Cytotoxic Terpenes from the Flowers of Inula japonica against Human Hepatocarcinoma Cells.

Two new 1,10-seco-eudesmanolides (1 and 2) were isolated from the flowers of Inula japonica together with two eudesmanolide analogs (3 and 4) and two monoterpene derivatives (5 and 6). Their structures were established on the basis of detailed spectroscopic analyses and electronic circular dichroism data. All isolates were evaluated for their antiproliferative activities against human hepatocarcinoma HepG2 and SMMC-7721 cells. Japonipene B (3) exhibited the most potent effect with the IC50 values of 14.60±1.62 and 22.06±1.34 µM against HepG2 and SMMC-7721 cells, respectively. Furthermore, japonipene B (3) showed significant efficacies of arresting the cell cycle at the S/G2-M stages, inducing mitochondria-mediated apoptosis, and inhibiting cell migration in HepG2 cells.

Quantitative Analysis of Super Resolution in Electromagnetic Inverse Scattering for Microwave Medical Sensing and Imaging.

Microwave medical sensing and imaging (MMSI) has been a research hotspot in the past years. Imaging algorithms based on electromagnetic inverse scattering (EIS) play a key role in MMSI due to the super-resolution phenomenon. EIS problems generally employ far-field scattered data to reconstruct images. However, the far-field data do not include information outside the Ewald's sphere, so theoretically it is impossible to achieve super resolution. The reason for super resolution has not been clarified. The majority of the current research focuses on how nonlinearity affects the super-resolution phenomena in EIS. However, the mechanism of super-resolution in the absence of nonlinearity is routinely ignored. In this research, we address a prevalent yet overlooked problem where the image resolution due to scatterers of extended structures is incorrectly analyzed using the model of point scatterers. Specifically, the classical resolution of EIS is defined by the Rayleigh criterion which is only suitable for point-like scatterers. However, the super-resolution in EIS is often observed for general scatterers like cylinders, squares or Austria shapes. Subsequently, we provide theoretical results for the Born approximation framework in EIS, and employ the Sparrow criteria to quantify the resolution for symmetric objects of extended structures. Furthermore, the modified Sparrow criterion is proposed to calculate the resolution of asymmetric scatterers. Numerical examples show that the proposed approach can better explain the super-resolution phenomenon in EIS.

A Novel Analysis of Super-Resolution for Born-Iterative-Type Algorithms in Microwave Medical Sensing and Imaging.

Microwave medical sensing and imaging (MMSI) is a highly active research field. In MMSI, electromagnetic inverse scattering (EIS) is a commonly used technique that infers the internal characteristics of the diseased area by measuring the scattered field. It is worth noting that the image formed by EIS often exhibits the super-resolution phenomenon, which has attracted much research interest over the past decade. A classical perspective is that multiple scattering leads to super-resolution, but this is subject to debate. This paper aims to analyze the super-resolution behavior for Born-iterative-type algorithms for the following three aspects. Firstly, the resolution defined by the traditional Rayleigh criterion can only be applied to point scatterers. It does not suit general scatterers. By using the Sparrow criterion and the generalized spread function, the super-resolution condition can be derived for general scatterers even under the Born approximation (BA) condition. Secondly, an iterative algorithm results in larger coefficients in the high-frequency regime of the optical transfer function compared to non-iterative BA. Due to the anti-apodization effect, the spread function of the iterative method becomes steeper, which leads to a better resolution following the definition of the Sparrow criterion mentioned above. Thirdly, the solution from the previous iteration, as the prior knowledge for the next iteration, will cause changes in the total field, which provides additional information outside the Ewald sphere and thereby gives rise to super-resolution. Comprehensive numerical examples are used to verify these viewpoints.

Analysis of the Development Status and Prospect of China's Agricultural Sensor Market under Smart Agriculture.

Agricultural sensors are essential technologies for smart agriculture, which can transform non-electrical physical quantities such as environmental factors. The ecological elements inside and outside of plants and animals are converted into electrical signals for control system recognition, providing a basis for decision-making in smart agriculture. With the rapid development of smart agriculture in China, agricultural sensors have ushered in opportunities and challenges. Based on a literature review and data statistics, this paper analyzes the market prospects and market scale of agricultural sensors in China from four perspectives: field farming, facility farming, livestock and poultry farming and aquaculture. The study further predicts the demand for agricultural sensors in 2025 and 2035. The results reveal that China's sensor market has a good development prospect. However, the paper garnered the key challenges of China's agricultural sensor industry, including a weak technical foundation, poor enterprise research capacity, high importation of sensors and a lack of financial support. Given this, the agricultural sensor market should be comprehensively distributed in terms of policy, funding, expertise and innovative technology. In addition, this paper highlighted integrating the future development direction of China's agricultural sensor technology with new technologies and China's agricultural development needs.

Total synthesis and stereochemical assignment of rakicidin F.

Total synthesis of rakicidin F was accomplished in 20 linear steps (0.68% overall yield), which enabled the configural determination of its six stereogenic centers as 2R, 15R, 16R, 17S, 19S, and 21S. The macrolactonization of the rakicidin linear precursor was investigated and the unsuccessful results might be attributed to the steric hindrance near C16-OH.

Probe Synthesis Reveals Eukaryotic Translation Elongation Factor†1 Alpha†1 as the Anti-Pancreatic Cancer Target of BE-43547A2.

The natural product, BE-43547A2 , decreases pancreatic cancer cell stemness. However, its anticancer molecular mechanisms have not been fully established. Based on structure-activity relationships of BE-43547A2 , we synthesized a probe and investigated its potential targets using an in situ click reaction. We found that BE-43547A2 exerts its anticancer effects by covalently binding the cysteine234 (C234) residue of eukaryotic translation elongation factor 1 alpha 1 (eEF1A1). This binding mode was confirmed by a series of experiments including a xenograft mouse model. We also determined that eEF1A1 plays an important role in regulating pancreatic cancer cell stemness. Analyses of 99 clinical pancreatic cancer samples revealed that eEF1A1 expressions are closely correlated with clinicopathological grade and patient survival. In conclusion, eEF1A1 is involved in pancreatic cancer progression and is therefore, a promising novel covalent target for pancreatic cancer treatment.

A Two-Phase Approach to Fusicoccane Synthesis To Uncover a Compound That Reduces Tumourigenesis in Pancreatic Cancer Cells.

Alterbrassicicene D (1) and 3(11)-epoxyhypoestenone (2) were synthesised via a two-phase approach featuring concise construction of the 5-8-5 tricyclic intermediate and a tandem base-mediated epoxide opening-transannular oxa-Michael addition cascade to forge the complex skeleton of 2. The route is scalable and we generated 15 g of the tricyclic intermediate in 8 steps from (R)-limonene and 720 mg of the penultimate bioactive intermediate in a protecting-group-free manner. Our synthesis enabled the structural determination of 2 and provided materials for preliminary anticancer evaluation. The penultimate intermediate showed therapeutic potential in terms of its ability to dramatically reduce the tumourigenic potential of PANC-1 pancreatic cancer cells according to a limiting dilution tumour-initiating assay. Our synthetic approach will facilitate unified access to naturally occurring fusicoccanes and their derivatives for anticancer evaluation.

A small molecule compound IX inhibits telomere and attenuates oncogenesis of drug-resistant leukemia cells.

Drug resistance is a common obstacle in leukemia treatment and failing to eradicate leukemia stem cells is the main cause of leukemia relapse. Previous studies have demonstrated that telomerase activity is associated with deregulated self-renewal of leukemia stem cells (LSCs). Here, we identified a novel compound IX, an imatinib derivative with a replacement fragment of a telomerase inhibitor, which can effectively eradicate LSCs but had no influence on normal hematopoietic stem cells (HSCs) survival. We showed that compound IX can decrease the viability of drug-resistant K562/G cells and blast crisis CML primary patient cells. Besides, IX can affect LSC survival, inhibit the colony-forming ability, and reduce LSC frequency. In vivo results showed that IX can relieve the tumor burden in patient-derived xenograft (PDX) model and prolong the lifespan. We observed that compound IX can not only decrease telomerase activity, but also affect the alternative lengthening of telomeres. In addition, IX can inhibit both the canonical and non-canonical Wnt pathways. Our data suggested this novel compound IX as a promising candidate for drug-resistant leukemia therapy.

Lmod3 promotes myoblast differentiation and proliferation via the AKT and ERK pathways.

Mutations in the Lmod3 gene have been identified as a genetic cause of nemaline myopathy. However, the mechanism underlying this disease and the function of Lmod3 remain largely unknown. In this study, we found that Lmod3 knockdown in C2C12 cells impaired myoblast differentiation, whereas enforced Lmod3 expression enhanced such differentiation. We also discovered that myoblast proliferation was promoted by Lmod3 overexpression but impeded by its knockdown. Additionally, knockdown of Lmod3 led to apoptosis in myoblasts. Concurrently, forced Lmod3 expression in C2C12 cells contributed to activation of the AKT and ERK pathways during myoblast differentiation and proliferation, respectively. Conversely, knockdown of Lmod3 in C2C12 cells produced the opposite results. Furthermore, administration of IGF-1, a booster of both AKT and ERK pathways, partially rescued the inhibitory effect of Lmod3 knockdown on both differentiation and proliferation of C2C12 cells. These results suggest that Lmod3 promotes differentiation and proliferation of myoblasts through the AKT and ERK pathways, respectively.

TNFSF15 facilitates human umbilical cord blood haematopoietic stem cell expansion by activating Notch signal pathway.

The lack of efficient ex vivo expansion methods restricts clinical use of haematopoietic stem cells (HSC) for the treatment of haematological malignancies and degenerative diseases. Umbilical cord blood (UCB) serves as an alternative haematopoietic stem cell source. However, currently what limits the use of UCB-derived HSC is the very low numbers of haematopoietic stem and progenitor cells available for transplantation in a single umbilical cord blood unit. Here, we report that TNFSF15, a member of the tumour necrosis factor superfamily, promotes the expansion of human umbilical cord blood (UCB)-derived HSC. TNFSF15-treated UCB-HSC is capable of bone marrow engraftment as demonstrated with NOD/SCID or NOD/Shi-SCID/IL2Rgnull (NOG) mice in both primary and secondary transplantation. The frequency of repopulating cells occurring in the injected tibiae is markedly higher than that in vehicle-treated group. Additionally, signal proteins of the Notch pathway are highly up-regulated in TNFSF15-treated UCB-HSC. These findings indicate that TNFSF15 is useful for in vitro expansion of UCB-HSC for clinical applications. Furthermore, TNFSF15 may be a hopeful selection for further UCB-HSC application or study.

Genome-wide identification and analysis of heterotic loci in three maize hybrids.

Heterosis, or hybrid vigour, is a predominant phenomenon in plant genetics, serving as the basis of crop hybrid breeding, but the causative loci and genes underlying heterosis remain unclear in many crops. Here, we present a large-scale genetic analysis using 5360 offsprings from three elite maize hybrids, which identifies 628 loci underlying 19 yield-related traits with relatively high mapping resolutions. Heterotic pattern investigations of the 628 loci show that numerous loci, mostly with complete-incomplete dominance (the major one) or overdominance effects (the secondary one) for heterozygous genotypes and nearly equal proportion of advantageous alleles from both parental lines, are the major causes of strong heterosis in these hybrids. Follow-up studies for 17 heterotic loci in an independent experiment using 2225 F2 individuals suggest most heterotic effects are roughly stable between environments with a small variation. Candidate gene analysis for one major heterotic locus (ub3) in maize implies that there may exist some common genes contributing to crop heterosis. These results provide a community resource for genetics studies in maize and new implications for heterosis in plants.

Sesquiterpenoids isolated from the flower of Inula japonica as potential antitumor leads for intervention of paclitaxel-resistant non-small-cell lung cancer.

Three new sesquiterpene lactone dimers (1-3) were isolated from the flowers of Inula japonica together with twenty-two known sesquiterpene derivatives (4-25). Their structures were established on the basis of detailed spectroscopic analyses. All isolates were evaluated for their antiproliferative activities against paclitaxel-resistant human non-small-cell lung cancer cell line A549/PTX. The preliminary structure-activity relationship was discussed. Compound 24 exhibited the most potent effect with the IC50 value of 0.34 ± 0.10 µM, even more active than the clinically used drug paclitaxel (PTX, IC50 = 1.40 ± 0.52 µM). Compound 24 showed significant efficacy of arresting the cell cycle at the G2-M stage, inducing apoptosis through mitochondria-mediated pathway, and inhibiting cell migration and invasion. Furthermore, compound 24 could reverse multidrug resistance through suppressing the expression of ABC family proteins.

Sesquiterpenoids from the roots of Inula helenium inhibit acute myelogenous leukemia progenitor cells.

One new eudesmane sesquiterpenoid, 11ß-hydroxy-13-chloro-eudesm-5-en-12, 8-olide (1), was isolated from the roots of Inula helenium together with nine eudesmanolides (2-10) and one germacranolide (11). Their structures were elucidated on the basis of detailed spectroscopic analyses. All isolates were evaluated for their antiproliferative activities against human leukemia stem-like cell line KG1a. Compound 10 exhibited the most potent effect with the IC50 value of 3.36 ±â€¯0.18 µM. A further investigation revealed that compound 10 could significantly induce apoptosis of KG1a cells. Additionally, compound 10 had an obvious effect on the levels of apoptosis-related proteins (Bcl-2, Bax, cytochrome c, caspase 9 and caspase 3), indicating that the antiproliferative effect of compound 10 on KG1a cells might be mediated through a mitochondria-dependent apoptotic pathway.

Design and synthesis of parthenolide-SAHA hybrids for intervention of drug-resistant acute myeloid leukemia.

A series of parthenolide-SAHA hybrids were synthesized and evaluated for their anti-AML activities against HL-60 and HL-60/ADR cell lines. The most active compound 26 exhibited high activity against HL-60/ADR cell line with IC50 value of 0.15 µM, which demonstrated 16.8-fold improvement compared to that of the parent compound PTL (IC50 = 2.52 µM). Moreover, it was six times more potent than the reference drug SAHA (IC50 = 0.90 µM) and fifty-one times more potent than ADR (IC50 = 7.72 µM). The preliminary molecular mechanism of 26 indicated that compound 26 could significantly induce apoptosis of HL-60/ADR cells. The effect of compound 26 was mainly through mitochondria pathway. Further investigation revealed that the protein level of HDAC1 and HDAC6 were reduced after the treatment of compound 26 with a dose-dependent manner. Compound 26 could significantly decrease ABCC1 expression, which increased the accumulation of intracellular drug for overcoming the drug resistance. On the base of these results, compound 26 might be considered as a promising candidate for further evaluation as a potential anti-AML drug.

Ovatodiolides: Scalable Protection-Free Syntheses, Configuration Determination, and Biological Evaluation against Hepatic Cancer Stem Cells.

A concise, scalable, six-step (longest linear sequence) synthetic route to ovatodiolide scaffolds was developed for the first time. This protecting-group-free route features tandem ring-opening metathesis/ring-closing metathesis reactions to install the macrocycle-fused butenolide ring and a tandem allylboration/lactonization to build the α-methylene-γ-lactone. Our syntheses have enabled the determination of the hitherto unknown stereochemical configurations of this family of natural products. Preliminary tests of structure-activity relationships were conducted with four natural ovatodiolides and three analogues. Further assays indicated that the synthetic natural product isoovatodiolide can significantly decrease the population of hepatic cancer stem cells and reduce the tumorsphere-forming capability of HepG2 cells.

Total Synthesis of the Highly N-Methylated Peptide Jahanyne.

Total synthesis of jahanyne (1) was achieved from commercially available materials on a 38 mg scale. The Boc- N-Me- L-Val-OH fragment along with the HATU/DIPEA coupling condition was applied to avoid the diketopiperazine side reaction in solution phase synthesis.

Synthesis and biological evaluation of dithiocarbamate esters of parthenolide as potential anti-acute myelogenous leukaemia agents.

A series of dithiocarbamate esters of parthenolide (PTL) was designed, synthesised, and evaluated for their anti- acute myelogenous leukaemia (AML) activities. The most promising compound 7l showed greatly improved potency against AML progenitor cell line KG1a with IC50 value of 0.7 µM, and the efficacy was 8.7-folds comparing to that of PTL (IC50 = 6.1 µM). Compound 7l induced apoptosis of total primary human AML cells and leukaemia stem cell (LSCs) of primary AML cells while sparing normal cells. Furthermore, 7l suppressed the colony formation of primary human leukaemia cells. Moreover, compound 12, the salt form of 7l, prolonged the lifespan of mice in two patient-derived xenograft models and had no observable toxicity. The preliminary molecular mechanism study revealed that 7l-mediated apoptosis is associated with mitogen-activated protein kinase signal pathway. On the basis of these investigations, we propose that 12 might be a promising drug candidate for ultimate discovery of anti-LSCs drug.

Synthesis of Cucurbitacin B Derivatives as Potential Anti-Hepatocellular Carcinoma Agents.

Cucurbitacin B shows potent activity against tumor cells, but its high toxicity limits its application in the clinic. A series of cucurbitacin B derivatives was synthesized and evaluated for their anti-hepatocellular carcinoma (HCC) activities against the HepG-2 cell line. These compounds were also tested for their toxicity against the L-O2 normal cell line. The compound with the most potential, 10b, exhibited potent activity against the HepG-2 cell line with an IC50 value of 0.63 µM. Moreover, compound 10b showed the highest TI value (4.71), which is a 14.7-fold improvement compared to its parent compound cucurbitacin B. A preliminary molecular mechanism study of 10b indicated that 10b could inhibit P-STAT3 to induce the activation of mitochondrial apoptotic pathways. An in vivo acute toxicity study indicated that the compound 10b has preferable safety and tolerability compared with cucurbitacin B. These findings indicate that compound 10b might be considered as a lead compound for exploring effective anti-HCC drugs.

Cyclic Depsipeptide BE-43547A2 : Synthesis and Activity against Pancreatic Cancer Stem Cells.

Asymmetric total synthesis of the cyclic depsipeptide BE-43547A2 was achieved in 15 linear steps on a 350 mg scale in one batch. The synthesis features the highly diastereoselective construction of an α-hydroxy-ß-ketoamide through α-hydroxylation with a d.r. of up to 86:1. BE-43547A2 significantly reduces the percentage of pancreatic cancer stem cells (PCSCs) in Panc-1 cell cultures, and dramatically reduces the tumorsphere-forming capability of Panc-1 cells. An in vivo tumor-initiation assay, a gold standard for cancer stem cell assays, confirmed that BE-43547A2 can abolish the tumorigenesis of Panc-1 cells. The anti-PCSC activity of BE-43547A2 could make this depsipeptide scaffold a promising starting point for discovering new PCSC-targeting drugs.