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Nitrogen mustard (NM), a kind of alkylating agent similar to sulfur mustard, remains a threat to public health.

Atractylodes lancea (Thunb.) DC. (AL) has been proven to be effective in the treatment of coronavirus disease 2019 (COVID-19). In this study, TCMSP, TCMID, OMIM, GeneCards, PharmMapper and SwissTargetPrediction were used to collect potential targets for AL against COVID-19. The online STRING analysis platform and Cytoscape were used for generating a (protein-protein interaction) PPI network. The Cytoscape and Autodock software were used for determining hub genes and key compounds. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed via DAVID database. A total of 84 common targets were obtained. The antiviral pathways were main pathways in traetment. 10 hub genes and key compounds were screened by CytoHubba. We found that AL2, AL6 and AL38 had lower binding energy with key proteins. Our study demonstrated that AL might be used to treat COVID-19 by improving the "cytokine storm", regulating some antiviral pathways, and inhibiting the key protein through which the SARS-CoV-2 invades the host cell. These findings give a pharmacological basis and support for treating COVID-19 with AL.

Major genomic drivers of hepatocellular carcinoma (HCC) are nowadays well recognized, although models to establish their roles in human HCC initiation remain scarce. Here, we used human liver organoids in experimental systems to mimic the early stages of human liver carcinogenesis from the genetic lesions of TP53 loss and L3 loop R249S mutation. In addition, chromatin immunoprecipitation sequencing (ChIP-seq) of HCC cell lines shed important functional insights into the initiation of HCC consequential to the loss of tumor-suppressive function from TP53 deficiency and gain-of-function activities from mutant p53.Human liver organoids were generated from surgical nontumor liver tissues. CRISPR knockout of TP53 in liver organoids consistently demonstrated tumor-like morphological changes, increased in stemness and unrestricted in vitro propagation. To recapitulate TP53 status in human HCC, we overexpressed mutant R249S in TP53 knockout organoids. A spontaneous increase in tumorigenic potentials and bona fide HCC histology in xenotransplantations were observed. ChIP-seq analysis of HCC cell lines underscored gain-of-function properties from L3 loop p53 mutants in chromatin remodeling and overcoming extrinsic stress. More importantly, direct transcriptional activation of PSMF1 by mutant R249S could increase organoid resistance to endoplasmic reticulum stress, which was readily abrogated by PSMF1 knockdown in rescue experiments. In a patient cohort of primary HCC tumors and genome-edited liver organoids, quantitative polymerase chain reaction corroborated ChIP-seq findings and verified preferential genes modulated by L3 mutants, especially those enriched by R249S.We showed differential tumorigenic effects from TP53 loss and L3 mutations, which together confer normal hepatocytes with early clonal advantages and prosurvival functions.

Hepatocellular Carcinoma (HCC) represents the third leading cause of cancer-related mortality worldwide. TP53 mutations are pivotal genomic drivers for HCC development through frequent concurrent loss-of-function (LOF) aberrations and protein-altering missense mutations. Over 90% of the TP53 missense mutations are distributed within the core DNA binding domain (DBD), where R249S is the most common. Cumulative studies have demonstrated the cancer-promoting properties of TP53R249S mutation in HCC, but its biological impact on tumor initiation remains to be defined. To mimic the early stages of liver carcinogenesis, we generated normal hepatic organoids from human liver tissues of 3 individuals. CRISPR-Cas9 mediated knockout of TP53 in liver organoids resulted in pleomorphic malignant features, including dysplasia, hyperchromasia, atypical and frequent mitosis, loss of polarity, and increased nuclear to cytoplasm ratio. To recapitulate TP53R249S genotype in HCC, we ectopically expressed R249S mutant in liver organoids through lentiviral infection. TP53R249S liver organoids displayed tumorigenic properties as evidenced by increased lesion forming incidence (37.5%) in subcutaneous xenografts when compared with TP53KO (17%) and TP53 wild-type (WT) organoids (0%). Chromatin immunoprecipitation sequencing (ChIP-seq) analysis with HCC cell lines substantiated the specific gain-of-function (GOF) transcriptional activities of R249S mutant. A unique subset of transcription start site-proximal peaks was exclusively found in R249S mutant cells when compared with other TP53 missense mutants and WT. Integration of ChIP-seq and RNA-seq analysis identified transcription factor ZMIZ2 as a direct transcription target of R249S mutant. Our results showed that ZMIZ2 is preferentially overexpressed in HCC patients carrying TP53R249S mutation and exerts a vital role for proliferation of R249S mutant HCC cells. Knockdown of ZMIZ2 profoundly suppressed global H3K27 acetylation (H3K27ac) and H3K4 trimethylation (H3K4me3) in HCC cells. Transcriptome profiling of ZMIZ2 knockdown cells identified multiple downstream targets enriched in chromatin binding and interaction with histone deacetylase, further reinforcing its involvement in epigenetic regulation. In summary, our study revealed that TP53R249S mutation confers distinct advantages in increased tumorigenicity to human liver organoids through GOF transcriptional activities. ZMIZ2 serves as a direct downstream effector contributing to the oncogenic growth arising from R249S mutation plausibly through altering chromatin remodelling. Citation Format: Mingjing Xu, Yin Kau Lam, Jianqing Yu, Kelvin Kwok Chai Ng, Nathalie Wong. TP53 R249S mutation confers hepatic organoids with gain-of-function (GOF) tumorigenic features through transcriptional activation of ZMIZ2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2590.

We introduce a Milnor metric on the determinant line of the cohomology of the underlying closed manifold with coefficients in a flat vector bundle, by means of interactions between the fixed points and the closed orbits of a Morse-Smale flow. This allows us to generalise the notion of the absolute value at zero point of the Ruelle dynamical zeta function, even in the case where this value is not well defined in the classical sense. We give a formula relating the Milnor metric and the Ray-Singer metric. An essential ingredient of our proof is Bismut-Zhang's Theorem., Final version

Rationale: Hyperactivation of HGF/MET signaling pathway is a critical driver in liver tumorigenesis. Cytochrome P450 1A2 (CYP1A2) was significantly down-regulated in hepatocellular carcinoma (HCC). However, little is explored about its tumor suppressive role in HCC. In this study, we examined the functional mechanisms and clinical implication of CYP1A2 in HCC. Methods: The clinical impact of CYP1A2 was evaluated in HCC patients in Hong Kong cohort. The biological functions of CYP1A2 were investigated in vitro and in vivo. A series of biochemical experiments including Western blot assay, immunohistochemistry, quantitative reverse transcription-polymerase chain reaction, and Co-immunoprecipitation assay were conducted. Results: CYP1A2 expression was prominently silenced in HCC tumor tissues and the high expression of CYP1A2 was significantly correlated with lower AFP level, less vascular invasion, and better tumor-free survival in local cohort of HCC patients. The overexpression of CYP1A2 inhibited HCC cell viability and clonogenicity, reduced cell migration and invasion abilities in vitro, and suppressed tumorigenicity in vivo, whereas CYP1A2 knockdown exhibited the opposite effects. CYP1A2 significantly hindered HGF/MET signaling and Matrix metalloproteinases (MMPs) expression in HCC cells. Mechanically, CYP1A2 decreased HGF level and diminished HIF-1α expression, both of which are recognized as key regulators of MET activation. As the transcriptional activator of MET, HIF-1α was identified as a binding partner of CYP1A2. Direct binding of CYP1A2 with HIF-1α induced ubiquitin-mediated degradation of HIF-1α, inhibiting HIF-1α-mediated transcriptions. Conclusions: In conclusion, our results have identified CYP1A2 as a novel antagonist of HGF/MET signaling, and CYP1A2 may serve as an independent new biomarker for the prognosis of HCC patients.

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide. The outcome of current standard treatments, as well as targeted therapies in advanced stages, are still unsatisfactory. Attention has been drawn to novel strategies for better treatment efficacy. Hepatocyte growth factor/c-mesenchymal-epithelial transition factor (HGF/c-Met) axis has been known as an essential element in the regulation of liver diseases and as an oncogenic factor in HCC. In this review, we collected the evidence of HGF/c-Met as a tumor progression and prognostic marker, discussed the anti-c-Met therapy in vitro, summarized the outcome of c-Met inhibitors in clinical trials, and identified potential impetus for future anti-c-Met treatments. We also analyzed the inconsistency of HGF/c-Met from various publications and offered reasonable explanations based on the current understanding in this area. In conclusion, HGF/c-Met plays a crucial role in the progression and growth of HCC, and the strategies to inhibit this pathway may facilitate the development of new and effective treatments for HCC patients.

Liver cancer stem cells (LCSCs) initiate hepatocellular carcinoma (HCC) and contribute to its recurrence and treatment resistance. Studies have suggested ZBP-89 as a candidate tumor suppressor in HCC. We explored the role of ZBP-89 in the regulation of LCSCs. This study was performed in liver tissue samples from 104 HCC patients, 2 cell lines and mouse tumor models. We demonstrated that ZBP-89 was weakly expressed in LCSCs. Patients with high expression of LCSC markers displayed reduced survivals and higher recurrence rates after curative surgical operation. The expression of ZBP-89 was predictive for decreased recurrence. LCSC markers were negatively correlated with ZBP-89 in HCC tissues and in enriched liver tumor spheres. The exogenous expression of ZBP-89 attenuated the tumor-sphere formation and secondary colony formation capabilities of LCSCs in vitro and tumorigenicity in vivo. Furthermore, the negative effect of ZBP-89 on cancer stemness was Notch1-dependent. Localized with Notch1 intracellular domain (NICD1) in the nucleus, ZBP-89 repressed the Notch1 signaling pathway by competitive binding to NICD1 with MAML1. Collectively, ZBP-89 negatively regulates HCC stemness via inhibiting the Notch1 signaling.

Spiroalanpyrroids A (1) and B (2), two sesquiterpene alkaloids with an unprecedented eudesmanolide–pyrrolizidine spiro[5.5] framework, were isolated together with two new sesquiterpene-amino acid adducts, helenalanprolines A (3) and B (4), from the roots of Inula helenium. Their structures were elucidated by spectroscopic data analysis, ECD calculations, and single-crystal X-ray diffraction analysis. A plausible biosynthetic pathway was proposed for 1 and 2. Bioassays showed that compounds 3 and 4 significantly inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with IC50 values of 15.8 and 13.5 μM, respectively.

Piper nigrum is an important aromatic plant, and its fruits (black and white pepper) are commonly used as food additives and spices. However, its stems were disposed as wastes. This research comprehensively investigated bioactive alkaloids of the stems, eight new dimeric amide alkaloids and eight known compounds were obtained. All obtained compounds showed excellent anti-inflammatory activity. Additionally, the dimeric amide alkaloids enhanced the anticancer effect of paclitaxel against cervical cancer cells. These results demonstrate that the stems of P. nigrum could be the sustainable source of bioactive alkaloids for development and utilization in the food and health fields.

The leguminosae of

Spiroalanfurantones A-D (1-4), four eudesmanolide-furan sesquiterpene adducts with an unprecedented pentacyclic 6/6/5/5/5 skeleton, were isolated from the roots of Inula helenium. Their structures were elucidated by spectroscopic data analysis and single-crystal X-ray diffraction analysis. The plausible biosynthetic pathway for 1-4 is presented. Bioassay showed that compounds 1 and 2 significantly inhibited nitric oxide production in lipopolysaccharide-induced RAW264.7 macrophages with IC50 values of 17.3 and 9.5 μM, respectively.

Two octahydro-protoberberine alkaloids, alangiifoliumines A (1) and B (2), and two new protoemetine derivatives, alangiifoliumines C (3) and D (4), together with 11 known compounds, have been isolated from the stems of Alangium salviifolium. While the structures of these compounds were elucidated by spectroscopic methods, the absolute configurations of the new alkaloids were determined by conformational analysis and time-dependent density functional theory-electronic circular dichroism spectra calculations on selected stereoisomers. Compounds 1 and 2 represent the first 5,8,8a,9,12,12a,13,13a-octahydro-protoberberine derivatives, in which the aromatic ring D was reduced to cyclohexene. All the compounds isolated were evaluated for their cytotoxic activity against three human cancer cell lines: A-549, HeLa, and SKOV-3. Alkaloids 1, 3, and 6-14 exhibited inhibitory effects against all three human cancer cell lines, with half-maximal inhibitory concentration (IC50) values in the range of 3 nM to 9.4 μM.

In the current study, nine amide alkaloids, including two new dimeric amides and a new natural product, were identified from Piper nigrum. Among them, seven compounds sensitized paclitaxel-resistant cervical cancer cells HeLa/PTX to paclitaxel. Piperine was a major component obtained from Piper nigrum, and its sensitization mechanism was investigated. Combination treatment enhanced cell apoptosis, which was mediated by downregulation of phospho-Akt and Mcl-1. Piperine (50 μM) combined with paclitaxel (200 nM) downregulated Mcl-1 protein expression with a decrease of 35.9 ± 9.5% ( P < 0.05). Moreover, overexpression of Mcl-1 attenuated the inhibitory effect of this combination. Furthermore, combination treatments of six dimeric amide alkaloids and paclitaxel all downregulated Mcl-1 protein expression with a decrease ranging from 23.5 ± 9.7% to 41.7 ± 7.2% ( P < 0.05). We reveal, for the first time, that dimeric amide alkaloids from plants possess a remarkable sensitization effect on cancer cells to paclitaxel.

Platinum resistance is a major limitation in the treatment of ovarian cancer. Combination of natural compounds with platinum-based agents is a new strategy for cancer chemotherapy. Recently, we found that scutellarin sensitized the anticancer effect of cisplatin to ovarian cancer cells. How scutellarin interacts with cisplatin and sensitizes its effect is unclear. Here, we found that the combination treatment of scutellarin and cisplatin enhanced apoptosis in ovarian cancer cells via increasing the extent of platinum-DNA adducts and the ratio of Bax/Bcl-2. The changes in UV-visible spectra indicated that scutellarin could form complex with cisplatin. Moreover, combination treatment prevented BamH1 digestion on pBR322 plasmid DNA more effectively suggesting that their interaction might cause a greater conformational change in the DNA, which finally induced the DNA strand breaks and enhanced apoptotic signaling pathway response. Our study supports that scutellarin acts as a potential sensitizer to cisplatin treatment and the combination of scutellarin and cisplatin may be a novel therapeutic strategy to overcome platinum resistance of ovarian cancer.

Rare earth elements (REEs) generally accumulate in natural bone; however, their enhanced effects on stem cell osteogenic differentiation and macrophage phagocytic activity remain to be clarified. Inspired by the components and architectures of natural bone, this was the first study to construct La-doped hydroxyapatite/chitosan (La-HA/CS) biomimetic scaffolds for bone tissue engineering. Intriguingly, the La element in the scaffolds significantly improved the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and the formation of new bone tissues via an activated Wnt/β-catenin signalling pathway. At the same time, La3+ ions in the La-HA/CS scaffolds remarkably promoted the proliferation and phagocytic activity of the macrophages, leading to a synchronous biodegradability. The cranial bone defect models of Sprague-Dawley rats further revealed that the La element fantastically synchronizes macrophage-induced biomaterial degradation and new bone formation. The capacity of osteoconduction held by HA/CS, osteoinduction by La3+, and biodegradability by a La-HA/CS composite, contributes to an ideal scaffold for osteointegration and remodelling. The exciting findings provide a critical and novel strategy to fabricate REE-doped scaffolds for a bone repair strategy.

Background: Hepatocellular carcinoma (HCC) is the predominant subtype of liver cancer with an extraordinary high mortality. Resistance to systemic therapy is a major cause of inferior clinical outcome in most patients with HCC. CD44 is a transmembrane cell-surface glycoprotein that is characterized by its variants displaying differential overexpression in human cancers. Aptamers, also known as chemical antibodies, can target cell-surface molecules with high affinity and specificity via structural recognition. Aptamer-mediated drug delivery hence is of high potentials in guiding therapy to improve efficacy. Methods: Variants CD44E and CD44s were studied for HCC relevance by investigating their expressions in primary HCC tumors, adjacent cirrhotic/fibrotic livers and normal livers using junction specific primers in qPCR assay. CD44E/s dual-targeted aptamers were uncovered by integrating loss-gain cell-SELEX and next generation sequencing. Selected aptamers were characterized for binding affinity and specificity, biostability, in vivo and in vitro cytotoxicity, in vivo homing and biodistribution, and ability to deliver 5-FU into targeted cells in vitro. Results: Both CD44E and CD44s isoforms showed significant upregulations in HCC tumors with CD44E/s activities promoting cell proliferation and migration. Loss-gain cell-SELEX uncover a CD44E/s dual-targeting aptamer, termed CD44-Apt1. Strong binding of CD44-Apt1 to cell-surface CD44 positive cells but not CD44-negative cells was demonstrated by flow-cytometry. CD44-Apt1 displayed strong affinity to CD44E and CD44s with KD as low as 1 nM but not the hyaluronic acid binding domain of CD44. Confocal imaging of CD44-positive cells stained with fluorescent-labeled CD44-Apt1 showed profound cytoplasmic localization, suggesting efficient cell-penetrating ability. Meanwhile, no apparent staining was observed in CD44-negative cells. CD44-Apt1 when conjugated with inhibitor 5-FU showed efficient guidance of 5-FU into HCC cells that significantly enhanced drug toxicity by more than thousands-fold. Both in vitro cell treatment and in vivo animal biodistribution indicated that CD44-Apt1 is non-toxic. In HCC xenograft model, CD44-Apt1 efficiently homed to tumor xenografts in a CD44 expression-dependent manner. Conclusion: Novel discovery of aptamer CD44-Apt1 that can bind both CD44E and CD44s illustrates high potential as nanoprobe to deliver anti-cancer therapeutics.

The status of FOXP3 and its isoforms in hepatocellular carcinoma (HCC) is unclear. We aimed to investigate the expression and function of FOXP3 and its isoforms in HCC. The study was performed on 84 HCC patients, HCC cell lines and a mouse tumor model. The levels of FOXP3 and its isoforms were determined by nested PCR, quantitative real-time PCR and immunohistochemistry (IHC) staining. The correlation between their levels and clinicopathologic characteristics was analyzed. The full length of FOXP3 (FOXP3) and exon 3-deleted FOXP3 (FOXP3Δ3) were found to be the major isoforms in HCC. The levels of FOXP3Δ3 mRNA and protein in HCC tumor samples were not significantly different from their adjacent normal tissues. The high expression of FOXP3 protein in HCC patients showed a good overall survival. The overexpression of FOXP3 significantly reduced tumor cell proliferation, migration and invasion. The immunofluorescence result indicated that FOXP3 needed to be translocated into the nucleus to exert its inhibitory function. The luciferase assay demonstrated that FOXP3 could be synergistic with Smad2/3/4 to inhibit the oncogene c-Myc. The co-immunoprecipitation results further revealed that FOXP3 could interact with Smad2/3/4. The chromatin immunoprecipitation (ChIP) assay showed that both FOXP3 and Smad2/3/4 bound the promoter of the c-Myc to inhibit it. The in vivo mouse tumor model study confirmed the inhibitory effect of FOXP3. Collectively, the expression of tumor FOXP3 can inhibit the growth of HCC via suppressing c-Myc directly or indirectly via interacting with Smad2/3/4. Therefore, FOXP3 is a tumor suppressor in HCC.

Background The status of FOXP3 and its isoforms in hepatocellular carcinoma (HCC) is unclear. We aimed to investigate the expression and function of FOXP3 and its isoforms in HCC. Methods The study was performed on 84 HCC patients, HCC cell lines and a mouse tumor model. The levels of FOXP3 and its isoforms were determined by nested PCR, quantitative real-time PCR and immunohistochemistry (IHC) staining. The correlation between their levels and clinicopathologic characteristics was analyzed. Results The full length of FOXP3 (FOXP3) and exon 3-deleted FOXP3 (FOXP3Δ3) were found to be the major isoforms in HCC. The levels of FOXP3Δ3 mRNA and protein in HCC tumor samples were not significantly different from their adjacent normal tissues. The high expression of FOXP3 protein in HCC patients showed a good overall survival. The overexpression of FOXP3 significantly reduced tumor cell proliferation, migration and invasion. The immunofluorescence result indicated that FOXP3 needed to be translocated into the nucleus to exert its inhibitory function. The luciferase assay demonstrated that FOXP3 could be synergistic with Smad2/3/4 to inhibit the oncogene c-Myc. The co-immunoprecipitation results further revealed that FOXP3 could interact with Smad2/3/4. The chromatin immunoprecipitation (ChIP) assay showed that both FOXP3 and Smad2/3/4 bound the promoter of the c-Myc to inhibit it. The in vivo mouse tumor model study confirmed the inhibitory effect of FOXP3. Conclusion Collectively, the expression of tumor FOXP3 can inhibit the growth of HCC via suppressing c-Myc directly or indirectly via interacting with Smad2/3/4. Therefore, FOXP3 is a tumor suppressor in HCC.

Sorafenib resistance has become the main obstacle in the effective treatment of advanced hepatocellular carcinoma (HCC) patients. Activation of nuclear factor kappa B (NF-κB) is a newly identified mechanism that contributes to desensitized sorafenib. Cytochrome P450 1A2 (CYP1A2) functions as a tumor suppressor in HCC and its expression is negatively associated with NF-κB in the liver. This study aimed to study whether CYP1A2 could overcome sorafenib resistance. To investigate whether CYP1A2 and NF-κB p65 played roles in sorafenib desensitization, we established sorafenib-resistant (SR) HCC cells. SR cells decreased the expression of CYP1A2 along with the upregulation of NF-κB p65. CYP1A2 overexpression attenuated SR cell proliferation, increased sorafenib sensitivity, and inhibited the NF-κB pathway, whereas CYP1A2 silence showed opposite effects. Sorafenib, in combination with omeprazole, a CYP1A2 inducer, significantly hindered the growth and invasion of SR cells in vitro as well as decreased the tumor growth in vivo. The combination treatment markedly increased CYP1A2 expression and inhibited the sorafenib-induced NF-κB signaling. In addition, the overexpression of NF-κB p65 stimulated the SR cell growth and desensitized sorafenib in SR cells, where CYP1A2 overexpression reversed the phenomenon. Lastly, the majority of HCC tissue samples displayed decreased CYP1A2 but increased NF-κB p65 protein expression. Collectively, CYP1A2 can sensitize SR cells to sorafenib via inhibiting NF-κB p65 axis. Omeprazole in combination with sorafenib exerts a synergistic effect in alleviating acquired sorafenib resistance.

One new cepheline-type alkaloid 8-hydroxyl-cepheline (1) and one new natural product Δ1′,2′-deoxytubulosine (2), together with 9 known alkaloids have been isolated from the fruits and seeds of Alangium salviifolium (L.f.) Wangerin. The structures of the new alkaloids were elucidated by means of extensive spectroscopic analysis (2D NMR, HRESIMS). All alkaloids were evaluated for their cytotoxic activity against three human cancer cell lines, A-549, Hela and SKOV-3. Compounds 1-4, 6, 8 and 9 exhibited significant inhibitory effects against three human cancer cells with IC50 values (0.1–14 μM) comparable to those of cisplatin.

Protocatechuic acid (PCA), present in many fruits and vegetables, exhibited various biological activities. Here, we provided evidence that it could be developed as a potential chemotherapeutic agent against human ovarian cancer. We found that PCA treatment significantly reduced the cell viability and colony formation of OVCAR-3, SKOV-3, and A2780 cells. OVCAR-3 cells were selected as a test model system for investigating molecular mechanism. PCA treatment induced cell cycle arrest in G2 /M phase, the activation of poly (ADP-ribose) polymerase (PARP) and caspase-3, the upregulation of Bax and downregulation of Bcl-2 in OVCAR-3 cells. We also observed that PCA treatment significantly caused upregulation of autophagy-related protein LC3-II and induced GFP-LC3 puncta formation. Furthermore, cotreatment with PCA and autophagy inhibitor attenuated the cytotoxicity induced by PCA in OVCAR-3 cells. Moreover, our results showed that PCA increased the intracellular levels of glutathione and decreased intracellular reactive oxygen species that might be related to the inhibition effect of PCA on OVCAR-3 cells. Our data revealed that PCA could modulate apoptosis and autophagy, suggesting the potential of PCA for chemoprevention and chemotherapy of ovarian cancer.

Effective repair of bone defects mainly depends on the osteoinductivity and biocompatibility of implants. Herein, we for the first time reported the bioinspired fabrication of carbonated hydroxyapatite/chitosan (CHA/CS) nanohybrid scaffolds using CaCO3/CS porous scaffolds as sacrificial templates, followed by loading TWS119 drugs (CHA/CS/TWS119). After treatment with phosphate buffer solutions, the CaCO3/CS porous scaffolds were in situ converted into CHA/CS nanohybrid scaffolds via the dissolution-precipitation reaction. The as-formed CHA nanoplates with thicknesses of ∼20 nm and widths of 1.0–2.0 μm were perpendicular to the scaffold surfaces. The three-dimensional interconnected macropores supported the adhesion and spreading of bone mesenchymal stem cells (BMSCs), and the mesopores within the CHA nanoplates as drug delivery channels improved the drug loading-release properties. The controlled drug release of the CHA/CS/TWS119 nanohybrid scaffolds significantly enhanced the osteogenic differentiation of BMSCs by the activated GSK3β/β-catenin pathway. Moreover, rat cranial defect models revealed the enhancing effects of the CHA/CS/TWS119 scaffold on bone tissue regeneration. The micro-CT, haematoxylin and eosin (H&E) staining, Van Gieson (VG) staining, Masson staining and double fluorochrome labelling results demonstrated that more new bone tissues were formed in the CHA/CS/TWS119 nanohybrid scaffolds than the control group without loading TWS119. Therefore, the CHA/CS/TWS119 nanohybrid scaffold is a promising therapeutic material for bone tissue regeneration.

Twenty-one eudesmane-type sesquiterpenes, including five new compounds, were isolated from the roots of Inula helenium. The structures of the new compounds (1–5) were determined by extensive spectroscopic data interpretation, single-crystal X-ray diffraction analysis and ECD calculations. Six compounds can synergistically enhance cisplatin effect against ovarian cancer cells, the structure − activity relationship for the synergistic effect of these compounds with cisplatin was revealed for the first time, which provides useful clues to develop novel sensitizers to overcome drug resistance in cancer. In addition, fifteen sesquiterpenes exhibited significant anti-inflammatory activity, which provided promising candidates for development of anti-inflammatory agent.

Antioxidant and antiproliferative activities of the Trapa bispinosa leaf were investigated in this study. The leaves of this plant were extracted with 95% ethanol and water, respectively. Both ethanol extract (EE) and water extract (WE) exhibited the antioxidant activity. EE exhibited stronger superoxide anion- scavenging capacity than WE. For antiproliferative activity of both crude extracts, EE was stronger than WE against all cancer cell lines tested, except for lung cancer cell line A549. Further separation was carried out on EE by macroporous resin to obtain eleven fractions. Among all fractions, the fraction eluted by 80% methanol had the highest total phenolic content (TPC) and the strongest antiproliferative property against three cancer cell lines. Phytochemical composition of this fraction was analyzed by HPLC-MS. The main components responsible for the antioxidant and antiproliferative activities were elucidated. These results suggest that the Trapa bispinosa leaf could also be potential sources for prevention of cancer and other diseases associated with oxidative stress.

Spiroalanfurantones A-D (

Two octahydro-protoberberine alkaloids, alangiifoliumines A (

This study was undertaken in order to investigate the antioxidant, anti-inflammatory and antimicrobial activities of various fractions and compounds obtained from the bark of

Objectives To explore effective extraction method and to find active constituents, we investigated the biological activity of three extracts and isolated active compounds from the fruits of Piper longum L. Methods Three extracts from the fruits were obtained by reflux, ultrasonic and supercritical fluid extraction, respectively. Active compounds were isolated by the bioassay-guided method. The anti-inflammatory activity, antiproliferation activity and cytotoxicity were evaluated. The apoptosis was detected by Hoechst 33258 staining assay. The relevant proteins were investigated by Western blot assay. Key findings The anti-inflammatory activity and cytotoxicity of supercritical fluid extract (SE) were stronger than those of the other two extracts. Among all isolated compounds, the anti-inflammatory activity of eight compounds was stronger than that of indomethacin, and compounds 8, 9, 11, 14 and 15 were found to possess anti-inflammatory effect for the first time. Compounds 1, 2, 3 and 14 exhibited significant cytotoxicity against cancer cells. SE and piperine were found to reduce colony formation, inhibit cell migration and promote apoptosis through increasing cleaved PARP and the ratio of Bax/Bcl-2. Conclusions The anti-inflammatory and antitumour effects of SE were better than those of the other two extracts. The compounds responsible for the activity were elucidated. SE and piperine inhibit cell growth through apoptosis.

This study was undertaken in order to investigate the antioxidant, anti-inflammatory and antimicrobial activities of various fractions and compounds obtained from the bark of P. hupehensis. The ethyl acetate fraction exhibited strong antioxidant, anti-inflammatory and antimicrobial effects. Six compounds were isolated from this fraction, three of which showed antioxidant activity and anti-inflammatory activity. The biological activities and the active compounds of P. hupehensis were reported for the first time.

Siegesbeckia orientalis L. (Asteraceae) is an annual herb with a worldwide distribution and has been used in Asia as folk medicine. In this study, the antimicrobial, antioxidant and cytotoxic activities of various fractions from Siegesbeckia orientalis L. were investigated. The ethyl acetate fraction showed the strongest antimicrobial, antioxidant and cytotoxic activities. The bioassay guided isolation of the ethyl acetate fraction led to twelve compounds: 16β-hydro-ent- kauran-17,19-dioic acid (1), 16α,17-dihydroxy-ent-kauran-19-oic acid (2), 16β,17,18- trihydroxy-ent-kauran-19-oic acid (3), 17,18-dihydroxy-ent-kauran-19-oic acid (4), siegesmethyletheric acid (5), 2-oxo-15,16,19-trihydroxy-ent-pimar-8(14)-ene(6), 3, 16-dihydroxyl-15-one-ent-pimar-8(14)-ene-3-O-β-d-glucopyranoside (7), quercetin (8), ursolic acid (9), β-sitosterol (10), stigmasterol (11) and uracil (12). Among all the twelve compounds, compounds 1-4 exhibited the striking antimicrobial activity against screened microorganisms, especially against methicillin-resistant Staphylococcus aureus. Compounds 1, 3 and 4 were found to possess antimicrobial activity for the first time. Compound 8 exhibited antioxidant and cytotoxic activities. Compound 9 exhibited cytotoxic activity. These results demonstrate that Siegesbeckia orientalis extracts and active compounds could be potential pharmaceutical products, especially against antibiotic-resistant microorganisms.

In this paper, we establish an equality between the analytic torsion introduced by Dar (Math Z 194(2): 193–216, 1987) and the orbifold analytic torsion defined by Ma (Trans Am Math Soc 357(6): 2205–2233, 2005) on an even dimensional manifold with isolated conical singularities which in addition has an orbifold structure. We assume the orbifold flat vector bundle is an honest vector bundle, although the metric on the flat bundle may not be flat.

The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process, involving the progressive accumulation of molecular alterations and transcriptomic alterations. The Forkhead-box (FOX) transcription factor family is characterized by its unique DNA binding domain (FKH or winged-helix domain). Human FOX family consists of about 17 subfamilies, at least 43 members. Some of them are liver-enriched transcription factors, suggesting that they may play a crucial role in the development or/and functions of the liver. Dysregulation of FOX transcription factors may contribute to the pathogenesis of HCC because they can activate or suppress the expression of various tumor-related molecules, and pinpoint different molecular and cellular events. Here we summarized, analyzed and discussed the status and the functions of the human FOX family of transcription factors in HCC, aiming to help the further development of them as potential therapeutic targets or/and diagnostic/prognostic markers for HCC.

Trigonella foenum-graecum L. (fenugreek) is used as a leafy vegetable and spice in China and North African countries. However, the biochemical components of its aerial parts were rarely explored. In this study, the bioactivities of the various extract fractions from the aerial parts of this edible plant were assessed, the ethyl acetate extract fraction exhibited strong antioxidant and anti-inflammatory effects. Through bioassay-guided isolation, one new pterocarpan (1), as well as twelve known pterocarpans (2-13) were obtained, nine of them (5-13) were first reported in the fenugreek, four pterocarpans (9, 11-13) had strong antioxidant activity, eleven pterocarpans (1-3, 5-12) possessed obvious anti-inflammatory activity. This study indicates that pterocarpans are main bioactive components of this edible plant. Apart from its nutritional value as food, the aerial parts of this plant can also be further explored as functional foods or antioxidants in food industry.

Protocatechuic acid (PCA), present in many fruits and vegetables, exhibited various biological activities. Here, we provided evidence that it could be developed as a potential chemotherapeutic agent against human ovarian cancer. We found that PCA treatment significantly reduced the cell viability and colony formation of OVCAR-3, SKOV-3, and A2780 cells. OVCAR-3 cells were selected as a test model system for investigating molecular mechanism. PCA treatment induced cell cycle arrest in G

Patrinia villosa Juss is a famous medicinal herb and is used as an anti-inflammatory and anti-bacterial agent. Its tender leaves have also been used as a wild vegetable in China. In this study, the antioxidant and cytotoxic activities of various fractions of ethanol extract from P. villosa were investigated, the ethyl acetate fraction (EE-PV) exhibited the strongest antioxidant activity and cytotoxic effect on four cancer cell lines. EE-PV also significantly inhibited the tumour growth in vivo. EE-PV was subjected to bioassay-guided isolation of active compounds by column chromatography. Phenolic compounds such as 5,7,4′-trihydroxy-3-methoxyflavone and p-hydroxybenzoic acid are mainly responsible for antioxidant activity. Ursolic acid as one of main constituents contributed to the antitumour activity of EE-PV. These results suggest that this plant extract could be considered as a potential source of functional food and pharmaceutical for preventing cancer and reducing the risk of chronic diseases associated with oxidative damage.

We prove the following generalization of the classical Lichnerowicz vanishing theorem: if $F$ is an oriented flat vector bundle over a closed spin manifold $M$ such that $TM$ carries a metric of positive scalar curvature, then $=0$, where $e(F)$ is the Euler class of $F$., Comment: 17 pages

In this paper, we first establish an S 1 S^1 -equivariant index theorem for Spin c ^c Dirac operators on Z / k \mathbb {Z}/k manifolds, and then combining this equivariant index theorem with the methods developed by Liu-Ma-Zhang and Taubes, we extend Witten’s rigidity theorem to the case of Z / k \mathbb {Z}/k Spin c ^c manifolds. Among others, our results resolve a conjecture of Devoto.

Combination of natural components with anticancer drugs is a new strategy for cancer chemotherapy to increase antitumour responses. In this study, we investigated the sensitisation effects of nine flavonoids from Scutellaria barbata to cisplatin (CDDP) on human ovarian cancer cells. The combinations of three flavonoids with CDDP showed the synergistic effects. The intracellular reactive oxygen species and the antioxidant activity were measured. The data suggest that the synergistic effects of flavonoids with CDDP on ovarian cancer cells did not directly correlate with their redox properties, but could be associated with the positions of hydroxyl group and methoxy group of flavonoids.

Alantolactone, a sesquiterpene lactone, possesses anti-inflammatory property. In this study, we provide evidence that it could be developed as a novel agent against human liver cancer. We observed that alantolactone treatment to HepG2, Bel-7402 and SMMC-7721 cells, human liver cancer cell lines resulted in a dose-dependent inhibition of cell growth. We selected HepG2 cell line as a test model system. Alantolactone treatment of HepG2 cells resulted in a dose-dependent induction of apoptosis and arrest of cells in G2-M phase. This induction of apoptosis seems to be mediated via modulating the protein levels of Bcl-2 family and activation of caspases. Moreover, caspase-8 and Bid activation, loss of mitochondrial transmembrane potential and cytochrome c release suggest the existence of a cross-talk between the death receptor and the mitochondrial pathways. We also observed that alantolactone treatment of cells resulted in a dose-dependent decrease in NF- κB/p65. In addition, a significant and progressive increase in the level of p53 protein in alantolactone-treated cells was observed. Taken together, our data suggest that alantolactone could be developed as an agent against human liver cancer.

Design reuse is becoming a widely accepted strategy to meet the increasingly fierce competition in product development. This paper presents a new approach to design reuse based on the decomposition of design processes. In this approach, the basic reusable template, design process unit (DPU), is developed by decomposing the design process, which has four important characteristics: reusability, hierarchical decomposition and composition, domain independence, and decision-centric with well-defined inputs and outputs. Then the criteria of process decomposition and the scale of design process reuse are established, respectively. Based on the methodology above, a multi-tier, three-phase reuse architecture with effective DPU retrieval is presented. Experimental results show that this approach greatly facilitates DPU reuse and is a worthwhile exploration of design reuse.

Emodin, a natural anthraquinone, has been reported to possess antiproliferative effects in many cancer cell lines. However, anticancer mechanism against human liver cancer remains unclear. In this study, we observed that emodin induced apoptosis in HepG2 cells and caused a significant accumulation of cells in the G1 phase. Western blot data showed that emodin treatment caused the increasing of release of cytochrome c into cytosol from mitochondria and the activation of caspase-8 and caspase-9, which suggest that the intrinsic and extrinsic pathways could be involved. Emodin treatment also resulted in a dose-dependent accumulation of intracellular reactive oxygen species. Furthermore, emodin increased the protein level of p53 and decreased the protein level of NF-κB/p65 in HepG2 cells, which indicated these two regulators might play a role in emodin-induced apoptosis. Computational modeling showed that emodin could directly bind to the BH3 domain of Bcl-2 through forming one hydrogen bond with Ala146 residue in Bcl-2. From these examinations, emodin not only significantly downregulated expression of Bcl-2 but also inhibited the heterodimerization of Bcl-2 with Bax because of strong interaction between emodin and Bcl-2. These suggest that emodin induces apoptosis in liver cancer cell line through a multifaceted complex cascade of events.