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The PPP-RTK system, which is capable of providing a centimeter-level real-time positioning service for an unlimited number of users, is becoming a promising tool in mass-market applications such as smartphones, the Internet of Things (IoT), and the automotive industry. The extended Kalman filter (EKF) is the conventional method for parameter estimation in the existing PPP-RTK system. Recently, an alternative method known as factor graph optimization (FGO), which fully leverages the time correlation among current and historical measurements, has the potential to further improve the accuracy and robustness of PPP-RTK solutions. In this contribution, a factor graph optimization-based PPP-RTK framework is developed, where raw pseudorange, phase measurements, precise atmospheric corrections, and time-differenced carrier-phase (TDCP) measurements serve as factors in FGO estimators. The continuously tracked phase ambiguities are estimated as the time-invariant state node and propagated by marginalization while ambiguity resolution is conducted independently between epochs. A second optimization process with the utilization of ambiguity-resolved solutions and time-differenced carrier-phase (TDCP) measurements is conducted to further improve the reliability of positioning results. The effectiveness of the proposed method is evaluated by vehicular tests in urban environments. Results indicate that the FGO method could improve the performance of ambiguity resolution by reducing the ambiguity search space and increasing the ratio values, leading to a significant accuracy improvement of 55% in an open-sky environment compared to the traditional EKF-based method. Furthermore, in GNSS signal partly block scenes, the FGO-based PPP-RTK is capable of obtaining more robust and accurate positioning solutions with fewer outliers compared to the EKF method. [ABSTRACT FROM AUTHOR]

Two new chiral ruthenium (II) complexes, Δ-[Ru (bpy) 2 (10-OH-dppz)]2+ (Δ- 1; bpy = 2,2ʹ-bipyridine, 10-OH-dppz = 10-hydroxyl-dipyrido [3,2- a :2′,3′- c ]phenazine) and Λ-[Ru (bpy) 2 (10-OH-dppz)]2+ (Λ- 1), have been synthesized and characterized in this work. The binding properties of the two enantiomers with an RNA triplex poly (U*A-U) [in text, dash (−) denotes the Watson-Crick base pairing and the asterisk (*) denotes the Hoogsteen base pairing] have been studied. Analysis of the absorption and fluorescence spectra suggest that the binding constant of enantiomer Λ- 1 toward the triplex is somewhat smaller than that of enantiomer Δ- 1 , which is further supported by viscosity experiments. Viscosity experiments showed that although the two enantiomers were intercalated to the triplex, the Δ-enantiomer was a better intercalator than the Λ-enantiomer. Furthermore, thermal denaturation experiments demonstrate that although the two enantiomers can significantly increase the triplex stabilization, unlike enantiomer Λ- 1 , enantiomer Δ- 1 stabilizes the Watson-Crick base-paired duplex and the Hoogsteen base-paired third strand of the triplex with obvious selectivity. In addition, the triplex stabilization by enantiomer Δ- 1 was significantly stronger than that by Λ- 1. The obtained results indicate that the binding ability of enantiomers Δ- 1 and Λ- 1 to the triplex is dependent on the chirality of enantiomers. • Bpy = 2,2ʹ-bipyridine and 10-OH-dppz = 6-hydroxyl-dipyrido [3,2- a :2′,3′- c ]phenazine. • Δ/Λ-[Ru (bpy) 2 (10-OH-dppz)]2+ (Δ/Λ- 1) were synthesize as binders for poly (U*A-U). • Unlike Λ- 1 , Δ- 1 stabilizes the triplex with obvious selectivity. • The third-strand stabilizing effect of Δ- 1 is more marked than that of Λ- 1. • [Ru (bpy) 2 (10-OH-dppz)]2+ is a non-specific intercalator for poly (U*A-U). [ABSTRACT FROM AUTHOR]

Heshouwu ( Polygonum multiflorum Thunb.) has been a common Chinese medicine and a folk Taoist medicine for over a thousand years. There are two drug forms, Shengshouwu ( Polygoni Multiflori Radix ) and Zhiheshouwu ( Polygoni Multiflori Radix Prapaerata ) in the Chinese Pharmacopoeia. In this review, we retrieved articles with such keywords as Heshouwu , liver protection and liver toxicity in the databases of PubMed and the China National Knowledge Infrastructure (CNKI). Hepatoprotection and hepatotoxicity of Shengshouwu and Zhiheshouwu in vitro and in vivo , and their clinical settings and adverse drug reactions (ADR) were summarized, analyzed and critically reviewed. In bench research, both drug forms had effects against nonalcoholic fatty liver disease, oxidation, fibrosis, cirrhosis, and liver cancer. Clinically, Heshouwu was used for treating fatty liver disease (FLD), hyperlipidemia, cirrhosis and hepatitis B. In contrast, both drug forms could lead to drug-induced liver injury and even death in vitro , in vivo and in clinical settings. In addition, the active components of both drug forms had hepatic benefits and toxicity in interaction with emodin, physcion, and probably 2,3,5,4′-tetrahydroxy-stilbene-2-O-beta- d -glucoside (TSG). In conclusion, Heshouwu exhibited both hepatoprotection and hepatotoxicity. It is essential to evaluate the advantages and disadvantages when Heshouwu is in clinical use. [ABSTRACT FROM AUTHOR]

RNA-sequencing, a powerful tool, yields a comprehensive view of whole transcriptome. Intracerebral hemorrhage (ICH) is a devastating form of stroke. To date, RNA-sequencing analysis of ICH has not been reported. Peripheral blood mononuclear cells (PBMCs) were used as a source of mRNA for gene expression profile analysis in stroke. In this study, we performed transcriptome analyses for PBMCs from four ICH patients and four healthy volunteers on Illumina platform. We identified 4040 significantly differentially expressed genes (DEGs). Functional annotation of DEGs with DAVID Bioinformatics Resources indicated that genes associated with cell apoptosis, autophagy, cell-cell adhesion, inflammatory response, protein binding, positive regulation of gene expression, and signal transduction were most significantly enriched by DEGs. Gene set enrichment analysis identified 40 significant Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, including chemokine signaling, cytokine-cytokine receptor interaction, oxidative phosphorylation, and glutathione metabolism processes. These data point to a complex mechanism for ICH pathogenesis. Overall, the present study demonstrated an altered gene expression profile of PBMCs in response to acute ICH. Our study provided important information for understanding the molecular mechanisms of ICH pathogenesis at system-wide levels. [ABSTRACT FROM AUTHOR]

In this work, the binding interactions between two new complexes, [Ru(bpy) 2 (6-OH-dppz)]2+ (Ru 1) and [Ru(bpy) 2 (6-F-dppz)]2+ (Ru 2), and the RNA triplex poly(rU)·poly(rA)×poly(rU) has been investigated. The binding modes of Ru 1 and Ru 2 to the triplex are intercalation, while the binding affinity for Ru 2 is greater than that for Ru 1. Unlike Ru 1 , Ru 2 can act as a "molecular light switch" for the triplex. Interestingly, Ru 1 and Ru 2 stabilize the third-strand of the triplex without significant differences, while they exhibit different selective stabilizing effects toward the triplex. In contrast to Ru 1 , Ru 2 shows a preference for stabilizing the template duplex under the conditions used in this study. The results demonstrate that the electronic effects of substituents on the main ligands can significantly affect the binding and stabilizing effects of Ru(II) polypyridyl complexes toward the RNA triplex poly(rU)·poly(rA)×poly(rU). [Display omitted] Two new ruthenium(II) polypyridyl complexes, [Ru(bpy) 2 (6-OH-dppz)]2+ (Ru 1 , bpy = 2,2′-bipyridine, 6-OH-dppz = 6-hydroxydipyrido[3,2- a :2′,3′- c ]phenazine) and [Ru(bpy) 2 (6-F-dppz)]2+ (Ru 2 , 6-F-dppz = 6-fluorodipyrido[3,2- a :2′,3′- c ]-phenazine), have been synthesized and characterized in this work. The interactions of Ru 1 and Ru 2 with the RNA triplex poly(rU)·poly(rA) × poly(rU) have been investigated by spectroscopic and viscometric techniques. Spectral titrations and viscosity experiments show that the binding modes of Ru 1 and Ru 2 to the triplex are intercalation, with the binding affinity for Ru 2 being greater than that for Ru 1. Fluorescence titrations indicate that Ru 2 , unlike Ru 1 , can act as a "molecular light switch" for the triplex. Furthermore, thermal denaturation experiments suggest that Ru 1 and Ru 2 stabilize the Hoogsteen base-paired strand (third-strand) of the triplex without significant differences, while the two complexes exhibit different selective stabilizing effects toward the triplex. In contrast to Ru 1 , Ru 2 shows a preference for stabilizing the template duplex under the conditions used in this study. Results of the present work demonstrate that the electronic effects of substituents on the main ligands can significantly affect the binding and stabilization effects of Ru(II) polypyridyl complexes toward the RNA triplex poly(rU)·poly(rA) × poly(rU). [ABSTRACT FROM AUTHOR]

Two chiral Ru(II) polypyridyl complexes, Δ-[Ru(bpy) 2 (6-F-dppz)]2+ (Δ- 1 ; bpy = 2,2′-bipyridine, 6-F-dppz = 6-fluorodipyrido[3,2- a :2′,3′- c phenazine) and Λ-[Ru(bpy) 2 (6-F-dppz)]2+ (Λ- 1), have been synthesized and characterized as binders for the RNA poly(U)•poly(A)*poly(U) triplex and poly(A)•poly(U) duplex in this work. Analysis of the UV–Vis absorption spectra and fluorescence emission spectra indicates that the binding of intercalating Δ- 1 with the triplex and duplex RNA is greater than that of Λ- 1 , while the binding affinities of the two enantiomers to triplex structure is stronger than that of duplex structure. Fluorescence titrations show that the two enantiomers can act as molecular "light switches" for triple- and double-helical RNA. Thermal denaturation studies revealed that that the two enantiomers are more stable to Watson-Crick base-paired double strand of the triplex than the Hoogsteen base-paired third strand, but their stability and selectivity are different. For Δ-enantiomer, the increase of the thermal stability of the Watson-Crick base-paired duplex (13 °C) is slightly stronger than of the Hoogsteen base-paired strand (10 °C), displaying no obvious selectivity. However, compared to the Hoogsteen base-paired strand (5 °C), the stability of the Λ-enantiomer to the Watson-Crick base-paired duplex (13 °C) is more significant, which has obvious selectivity. The overall increase in viscosity of the RNA-(Λ - 1) system and its curve shape are similar to that of the RNA-(Δ- 1) system, suggesting that the binding modes of two enantiomers with RNA are intercalation. The obtained results in this work may be useful for understanding the binding differences in chiral Ru(II) polypyridyl complexes toward RNA triplex and duplex. Enantiomers Δ/Λ-[Ru(bpy) 2 (6-F-dppz)]2+ were synthesized as binders for RNA poly(U)•poly(A)⁎poly(U) and poly(A)•poly(U) in this work. Results indicate that Λ-enantiomer prefered to stabilize the template duplex, while Δ-enantiomer stabilizes third-strand and the template duplex without preference, suggesting [Ru(bpy) 2 (6-F-dppz)]2+ is similar as a non-specific metallointercalator for the two forms of RNA. Unlabelled Image • Bpy = 2,2′-bipyridine and 6-F-dppz = 6-fluorodipyrido[3,2- a :2′,3′- c phenazine. • Λ/Δ-[Ru(bpy) 2 (6-F-dppz)]2+ (Λ/Δ- 1) were prepared as binders for two forms of RNA. • Λ- 1 prefered to stabilize the template duplex. • Δ- 1 stabilizes the third strand and the template duplex without preference. • Complex [Ru(bpy) 2 (6-F-dppz)]2+ is a non-specific metallointercalator in this study. [ABSTRACT FROM AUTHOR]

Background and Purpose: Thrombosis is a major cause of morbidity and mortality worldwide. Platelet activation by exposed collagen through glycoprotein VI (GPVI) and formation of neutrophil extracellular traps (NETs) are critical pathogenic factors for arterial and venous thrombosis. Both events are regulated by spleen tyrosine kinase (Syk)‐mediated signalling events. Asebogenin is a dihydrochalcone whose pharmacological effects remain largely unknown. This study aims to investigate the antithrombotic effects of asebogenin and the underlying molecular mechanisms. Experimental Approach: Platelet aggregation was assessed using an aggregometer. Platelet P‐selectin exposure, integrin activation and calcium mobilization were determined by flow cytometry. NETs formation was assessed by SYTOX Green staining and immunohistochemistry. Quantitative phosphoproteomics, microscale thermophoresis, in vitro kinase assay and molecular docking combined with dynamics simulation were performed to characterize the targets of asebogenin. The in vivo effects of asebogenin on arterial thrombosis were investigated using FeCl3‐induced and laser‐induced injury models, whereas those of venous thrombosis were induced by stenosis of the inferior vena cava. Key Results: Asebogenin inhibited a series of GPVI‐induced platelet responses and suppressed NETs formation induced by proinflammatory stimuli. Mechanistically, asebogenin directly interfered with the phosphorylation of Syk at Tyr525/526, which is important for its activation. Further, asebogenin suppressed arterial thrombosis demonstrated by decreased platelet accumulation and fibrin generation and attenuated venous thrombosis determined by reduced neutrophil accumulation and NETs formation, without increasing bleeding risk. Conclusion and Implications: Asebogenin exhibits potent antithrombotic effects by targeting Syk and is a potential lead compound for the development of efficient and safe antithrombotic agents. [ABSTRACT FROM AUTHOR]

Background and Purpose: Considerable evidence indicates that the beta(2)-adrenoceptor agonist clenbuterol decreases apoptosis in a rodent model of ischaemic cardiomyopathy. In this study, we investigated the effects of clenbuterol on infarct size caused by myocardial ischaemia/reperfusion (I/R) in anaesthetized rats.Experimental Approach: Rats were randomly assigned to the following groups: (i) sham (ii) I/R (iii) clenbuterol + I/R (iv) ICI 118551 + clenbuterol + I/R (v) metoprolol + clenbuterol + I/R (vi) metoprolol + I/R (vii) pertussis toxin + clenbuterol + I/R. Under anaesthesia, left anterior descending coronary artery was occluded for 30 min followed by reperfusion for 2 h.Key Results: Compared with the control I/R group,the clenbuterol (0.5 mg.kg(-1), i.p.) group had reduced infarct size, improved diastolic function and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA) activity, increased superoxide dismutase activity, and decreased malondialdehyde (MDA) level and LDH, CK release. Clenbuterol increased the phosphorylation of ERK1/2, which resulted in inhibition of myocardial apoptosis as indicated by the reduction of terminal deoxynucleotidyltransferase end labelling-positive staining, Bax/Bcl-2 mRNA and caspase-3 protein expression. The G(i)-protein inhibitor pertussis toxin blocked the clenbuterol-induced improvement in cardiac function and infarct size. Pretreatment with ICI 118551(a selective beta(2)-adrenoceptor antagonist) inhibited the effects of clenbuterol mentioned above. The beta(1)-adrenoceptor agonist metoprolol had similar effects to clenbuterol but failed to reduce MDA and improve SERCA activity. When administered together, metoprolol and clenbuterol did not induce synergistic effects.Conclusions and Implications: Clenbuterol pretreatment provides significant cardioprotection against ischaemia/reperfusion injury and this is mediated by the beta(2)-adrenoceptor-G(i)-protein signalling. A combination of the beta(2)-adrenoceptor agonist clenbuterol and the beta(1)-antagonist metoprolol did not lead to a synergistic anti-apoptotic effect. [ABSTRACT FROM AUTHOR]

Cervical cancer is the second most common cancer in women. Despite advances in cervical cancer therapy, tumor recurrence and metastasis remain the leading causes of mortality. High expression of BMI1 is significantly associated with poor tumor differentiation, high clinical grade, and poor prognosis of cervical cancer, and is an independent prognostic factor in cervical carcinoma. Alantolactone (AL), a sesquiterpene lactone, exhibits potent anti-inflammatory and anticancer activities. In this paper, we investigated the mechanism of AL in reducing the proliferation, migration, and invasion of HeLa and SiHa cervical cancer cells as well as its promotion of mitochondrial damage and autophagy. BMI1 silencing decreased epithelial-mesenchymal transformation-associated proteins and increased autophagy-associated proteins in HeLa cells. These effects were reversed by overexpression of BMI1 in HeLa cells. Thus, BMI1 expression is positively correlated with invasion and negatively correlated with autophagy in HeLa cells. Importantly, AL decreased the weight, volume, and BMI1 expression in HeLa xenograft tumors. Furthermore, the structure of BMI1 and target interaction of AL were virtually screened using the molecular docking program Autodock Vina; AL decreased the expression of N-cadherin, vimentin, and P62 and increased the expression of LC3B and Beclin-1 in xenograft tumors. Finally, expression of BMI1 increased the phosphorylation of STAT3, which is important for cell proliferation, survival, migration, and invasion. Therefore, we suggest that AL plays a pivotal role in inhibiting BMI1 in the tumorigenesis of cervical cancer and is a potential therapeutic agent for cervical cancer. [ABSTRACT FROM AUTHOR]

Aberrant signal transducer and activator of transcription 3 (STAT3) signaling promotes the initiation and progression of cancer in humans by either inhibiting apoptosis or inducing cell proliferation, angiogenesis, invasion, and metastasis. The role of resveratrol（RES）in inhibiting the STAT3 signaling pathway in vivo, particularly in cervical cancer is still unknown. This study aims to investigate the role of STAT3 and its phosphorylation in RES‐mediated suppression of cervical cancer. The effects of RES on cervical cancer were determined by examining tumor tissues, their histological changes, and the volume and weight of tumor tissues grown from HeLa cells injected in female athymic BALB/C nude mice. The structure and target interaction of RES were virtually screened using the molecular docking program Autodock Vina. The status of phosphorylated STAT3, protein levels of epithelial‐mesenchymal transition molecular markers and extracellular matrix degradation enzymes were determined through Western blot. We demonstrated that RES could suppress the proliferation and metastatic potential of cervical cancer cells by inactivating phosphorylation of STAT3 at Tyr705 but not Ser727. This effect was intensified by inhibition of the STAT3 signal pathway. [ABSTRACT FROM AUTHOR]

Objectives: Chemoresistance induced by cisplatin has become the major impediment to lung cancer chemotherapy. This study explored the potential chemoresistant genes and underlying mechanisms of chemoresistance in NSCLC. Materials and methods: Gene expression profile was integrated with DNA methylation profile to screen the candidate chemoresistant genes. Bioinformatic analysis and immunohistochemistry were used to analyse the association of a candidate gene with the characteristics of NSCLC patients. Recombinant lentivirus vectors were utilized to overexpress or silence candidate gene. Microarrays and immunoblotting were applied to explore the downstream targets of candidate gene. Xenograft models were established to validate the findings in vitro. Results: An increased ZNF300 expression was detected in three chemoresistant cell lines of NSCLC, and the higher expression of ZNF300 was associated with poor OS of NSCLC patients. Cells with upregulated ZNF300 presented chemoresistance and enhanced aggressive growth compared to cells with downregulated ZNF300. ZNF300 inhibited MAPK/ERK pathways and activated CDK1 through inhibiting WEE1 and MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. ICA and ATRA improved the anti‐tumour effect of cisplatin on chemoresistant cells by inducing differentiation. Conclusions: ZNF300 promotes chemoresistance and aggressive behaviour of NSCLC through regulation of proliferation and differentiation by downregulating MAPK/ERK pathways and regulation of slow‐cycling phenotype via activating CDK1 by inhibiting WEE1/MYT1 and modulating MYC/AURKA/BORA/PLK1 axis. Cisplatin, combined with ATRA and ICA, might be beneficial in chemoresistant cases of NSCLC. [ABSTRACT FROM AUTHOR]

• Comprehensive expression analysis of seven GA2-oxidase genes using translational reporter lines reveals their distinct expression patterns during Arabidopsis growth and development. • Overexpression of these genes inhibits high temperature-induced hypocotyl elongation. Bioactive gibberellins (GAs) play multiple roles in plant development and stress responses. GA2-oxidases (GA2oxs) are a class of 2-oxoglutarate-dependent dioxygenases that regulate the deactivation of bioactive GAs. In this study, we investigated the phylogeny and domain structures of the seven GA2ox genes present in the Arabidopsis thaliana genome. Comprehensive expression analysis using translational reporter lines showed that the seven GA2ox genes are differentially expressed during Arabidopsis growth and development: GA2ox1 is specifically expressed in the hypocotyl and lateral root primordium; GA2ox2 is highly expressed in aboveground tissues; GA2ox3 is expressed in the chalazal endosperm of the early embryo sac and inflorescences; GA2ox4 is expressed in the shoot apical meristem and during lateral root initiation; GA2ox6 is expressed in the maturation zone, but not in the meristem or elongating zone of the root; GA2ox7 is constitutively expressed during almost all developmental stages; and GA2ox8 is exclusively expressed in stomatal cells. Overexpression of each of these GA2ox genes inhibited high temperature-induced hypocotyl elongation in both wild-type and elongated hypocotyl 5 plants, which have an elongated hypocotyl phenotype, suggesting that these genes negatively regulate hypocotyl elongation by reducing bioactive GA levels. This study provides a valuable resource for further elucidating the roles of GA2ox genes during different stages of development. [ABSTRACT FROM AUTHOR]

The study determined the chemical constituents and anti-inflammatory effects of leaf oil from Cinnamomum subavenium (CS-LO) that has been used in folk medicine to treat various symptoms including inflammation. The anti-inflammatory effects of the oil were evaluated by LPS-stimulated RAW264.7 cells and the Carr-induced hind mouse paw edema model, respectively. In vitro, nitric oxide (NO), prostaglandin E2 (PGE2), TNF-α, IL-6, and IL-1β were significantly decreased by CS-LO, and the expression of nuclear factor-κB (NF-κB) protein was blocked as well. In in vivo, the malondialdehyde (MDA) and paw edema levels were decreased by CS-LO, and the same result came up on the NO and tumor necrosis factor (TNF-a) of serum at the 5th h after Carr injection. In addition, iNOS and COX-2 immunoreactive cells of the paw tissue were decreased significantly by CS-LO (200 mg/kg) in histological examination. The present findings indicated that CS-LO have anti-inflammatory properties, and the effects might be caused through inhibiting iNOS, COX-2, TNF-α, IL-1β, and IL-6 expression via affecting NF-κB pathway, which will provide a power scientific basis for CS-LO to be used as the treatment of inflammatory diseases. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the major incidence and one of the most life-threatening cancer. How to conquer HCC is a worldwide issue for patients. Zhiheshouwu ( Polygoni multiflori Radix Praeparata) is a Chinese medicinal herb exhibiting both lowering lipid and inhibiting cancer cells. However, it remains a matter if its inhibiting cancer cells is related to its lowering lipid. In this study, we investigate the effects of Zhiheshouwu ethanolic extract (HSWE) on apoptosis and the underlying mechanisms in Bel-7402 cells. The results showed that HSWE inhibited the proliferation with an increased level of ALT and AST in Bel-7402 cells. The decreased mitochondrial membrane potential (ΔΨm) was observed in HSWE-treated Bel-7402 cells. The flow cytometry results showed that HSWE triggered apoptosis. Since mitochondrial injury is characterized as intrinsic apoptotic cell death, these data indicated that HSWE may induce intrinsic apoptosis in Bel-7402 cells. In addition, HSWE decreased the production of unsaturated fatty acids, and inhibited the mRNA and protein of SCD1 and its up-stream factor, sterol-regulatory element binding proteins 1 (SREBP1), a master transcriptional regulator of lipogenic gene. Taken together, these data suggest that HSWE induces an intrinsic apoptosis, and reduced unsaturated fatty acids by blocking SREBP1 in hepatocellular carcinoma cells. [ABSTRACT FROM AUTHOR]

Skeletal muscle serving as the major organ is responsible for energy expenditure and exercise endurance, which directly influence cardiometabolic risk factors. Transient receptor potential melastatin 8 (TRPM8), a Ca 2 + -permeable non-selective cation channel, plays vital roles in the regulation of various cellular functions. It has been reported that TRPM8 activation enhanced the energy metabolism of adipocytes. However, the involvement of TRPM8 in the energy metabolism of skeletal muscle remains unexplored. Our data revealed that TRPM8 was expressed in cultured C2C12 myocytes. Menthol treatment increased uncoupling protein 1 (UCP1) and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) expression in C2C12 myotubes through TRPM8 activation. Moreover, dietary menthol upregulated the expression of UCP1 and PGC1α in skeletal muscle of mice. In addition, dietary menthol enhanced exercise endurance and reduced blood lactic acid and triglycerides through TRPM8 activation. It is concluded that dietary menthol improves energy metabolism and exercise endurance by increasing UCP1 and PGC1α in skeletal muscles, suggesting dietary menthol might be a novel therapeutic approach for cardiometabolic diseases management and prevention. [ABSTRACT FROM AUTHOR]

Purpose The present study was to evaluate the prognostic value of protein expression of Pofut1 and Notch1 signaling in breast cancer. Material and methods Formalin-fixed paraffin-embedded 314 breast specimens including 174 infiltrating ductal carcinoma(IDC), 50 ductal carcinoma in situ(DCIS) and 90 adjacent normal tissue(ANT) were immunohistochemically examined to evaluate the protein expression of Pofut1, activated Notch1(N1IC) and Slug on specimens. Survival analysis was performed by Kaplan-Meier method and Cox's proportional-hazards model. A online database was computationally used to further explore the prognostic role of Pofut1 and Notch1 mRNA expression by Kaplan-Meier Plotter. Results Pofut1, Slug and N1IC expression were significantly increased in IDC compared to ANT(all p < 0.05). High expression of Pofut1, Slug and N1IC were associated with tumor aggressiveness including lymph node metastasis (LNM: p = 0.005 for Pofut1, p < 0.001 for N1IC, p = 0.017 for Slug), advanced stage( p = 0.039 for Pofut1, p = 0.025 for N1IC) and higher histological grade( p = 0.001 for N1IC). Additionally, high expression of Pofut1 was found to be significantly associated with high expressions of N1IC and Slug in IDC(r = 0.244, p = 0.001; r = 0.374, p < 0.001, respectively), similar correlation was also observed between high N1IC and Slug expression(r = 0.496, p < 0.001). Moreover, Kaplan-Meier and Cox's regression analysis indicated the significant prognostic value of elevated Pofut1, N1IC, Slug expressions, positive LNM and advanced tumor stage for the prediction of a shorter disease-free survival (DFS) and overall survival(OS). The web-based analysis also suggested a significant association of high Pofut1 and Notch1 mRNA expression with worse survival outcome. Conclusion Our findings suggested that overexpression of Pofut1 and activated Notch1 signaling may be associated with a poor prognosis in breast cancer. [ABSTRACT FROM AUTHOR]

Polygoni Multiflori Radix Praeparata (Zhiheshouwu) has been a Wudang Taoist medicine for tonifying the liver and kidney, resolving turbidity and reducing lipid. Emodin is one of the active anthraquinones in Zhiheshouwu. Our previous studies showed that emodin (EM) and the other anthraquinones in Zhiheshouwu extract (HSWE) exerted similar inhibitory effects on liver cancer cells in vitro. However, it is still unknown if the other anthraquinones enhance pharmacokinetics (PK) of EM in HSWE in vivo. In this study, we compared the PK characteristics of EM alone with that in Zhiheshouwu aiming to explore which anthraquinones in HSWE contribute to the changed PK of EM in rats. Quality control of HSWE was determined using high performance liquid chromatography (HPLC). The ratios of emodin to other anthraquinones, physcion (PH), chrysophanol (CH), rhein (RH), aloe-emodin (AE), emodin-8-O- β -D-glycoside (EMG), physcion-1-O- β -D-glycoside (PHG) and chrysophanol-8-O- β -D-glycoside (CHG) in HSWE were determined and analyzed using UPLC combined with tandem mass spectrometry (UPLC/MS). The PK parameters and intestinal tissue concentration of EM alone, EM in HSWE, or with other anthraquinones in SD rats were analyzed using UPLC/MS. The quality of the Zhiheshouwu samples met the quality standard of the Chinese Pharmacopoeia (Version 2020). The PK results showed that compared with EM alone, C max (239.90 ± 146.71 vs. 898.46 ± 291.62, P < 0.001), T max (0.26 ± 0.15 vs. 12.55 ± 1.33, P < 0.001), AUC 0-t (1575.09 ± 570.46 vs. 12154.96 ± 5394.25, P < 0.001), and AUC 0-∞ (4742.51 ± 1837.62 vs. 37131.34 ± 21647.39, P < 0.001) of EM in HSWE were decreased due to PH and EMG, while the values of V d (380.75 ± 217.74 vs. 11.75 ± 7.35, P < 0.001), T 1/2 (10.81 ± 1.99 vs. 6.65 ± 2.76, P < 0.05) and CL (19.30 ± 7.82 vs. 2.78 ± 1.88, P < 0.001) of EM in HSWE were increased due to PH and AE. In addition, the intestinal tissue concentration of emodin in HSWE was decreased compared with that of EM alone in 20 and 780 min (25.37 ± 5.98 vs. 43.29 ± 4.16 and 26.72 ± 4.03 vs. 43.40 ± 14.19, respectively. P < 0.05) dominantly due to RH and PH. In conclusion, compared with treatment of EM alone, the AUC 0-t value of EM in HSWE was decreased with different ways in rats. PH shortened T max , and increased V d and CL. While AE prolonged T 1/2 of EM. This indicated that the other anthraquinones in HSWE changed the PK of EM in rats and participated in the complex effects of EM on liver cancer. Besides the other anthraquinones, other components (e.g., 2,3,5,4′-tetrahydroxystilbene-2-O- β -D-glucoside) in Zhiheshouwu may contribute in the pharmacokinetic and pharmacodynamic interactions with EM for anti-liver cancer. [Display omitted] • Emodin is one of the active anthraquinones in Wudang Taoist herb Zhiheshouwu. • Other anthraquinones decrease AUC 0–t value of emodin by different ways in rats. • Physcion decrease C max and T max , and increases V d and CL of emodin. • Aloe-emodin prolongs T 1/2 of emodin. [ABSTRACT FROM AUTHOR]

ELONGATED HYPOCOTYL 5 (HY5), a member of the bZIP gene family, is a positive regulator of the light signaling pathway in Arabidopsis thaliana. Whereas the hy5 mutant exhibits an elongated hypocotyl when grown in the light, the hy5 homolog (hyh) mutant does not. Although the functions of HY5 and HYH in light-mediated seedling development have been revealed, the tissue-specific expression patterns of HY5 and HYH and their interconnected regulation are largely unknown. Here, we report that HY5 regulates HYH expression in roots and contributes to root growth under different light conditions. We generated HY5 and HYH transcriptional and translational fusion reporter lines to investigate their expression patterns. HY5 was constitutively expressed in all root tissues, while HYH was predominantly expressed in root xylem cells. Root growth after a dark-to-light transition was perturbed in the hy5 and hy5hyh mutant lines, but not in the hyh mutant line, indicating that HY5 plays a major role in light-regulated root growth. Light-induced HY5/HYH expression occurred autonomously in roots. HYH expression in roots was decreased in the hy5 mutant, suggesting that HY5 regulates HYH expression. Collectively, these results indicate that an organ-specific HY5-mediated pathway controls root photomorphogenic development independently of light signaling in the shoot. [ABSTRACT FROM AUTHOR]

Arabidopsis thaliana LONG HYPOCOTYL5 (HY5) is a positive regulator of the light signaling pathway. The hy5 mutant has an elongated hypocotyl in all light conditions, whereas the hy5 homolog ( hyh ) mutant has a very weak phenotype, but only in blue light. However, overexpression of HYH rescues the elongated hypocotyl phenotype in the hy5 null mutant. Here, we report the identification of four HYH splicing variants in Arabidopsis . Alternative splicing in the 5′ region of the HYH gene occurred such that the proteins encoded by all four HYH variants retained their bZIP domain. In hypocotyl tissue, transcript levels of HYH.2 , HYH.3 , and HYH.4 were higher than those of HYH.1 . Like HY5 , all HYH variants were induced by light. Functional analysis of the four HYH variants, based on their abilities to complement the hy5 mutant, indicated that they have similar roles in hypocotyl development, and may function redundantly with HY5 . Our results indicate that the bZIP domain in HYH is critical for the function of four variants in the compensation of hy5 mutant in hypocotyl development. Additionally, while HY5/HYH is found in plant species ranging from green algae to flowering plants, the potential alternative splicing events are distinct in different species, with certain HYH variants found with greater frequency in some species than others. [ABSTRACT FROM AUTHOR]

[Display omitted] • Global transcriptome analysis revealed key metabolites biosynthetic related genes. • Organ-specific transcription factors may mediate root metabolic processes. • Novel simple sequence repeats were identified. • Root accumulating resveratrol and emodin are correlated to the local activities of their biosynthetic genes. Polygonum cuspidatum is an important medicinal plant, which produces bioactive stilbenes and quinones, has been developed to be an important economic crop and cultivated in the Qinba mountain area, central China for years. Little is understood about its genetic characterization, which has impeded functional genomic studies of P. cuspidatum. In order to tackle genetic insights into the metabolic pathways of natural products, a comprehensive transcriptome analysis was conducted using Illumina sequencing amongst five major organs, namely roots, stems, leaves, flowers, and fruits in P. cuspidatum. As a result, 219,411 non-redundant transcripts and 159,545 functionally annotated unigenes were identified with mean lengths of 662 and 813 nucleotides, respectively. Organ-specific gene analysis unveiled that flowers presents the most abundance of unique transcripts (7,366), whereas the least does in roots (1,052). The gene expression profiles related to the metabolism of resveratrol and anthraquinone were investigated, and the contents of bioactive compounds in the different organs were determined, revealing that resveratrol and emodin were preferentially accumulated in the roots. In addition, our transcription factor analysis suggested that some bHLH- and MYB-TF family genes showed organ-enriched expression patterns and may mediate the metabolic processes. A total number of 25,404 simple sequence repeats were identified, which will benefit germplasm identification and discrimination of P. cuspidatum varieties. This study presents the assembly of a de novo transcriptome that will promote the investigation of the biosynthetic genes of natural products in P. cuspidatum , and enrich the genetic knowledge of this medical plant. [ABSTRACT FROM AUTHOR]

[Display omitted] • 11 type-A withanolides including 4 new ones, were isolated from the dietary tomatillo. • Physalin F was found to be a new inhibitor of mutant IDH1. • Its inhibitory activity was confirmed by mutant IDH1 and cell-based experiments. • Tomatillo could be used as potential antitumor functional food or drug. Isocitrate dehydrogenase (IDH) is one key rate-limiting enzyme in the tricarboxylic acid cycle, which is related to various cancers. Tomatillo (Physalis ixocarpa), a special tomato, is widely consumed as nutritious vegetable in Mexico, USA, etc. As a rich source for withanolides, the fruits of P. ixocarpa were investigated, leading to the isolation of 11 type-A withanolides including 4 new ones (1 is an artificial withanolide). All these withanolides were evaluated for their inhibition on mutant IDH1 enzyme activity. Among them, physalin F (11) exhibited potent enzyme inhibitory activity and binding affinity with mutant IDH1. It inhibits the proliferation of HT1080 cells by selectively inhibiting the activity of mutant IDH1. Since Ixocarpalactone A, another major type-B withanolide in this plant, could act on another energy metabolism target PHGDH, the presence of different types of withanolides in tomatillo and their synergistic effect could make it a potential antitumor functional food or drug. [ABSTRACT FROM AUTHOR]

• The correlation between bioactive compounds and rhizosphere microbiome in P. cuspidatum. • The Stenotrophomonas was specifically enriched in the root endosphere. • Bcteroides , and Erysipelatoclostridium might promote resveratrol synthesis. Polygonum cuspidatum (Polygonum cuspidatum Sieb. & Zucc.), a medicinal plant that is abundantly accumulating bioactive compounds in its roots, is the primary source of resveratrol in industry and has long been recognized as raw materials for traditional Chinese medicine. Plant root secondary metabolism is correlated to its surrounding microbial communities. However, the root-associated microbiomes of P. cuspidatum and the potential correlation between the bioactive compounds and microbiomes are poorly understood. To unveil the root-associated bacterial community, the microbiome compositions of P. cuspidatum roots across four cultivation years were analyzed by using 16S rRNA gene sequencing. Furthermore, the relationships among root-associated bacteria, soil properties, and four major bioactive compounds (polydatin, resveratrol, emodin, and physcion) were explored by a multivariate correlation study. The composition of the rhizosphere microbiome significantly differed from that of the endosphere microbiome. The composition of the rhizosphere microbiome significantly varied across different cultivation years and soil properties, contributing to the majority of variance. Regarding different cultivation years and soil properties, the compositions of the root endosphere microbiome remained relatively stable, indicating a strong selection effect in P. cuspidatum roots. Among root endosphere microbes, Stenotrophomonas was specifically enriched from rhizosphere with a 15 times increase of relative abundance, exhibiting no significant variation across different cultivation years. The relative abundance of rhizosphere Stenotrophomonas was positively correlated with the content of emodin. Taken together, this study demonstrated that the stability of the root endosphere microbiome with a dominance of Stenotrophomonas may maintain the growth of P. cuspidatum through the combined effect of emodin. The contents of bioactive compounds in roots exhibited distinct correlations with specific bacteria, suggesting that Bacteroides , Acinetobacter , Erysipelatoclostridium , and Achromobacter may enhance the accumulation of resveratrol. This study provides insights into the interaction networks among P. cuspidatum root-associated bacteria, cultivation years, soil properties, and bioactive compounds, giving us a new opportunity to manipulate the production of bioactive compounds, and thus improve the industrial and medicinal value of P. cuspidatum in future. [ABSTRACT FROM AUTHOR]

Currently, decision-making regarding biochemical recurrence (BCR) following prostatectomy relies solely on clinical parameters. We therefore attempted to develop an integrated prediction model based on a molecular signature and clinicopathological features, in order to forecast the risk for BCR and guide clinical decision-making for postoperative therapy. Using high-throughput screening and least absolute shrinkage and selection operator (LASSO) in the training set, a novel gene signature for biochemical recurrence-free survival (BCRFS) was established. Validation of the prognostic value was performed in five other independent datasets, including our patient cohort. Multivariate Cox regression analysis was performed to evaluate the importance of risk for BCR. Time-dependent receiver operating characteristic (tROC) was used to evaluate the predictive power. In combination with relevant clinicopathological features, a decision tree was built to improve the risk stratification. The gene signature exhibited a strong capacity for identifying high-risk BCR patients, and multivariate Cox regression analysis demonstrated that the gene signature consistently acted as a risk factor for BCR. The decision tree was successfully able to identify the high-risk subgroup. Overall, the gene signature established in the present study is a powerful predictor and risk factor for BCR after radical prostatectomy. [ABSTRACT FROM AUTHOR]