAs). Both target chemical modifications of ribosomal RNAs (rRNAs) and small nuclear RNAs (snRNAs). In plants, the snoRNA genes are organized in clusters, transcribed by RNA Pol II from a common promoter and subsequently processed into mature molecules. The promoter regions of snoRNA polycistronic genes in plants are highly enriched in two conserved cis-regulatory elements (CREs), Telo-box and Site II, which coordinate the expression of snoRNAs and ribosomal protein coding genes throughout the cell cycle. RESULTS: In order to identify novel ncRNA genes, we have used the snoRNA Telo-box/Site II motifs combination as a functional promoter indicator to screen the Arabidopsis genome. The predictions generated by this process were tested by detailed exploration of available RNA-Seq and expression data sets and experimental validation. As a result, we have identified several snoRNAs, scaRNAs and 'orphan' snoRNAs. We also show evidence for 16 novel ncRNAs that lack similarity to any reported RNA family. Finally, we have identified two dicistronic genes encoding precursors that are processed to mature snoRNA and miRNA molecules. We discuss the evolutionary consequences of this result in the context of a tight link between snoRNAs and miRNAs in eukaryotes. CONCLUSIONS: We present an alternative computational approach for non-coding RNA detection. Instead of depending on sequence or structure similarity in the whole genome screenings, we have explored the properties of promoter regions of well-characterized ncRNAs. Interestingly, besides expected ncRNAs predictions we were also able to recover single precursor arrangement for snoRNA-miRNA. Accompanied by analyses performed on rice sequences, we conclude that such arrangement might have interesting functional and evolutionary consequences and discuss this result in the context of a tight link between snoRNAs and miRNAs in eukaryotes.

Stop and Smell the Pollen: The Role of Olfaction and Vision of the Oriental Honey Buzzard in Identifying Food.

The importance of olfaction for various avian behaviors has become increasingly evident. So far, the use of olfaction for food detection among raptors has only been demonstrated for Cathartes vultures. The Oriental honey buzzard (Pernis orientalis) is a resident and migrant in Taiwan and regularly forages in apiaries. One of its foods in apiaries is yellow pollen dough, a softball-sized mixture of pollen, soybeans, and sugar that beekeepers provide as a supplementary food for bees. Given that pollen dough is not similar to any naturally occurring food, we hypothesized that buzzards identify the dough's nutritious contents using olfaction, perhaps in combination with vision. Using a series of choice experiments in which individuals could choose between two doughs, we showed that (1) buzzards almost unerringly chose pollen-containing over pollen lacking doughs when otherwise the doughs were identical in size, shape, and yellow color; (2) buzzards always preferred yellow over black or green doughs if both doughs contained pollen; (3) buzzards still preferred pollen-containing over pollen-lacking doughs when both doughs were black, but at a lower rate than in (1). We statistically excluded the possible influences of the doughs' relative brightness or of repeat visits by the same individuals. Our experiments thus suggest the use of a 'multi-modal foraging strategy' among buzzards whereby olfaction and vision are likely to be both used in identifying food at close distances. We also estimated the olfactory receptor gene repertoire size in the buzzard's genome which is almost five times as large as that of three other raptor species. Therefore, olfaction is likely of far greater ecological importance to this species than to other raptor species. We suggest that olfaction should be considered in the design of behavioral and genetic studies to better understand the use of multiple senses in avian behaviors.

Transcriptome diversity among rice root types during asymbiosis and interaction with arbuscular mycorrhizal fungi.

Root systems consist of different root types (RTs) with distinct developmental and functional characteristics. RTs may be individually reprogrammed in response to their microenvironment to maximize adaptive plasticity. Molecular understanding of such specific remodeling--although crucial for crop improvement--is limited. Here, RT-specific transcriptomes of adult rice crown, large and fine lateral roots were assessed, revealing molecular evidence for functional diversity among individual RTs. Of the three rice RTs, crown roots displayed a significant enrichment of transcripts associated with phytohormones and secondary cell wall (SCW) metabolism, whereas lateral RTs showed a greater accumulation of transcripts related to mineral transport. In nature, arbuscular mycorrhizal (AM) symbiosis represents the default state of most root systems and is known to modify root system architecture. Rice RTs become heterogeneously colonized by AM fungi, with large laterals preferentially entering into the association. However, RT-specific transcriptional responses to AM symbiosis were quantitatively most pronounced for crown roots despite their modest physical engagement in the interaction. Furthermore, colonized crown roots adopted an expression profile more related to mycorrhizal large lateral than to noncolonized crown roots, suggesting a fundamental reprogramming of crown root character. Among these changes, a significant reduction in SCW transcripts was observed that was correlated with an alteration of SCW composition as determined by mass spectrometry. The combined change in SCW, hormone- and transport-related transcript profiles across the RTs indicates a previously overlooked switch of functional relationships among RTs during AM symbiosis, with a potential impact on root system architecture and functioning.

Sulforaphane down-regulates SKP2 to stabilize p27(KIP1) for inducing antiproliferation in human colon adenocarcinoma cells.

Sulforaphane is a cruciferous vegetable-derived isothiocyanate with promising chemopreventive and therapeutic activities. Induction of proliferation arrest and apoptosis principally contribute to sulforaphane's anticancer activity, but the precise molecular mechanisms remain elusive. The oncoprotein SKP2 is a key component of the SKP1-CULLIN1-F-box (SCF) E3 ligase complex and is responsible for directing SCF-mediated degradation of cyclin-dependent kinase inhibitor p27(KIP1) to promote cell proliferation. We herein provide the first evidence supporting the critical involvement of the SKP2-p27(KIP1) axis in sulforaphane-induced antiproliferation in various human colon adenocarcinoma cell lines. Specifically, sulforaphane markedly suppressed the levels of bromodeoxyuridine (BrdU) incorporation and clonogenicity in all tested cell lines, illustrating the antiproliferative effect of sulforaphane. Of note, sulforaphane-induced antiproliferation was accompanied with down-regulation of SKP2, leading to the stabilization and thus up-regulation of p27(KIP1). Additionally, sulforaphane was found to down-regulate SKP2 mainly through transcriptional repression, as sulforaphane lowered SKP2 mRNA expression and the SKP2 promoter activity. Furthermore, sulforaphane treatment led to the activation of both AKT and ERK, thus ruling out the possibility that sulforaphane down-regulates SKP2 by inhibiting AKT or ERK. Notably, sulforaphane-elicited suppression of BrdU incorporation and clonogenicity were significantly rescued in the context of SKP2 overexpression or p27(KIP1) depletion, therefore highlighting the important role of SKP2 down-regulation and the ensuing stabilization of p27(KIP1) in sulforaphane-induced antiproliferation. Collectively, these data expand our molecular understanding about how sulforaphane elicits proliferation arrest, but also implicate the application of sulforaphane in therapeutic modalities targeting SKP2.

Subamolide B Isolated from Medicinal Plant Cinnamomum subavenium Induces Cytotoxicity in Human Cutaneous Squamous Cell Carcinoma Cells through Mitochondrial and CHOP-Dependent Cell Death Pathways.

Subamolide B is a butanolide isolated from Cinnamomum subavenium, a medicinal plant traditionally used to treat various ailments including carcinomatous swelling. We herein reported for the first time that subamolide B potently induced cytotoxicity against diverse human skin cancer cell lines while sparing nonmalignant cells. Mechanistic studies on human cutaneous squamous cell carcinoma (SCC) cell line SCC12 highlighted the involvement of apoptosis in subamolide B-induced cytotoxicity, as evidenced by the activation of caspases-8, -9, -4, and -3, the increase in annexin V-positive population, and the partial restoration of cell viability by cotreatment with the pan-caspase inhibitor z-VAD-fmk. Additionally, subamolide B evoked cell death pathways mediated by FasL/Fas, mitochondria, and endoplasmic reticulum (ER) stress, as supported by subamolide B-induced FasL upregulation, BCL-2 suppression/cytosolic release of cytochrome c, and UPR activation/CHOP upregulation, respectively. Noteworthy, ectopic expression of c-FLIPL or dominant-negative mutant of FADD failed to impair subamolide B-induced cytotoxicity, whereas BCL-2 overexpression or CHOP depletion greatly rescued subamolide B-stimulated cells. Collectively, these results underscored the central role of mitochondrial and CHOP-mediated cell death pathways in subamolide B-induced cytotoxicity. Our findings further implicate the potential of subamolide B for cutaneous SCC therapy or as a lead compound for developing novel chemotherapeutic agents.