The role of adjuvant transcatheter arterial chemoembolization following repeated curative resection/ablation for hepatocellular carcinoma with early recurrence: a propensity score matching analysis.

BACKGROUND: The role of adjuvant transcatheter arterial chemoembolization (TACE) following repeated resection/ablation for recurrent hepatocellular carcinoma (HCC) remains uncertain. The aim of this study was to assess the effectiveness of adjuvant TACE following repeated resection or ablation in patients with early recurrent HCC. METHODS: Information for patients who underwent repeated surgery or radiofrequency ablation (RFA) for early recurrent HCCs (< 2 years) at our institution from January 2017 to December 2020 were collected. Patients were divided into adjuvant TACE and observation groups according to whether they received adjuvant TACE or not. The recurrence-free survival (RFS) and overall survival (OS) were compared between the two groups before and after propensity score matching (PSM). RESULTS: Of the 225 patients enrolled, the median time of HCC recurrence was 11 months (IQR, 6-16 months). After repeated surgery or radiofrequency ablation (RFA) for recurrent tumors, 45 patients (20%) received adjuvant TACE while the remaining 180 (80%) didn't. There were no significant differences in RFS (P = 0.325) and OS (P = 0.072) between adjuvant TACE and observation groups before PSM. There were also no significant differences in RFS (P = 0.897) and OS (P = 0.090) between the two groups after PSM. Multivariable analysis suggested that multiple tumors, liver cirrhosis, and RFA were independent risk factors for the re-recurrence of HCC. CONCLUSION: Adjuvant TACE after repeated resection or ablation for early recurrent HCCs was not associated with a long-term survival benefit in this single-center cohort.

Tin Active Sites Confined in Zeolite Framework as a Promising Shape-Selective Catalyst for Ethylene Oxide Hydration.

Shape-selective stannosilicates have been post-synthesized for the hydration of epoxide to diols. A simple acid treatment has been employed to remove extensively the interlayer double four ring units, converting the three-dimensional (3D) UTL germanosilicate into a 2D layered IPC-1P intermediate. Isomorphous incorporation of tetrahedrally coordinated Sn active centers was realized via solid-liquid treatment of IPC-1P with diammonium hexachlorostannate aqueous solution, which was accompanied by the spontaneous condensation of neighboring silica-rich cfi layers upon calcination and structural construction of a 3D PCR structure. Sn-PCR stannosilicates with tunable Sn contents were thus prepared. With Sn-derived robust Lewis acidity confined in the intersecting 10- and 8-ring channels, the Sn-PCR (Si/Sn molar ratio of 77) catalyst served as a shape-selective nanoreactor for the hydration of ethylene oxide (EO) into ethylene glycol (EG), exhibiting a remarkable EO conversion (99.5 %) as well as a steady EG selectivity (>98.4 %) at greatly reduced H2 O/EO molar ratio and near-ambient reaction temperature.

Bim contributes to the progression of Huntington's disease-associated phenotypes.

Huntington's disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.

Coumarin-monoterpenes from Gerbera anandria (Linn.) Sch.-Bip and their neuroprotective activity.

Thirty-two undescribed coumarin-monoterpenes, including the first report of six pairs of enantiomeric and twenty congeners, were isolated from the petroleum ether extract of the stems of Gerbera anandria (Linn.) Sch.-Bip. Structurally, these compounds represented C3-substituted 5-methyl-4-hydroxycoumarin-monoterpenes. Among them, 1-7 and 10-24 were rare 5-methylcoumarin-monoterpenes formed through a furan ring. Their chemical structures and absolute configurations were determined by comprehensive analysis of spectroscopic data, including HRESIMS, 1D and 2D NMR spectroscopic data, Mosher's method, ECD calculations and single crystal X-ray diffraction. Furthermore, biological studies revealed that compounds 1-3, 3a, 5, 5a, 11-12, 21-22 and 26 had the neuroprotective effects on scopolamine-induced injury in PC12 cells. Notably, 3 exhibited the strongest neuroprotective activity with the cell viability values of 77.24%. Meanwhile, pretreatment with 3 significantly downregulate apoptosis and reactive oxygen species (ROS) production, as well as strengthen antioxidant enzyme activities (MDA and SOD). Moreover, pretreatment with 3 also could attenuate the down-regulation of HO-1 and Nrf2 induced by scopolamine. In conclusion, these results demonstrated that these compounds possessed the protective effects on scopolamine-injured PC12 cells through anti-apoptotic and anti-oxidant activities.

Transcriptomes analysis reveals novel insight into the molecular mechanisms of somatic embryogenesis in Hevea brasiliensis.

BACKGROUND: Somatic embryogenesis (SE) is a promising technology for plant vegetative propagation, which has an important role in tree breeding. Though rubber tree (Hevea brasiliensis Muell. Arg.) SE has been founded, few late SE-related genes have been identified and the molecular regulation mechanisms of late SE are still not well understood. RESULTS: In this study, the transcriptomes of embryogenic callus (EC), primary embryo (PE), cotyledonary embryo (CE), abnormal embryo (AE), mature cotyledonary embryo (MCE) and withered abnormal embryo (WAE) were analyzed. A total of 887,852,416 clean reads were generated, 85.92% of them were mapped to the rubber tree genome. The de novo assembly generated 36,937 unigenes. The differentially expressed genes (DEGs) were identified in the pairwise comparisons of CE vs. AE and MCE vs. WAE, respectively. The specific common DEGs were mainly involved in the phytohormones signaling pathway, biosynthesis of phenylpropanoid and starch and sucrose metabolism. Among them, hormone signal transduction related genes were significantly enriched, especially the auxin signaling factors (AUX-like1, GH3.1, SAUR32-like, IAA9-like, IAA14-like, IAA27-like, IAA28-like and ARF5-like). The transcription factors including WRKY40, WRKY70, MYBS3-like, MYB1R1-like, AIL6 and bHLH93-like were characterized as molecular markers for rubber tree late SE. CML13, CML36, CAM-7, SERK1 and LEAD-29-like were also related to rubber tree late SE. In addition, histone modification had crucial roles during rubber tree late SE. CONCLUSIONS: This study provides important information to elucidate the molecular regulation during rubber tree late SE.

Tobacco rattle virus-induced gene silencing in Hevea brasiliensis.

Virus-induced gene silencing (VIGS) is a powerful gene-silencing tool that has been intensively applied in plants. To data, the application of VIGS in rubber tree has not yet been reported. In this study, we described the efficient gene silencing in rubber tree by VIGS. The gene encoding Hevea brasiliensis phytoene desaturase (HbPDS) was identified in rubber tree genome. Small interfering RNAs from HbPDS and the silencing gene fragment were predicted and a length of 399 bp was selected to be tested. We showed that the tobacco rattle virus (TRV)-VIGS could induce effective HbPDS silencing in rubber tree. This study was the first to report VIGS in rubber tree. The present TRV-VIGS method could be used to perform reverse genetic approaches to identify unknown gene functions and might be further applied to produce gene silenced rubber tree plants, to advance functional gene of rubber tree.

Veratramine modulates AP-1-dependent gene transcription by directly binding to programmable DNA.

Because the transcription factor activator protein-1 (AP-1) regulates a variety of protein-encoding genes, it is a participant in many cellular functions, including proliferation, transformation, epithelial mesenchymal transition (EMT), and apoptosis. Inhibitors targeting AP-1 have potential use in the treatment of cancer and other inflammatory diseases. Here, we identify veratramine as a potent natural modulator of AP-1, which selectively binds to a specific site (TRE 5'-TGACTCA-3') of the AP-1 target DNA sequence and regulates AP-1-dependent gene transcription without interfering with cystosolic signaling cascades that might lead to AP-1 activation. Moreover, RNA-seq experiments demonstrate that veratramine does not act on the Hedgehog signaling pathway in contrast to its analogue, cyclopamine, and likely does not harbor the same teratogenicity and toxicity. Additionally, veratramine effectively suppresses EGF-induced AP-1 transactivation and transformation of JB6 P+ cells. Finally, we demonstrate that veratramine inhibits solar-ultraviolet-induced AP-1 activation in mice. The identification of veratramine and new findings in its specific regulation of AP-1 down stream genes pave ways to discovering and designing regulators to regulate transcription factor.

Protection of Fecal Microbiota Transplantation in a Mouse Model of Multiple Sclerosis.

Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS.

Identification of histone methylation modifiers and their expression patterns during somatic embryogenesis in Hevea brasiliensis.

Histone methylation plays a crucial role in various biological processes, from heterochromatin formation to transcriptional regulation. Currently, no information is available regarding histone methylation modifiers in the important rubber-producing plant Hevea brasiliensis. Here, we identified 47 histone methyltransferase (HMT) genes and 25 histone demethylase (HDM) genes as possible members of the histone methylation modifiers in the rubber tree genome. According to the structural features of HMT and HDM, the HbHMTs were classified into two groups (HbPRMs and HbSDGs), the HbHDMs have two groups (HbLSDs and HbJMJs). Expression patterns were analyzed in five different tissues and at different phases of somatic embryogenesis. HbSDG10, 21, 25, 33, HbJMJ2, 18, 20 were with high expression at different phases of somatic embryogenesis. HbSDG10,14, 20, 21, 33 and HbPRMT4 were expressed highly in anther, HbSDG14, 20, 21, 22, 23, 33, 35 and HbPRMT1 HbJMJ7 and HbLSD1, 2, 3, 4 showed high expression levels in callus. HbSDG1, 7, 10, 13, 14, 18, 19, 21, 22, 23, 35, HbPRMT1, 8, HbJMJ5, 7, 11, 16, 20 and HbLSD2, 3, 4 were expressed highly in somatic embryo. HbSDG10, 21, 25, 33, HbLSD2, 3 were expressed highly in bud of regenerated plant. The analyses reveal that HbHMTs and HbHDMs exhibit different expression patterns at different phases during somatic embryogenesis, implying that some HbHMTs and HbHDMs play important roles during somatic embryogenesis. This study provide fundamental information for further studies on histone methylation in Hevea brasiliensis.

Characterization of a long noncoding RNA Pcdh17it as a novel marker for immature premyelinating oligodendrocytes.

Oligodendrocyte precursors (OPs) proliferate and differentiate into oligodendrocytes (OLs) during postnatal development and into adulthood in the central nervous system (CNS). Following the initiation of differentiation, OPs give rise to immature, premyelinating OLs, which undergo further differentiation and mature into myelin-forming OLs. We identified an immature OL-specific long noncoding RNA, named Pcdh17it. Through co-localization analysis and morphological characterization of OLs, we found that Pcdh17it is a specific marker for newly born immature OLs in the developing and adult forebrain of mice, and we used this new marker to analyze OL generation over the lifespan of mice. Pcdh17it is an effective tool for monitoring newly born OLs in adult brain, allowing detailed study of the dynamics of OP differentiation into OLs in the normal and pathological CNS.

Nitidine chloride exerts anti-inflammatory action by targeting Topoisomerase I and enhancing IL-10 production.

In the effort to identify natural products that regulate immunity and inflammation, we found that nitidine chloride (NC), an alkaloid from herb Zanthoxylum nitidum, enhanced IL-10 production in lipopolysaccharide (LPS)-stimulated myeloid cells. While NC was shown to be capable of inhibiting topoisomerase I (TOP1), NC analogs that could not inhibit TOP1 failed to increase IL-10 production. Moreover, medicinal TOP1 inhibitors TPT and SN-38 also augmented IL-10 production significantly, whereas knockdown of TOP1 prevented NC, TPT, and SN-38 from enhancing IL-10 expression. Thus, NC promoted IL-10 production by inhibiting TOP1. In LPS-induced endotoxemic mice, NC and TOP1 inhibitors increased IL-10 production, suppressed inflammatory responses, and reduced mortality remarkably. The anti-inflammatory activities of TOP1 inhibition were markedly reduced by IL-10-neutralizing antibody and largely absent in IL-10-deficient mice. In LPS-stimulated RAW264.7 cells and in peritoneal macrophages from endotoxemic mice, NC and TOP1 inhibitors significantly enhanced the activation of Akt, a critical signal transducer for IL-10 production, and inhibition of Akt prevented these compounds from enhancing IL-10 production and ameliorating endotoxemia. These data indicated that NC and TOP1 inhibitors are able to exert anti-inflammatory action through enhancing Akt-mediated IL-10 production and may assist with the treatment of inflammatory diseases.

G protein-coupled receptor 37-like 1 modulates astrocyte glutamate transporters and neuronal NMDA receptors and is neuroprotective in ischemia.

We show that the G protein-coupled receptor GPR37-like 1 (GPR37L1) is expressed in most astrocytes and some oligodendrocyte precursors in the mouse central nervous system. This contrasts with GPR37, which is mainly in mature oligodendrocytes. Comparison of wild type and Gpr37l1-/- mice showed that loss of GPR37L1 did not affect the input resistance or resting potential of astrocytes or neurons in the hippocampus. However, GPR37L1-mediated signalling inhibited astrocyte glutamate transporters and - surprisingly, given its lack of expression in neurons - reduced neuronal NMDA receptor (NMDAR) activity during prolonged activation of the receptors as occurs in ischemia. This effect on NMDAR signalling was not mediated by a change in the release of D-serine or TNF-α, two astrocyte-derived agents known to modulate NMDAR function. After middle cerebral artery occlusion, Gpr37l1 expression was increased around the lesion. Neuronal death was increased by ∼40% in Gpr37l1-/- brain compared to wild type in an in vitro model of ischemia. Thus, GPR37L1 protects neurons during ischemia, presumably by modulating extracellular glutamate concentration and NMDAR activation.

The 14-3-3 protein HbGF14a interacts with a RING zinc finger protein to regulate expression of the rubber transferase gene in Hevea brasiliensis.

Hevea brasiliensis is a key commercial source of natural rubber (cis 1,4-polyisoprene). In H. brasiliensis, rubber transferase is responsible for cis-1,4-polymerization of isoprene units from isopentenyl diphosphate and thus affects the yield of rubber. Little is known about the regulatory mechanisms of the rubber transferase gene at a molecular level. In this study we show that the 5'UTR intron of the promoter of the rubber transferase gene (HRT2) suppresses the expression of HRT2. A H. brasiliensis RING zinc finger protein (designated as HbRZFP1) was able to interact specifically with the HRT2 promoter to down-regulate its transcription in vivo. A 14-3-3 protein (named as HbGF14a) was identified as interacting with HbRZFP1, both in yeast and in planta. Transient co-expression of HbGF14a and HbRZFP1-encoding cDNAs resulted in HbRZFP1-mediated HRT2 transcription inhibition being relieved. HbGF14a repressed the protein-DNA binding of HbRZFP1 with the HRT2 promoter in yeast. We propose a regulatory mechanism by which the binding of HbGF14a to HbRZFP1 interferes with the interaction of HbRZFP1 with the HRT2 promoter, thereby repressing the protein-DNA binding between them. This study provides new insights into the role of HbGF14a in mediating expression of the rubber transferase gene in Hevea brasiliensis.

Jasmonate signalling in the regulation of rubber biosynthesis in laticifer cells of rubber tree, Hevea brasiliensis.

Rubber trees are the world's major source of natural rubber. Rubber-containing latex is obtained from the laticifer cells of the rubber tree (Hevea brasiliensis) via regular tapping. Rubber biosynthesis is a typical isoprenoid metabolic process in the laticifer cells; however, little is known about the positive feedback regulation caused by the loss of latex that occurs through tapping. In this study, we demonstrate the crucial role of jasmonate signalling in this feedback regulation. The endogenous levels of jasmonate, the expression levels of rubber biosynthesis-related genes, and the efficiency of in vitro rubber biosynthesis were found to be significantly higher in laticifer cells of regularly tapped trees than those of virgin (i.e. untapped) trees. Application of methyl jasmonate had similar effects to latex harvesting in up-regulating the rubber biosynthesis-related genes and enhancing rubber biosynthesis. The specific jasmonate signalling module in laticifer cells was identified as COI1-JAZ3-MYC2. Its activation was associated with enhanced rubber biosynthesis via up-regulation of the expression of a farnesyl pyrophosphate synthase gene and a small rubber particle protein gene. The increase in the corresponding proteins, especially that of farnesyl pyrophosphate synthase, probably contributes to the increased efficiency of rubber biosynthesis. To our knowledge, this is the first study to reveal a jasmonate signalling pathway in the regulation of rubber biosynthesis in laticifer cells. The identification of the specific jasmonate signalling module in the laticifer cells of the rubber tree may provide a basis for genetic improvement of rubber yield potential.

Identification, characterization and expression analysis of genes involved in steroidal saponin biosynthesis in Dracaena cambodiana.

Dracaena cambodiana is a traditional medicinal plant used for producing dragon's blood. The plants and dragon's blood of D. cambodiana contain a rich variety of steroidal saponins. However, little is known about steroidal saponin biosynthesis and its regulation in D. cambodiana. Here, 122 genes encoding enzymes involved in steroidal saponin biosynthesis were identified based on transcriptome data, with 29 of them containing complete open reading frames (ORF). Transcript expression analysis revealed that several genes related to steroidal saponin biosynthesis showed distinct tissue-specific expression patterns; the expression levels of genes encoding the key enzymes involved in the biosynthesis and early modification of steroidal saponins were significantly down-regulated in the stems in response to the inducer of dragon's blood, exhibiting positive correlations with the content of steroidal saponins. These results provide insights on the steroidal saponins biosynthetic pathway and mechanisms underlying induced formation of dragon's blood in D. cambodiana.

[Chemical constituents from ethyl acetate-soluble extraction of Valeriana jatamansi].

Application of a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, macroporous adsorbent resin, and reversed-phase HPLC, led to the isolation of 173 compounds including irdidoids, monoterpenes, sesquiterpenes, triterpenes, lignans, flavonoids, and simple aromatic derivatives from the ethyl acetate-soluble fraction of the whole plants of Valeriana jatamansi(Valerianaceae), and their structures were elucidated by spectroscopic methods including 1D, 2D NMR UV, IR, and MS techniques. Among them, 77 compounds were new. In previous reports, we have described the isolation, structure elucidation, and bioactivities of 68 new and 25 known compounds. As a consequence, we herein reported the isolation and structure elucidation of the remaining 9 new and 71 known compounds, the structure revision of valeriotriate A(8a), as well as cytotoxicity of some compounds.

Inhibition of HL-60 cell growth via cell cycle arrest and apoptosis induction by a cycloartane-labdane heterodimer from Pseudolarix amabilis.

Pseudolaridimer C (), a rarely encountered cycloartane-labdane Diels-Alder adduct was isolated from the cones of Pseudolarix amabilis. The structure and absolute configuration of were established by comprehensive NMR and CD spectral analysis. The WST-8 assay indicated that time and dose dependently inhibited the proliferation of human leukemia cells HL-60 at 1-10 µM. DAPI and Annexin V-FITC/PI double staining method, and DNA ladder experiments all proved that had significant dose-dependent effects on HL-60 cell apoptosis. A further mechanism study indicated that the apoptosis was associated with the cell cycle arrest during the G2/M phase, and the activation of caspase-9, -3, -7, and poly-(ADP-ribose)-polymerase (PARP).

Isolation, Structure Elucidation, and Absolute Configuration of Highly Oxygenated Germacranolides from Carpesium cernuum.

The new highly oxygenated germacranolides cernuumolides A-J (1-10) and the known compounds 11-20 were isolated from Carpesium cernuum. Among these compounds, 1-4 are 11-methoxymethylgermacranolides and 5-7 as well as 11-17 are 2,9-hemiacetal-linked germacranolides. Their structures were elucidated using NMR and HRESIMS analyses, and X-ray diffraction studies were used to confirm the absolute configurations of 1, 2, 5, 6, 8, and 9. Cernuumolides A-J were evaluated for their in vitro cytotoxicity against the A549, HCT116, MDA-MB-231, and BEL7404 cell lines, and 8 exhibited moderate cytotoxicity with IC50 values in the 0.87-2.02 µM range.

Chemical Constituents from Campylotropis hirtella.

A phytochemical investigation on the roots of Campylotropis hirtella afforded nine new isoflavones (3-9, 12, 15), two new isoflavans (10 and 11), one new coumestan (1), and three new prenylated benzoic acid derivatives (2, 13, 14), together with twenty-four known compounds. Their structures were established by spectroscopic analysis and circular dichroism data. The isolated compounds were also evaluated for their antibacterial activities against Enterococcus faecalis, Salmonella gallinarum, Streptococcus suis, Streptococcus agalactiae, Aeromonas hydrophila, Pseudomonas aeruginosa, Bacillus subtilis, Riemerella anatipestifer, and Vibrio alginolyticus.

Identification and characterization of MAGO and Y14 genes in Hevea brasiliensis.

Mago nashi (MAGO) and Y14 proteins are highly conserved among eukaryotes. In this study, we identified two MAGO (designated as HbMAGO1 andHbMAGO2) and two Y14 (designated as HbY14aand HbY14b) genes in the rubber tree (Hevea brasiliensis) genome annotation. Multiple amino acid sequence alignments predicted that HbMAGO and HbY14 proteins are structurally similar to homologous proteins from other species. Tissue-specific expression profiles showed that HbMAGO and HbY14 genes were expressed in at least one of the tissues (bark, flower, latex, leaf and root) examined. HbMAGOs and HbY14s were predominately located in the nucleus and were found to interact in yeast two-hybrid analysis (YTH) and bimolecular fluorescence complementation (BiFC) assays. HbMAGOs and HbY14s showed the highest transcription in latex and were regulated by ethylene and jasmonate. Interaction between HbMAGO2 and gp91phox (a large subunit of nicotinamide adenine dinucleotide phosphate) was identified using YTH and BiFC assays. These findings suggested that HbMAGO may be involved in the aggregation of rubber particles in H. brasiliensis.