Search

Simple Summary: Chouioia cunea Yang is a crucial natural enemy in the management of the fall webworm (Hyphantria cunea), which is a globally significant quarantine pest. The feeding behavior, dispersal, and high reproductive capacity of Hy. cunea cause substantial economic and ecological damage. Apart from Hy. cunea, C. cunea also exhibits parasitic behavior toward various Lepidoptera species, including those from the families Lasiocampidae, Lymantridae, Notodontidae, Psychidae, and Noctuidae. It also targets certain Coleoptera species, such as those from the families Chrysomelidae and Coccinellidae, most of which are leaf-eating pests. C. cunea feeds on the hemolymph of its host. Variations in the hemolymph's nutrient content, chemical properties, and immune response among different host species may influence the gut microbiome of the wasps. Moreover, microbial communities present in the host can be ingested by the parasitic wasps, leading to differences in their gut microbiome compositions depending on the host. In this study, we investigated the developmental patterns and intestinal microbiota diversity of C. cunea parasitizing various hosts. Our objective was to elucidate how different hosts impact the development and intestinal microbiota composition of C. cunea. This research provides scientific evidence for optimizing biological control strategies and applications involving insect pathogenic microorganisms. Chouioia cunea are known to exploit in varying degrees a wide range of lepidopteran species and its offspring development may vary with host species. This study examined its preimaginal development and larval gut microbiota in parasitizing five folivorous lepidopteran hosts including Hyphantria cunea (referred to thereafter as CcHc), Antherea pernyi (CcAp), Helicoverpa armigera (CcHa), Spodoptera exigua (CcSe), and Spodoptera frugiperda (CcSf). Though rates of parasitism and offspring eclosion did not change with host species, the development period and number of offspring eclosed varied with hosts, with the shortest period in CcSf and the highest number from CcAp. For offspring larval gut microbiota, though phylum Proteobacteria was dominant for attacking CcAp, Firmicutes was so for the other hosts. All microbial genera except Enterococcus were less abundant for CcSf than the other hosts. The database-based predictions indicate a significant positive correlation between Cutibacterium and Aureimonas with the relative number of wasp emergence, while Blastomonas exhibits a strong positive association with the developmental period. Our results imply the potential relevance of the gut microbial community in offspring larvae to host species attacked by C. cunea. [ABSTRACT FROM AUTHOR]

Cinnamaldehyde (CA) showed potent activity against melanoma in our previous study, and the structure of unsaturated aldehydes is envisaged to play a role. Nevertheless, its limited drug availability restricts its clinical application. Therefore, a series of CA analogues were synthesized to evaluate their anti-melanoma activities across various melanoma cell lines. These compounds were also tested for their toxicity against the different normal cell lines. The compound with the most potential, CAD-14, exhibited potent activity against the A375, A875 and SK-MEL-1 cells, with IC50 values of 0.58, 0.65, and 0.82 µM, respectively. A preliminary molecular mechanism study of CAD-14 indicated that it could inhibit the p38 pathway to induce apoptosis, and suppress tumor growth by inhibiting the expression of ENO1. Furthermore, an acute toxicity study depicted that CAD-14 has better safety and tolerability than CA in vivo. These findings indicate that CAD-14 might be a lead compound for exploring effective anti-melanoma drugs. [ABSTRACT FROM AUTHOR]

Hen eggs are one of the most popular foods worldwide, and their safety is critical. Employing 16S rRNA full-length sequencing is an effective way to identify microorganisms on or in eggs. Here, hen eggs collected from poultry farms over four seasons, as well as from markets in Shanghai, were analyzed with third-generation sequencing. Firmicutes (44.46%) and Proteobacteria (35.78%) were the two dominant phyla, and Staphylococcus, Acinetobacter, Aerococcus, Psychrobacter, and Lactobacillus were the dominant genera. The dominant genera on the eggshell surfaces from the farms varied with the seasons, and the highest contamination of Staphylococcus (32.93%) was seen in the eggs collected during the summer. For the market samples, Pseudomonas was the most abundant in content, with Staphylococcus being the most-often genera found on the eggshell surfaces. Moreover, several potential pathogenic bacteria including Riemerella anatipestifer (species), Klebsiella (genus), and Escherichia/shigella (genus) were detected in the samples. The results revealed the impacts of weather on the microbiota deposited on an eggshell's surface, as well as the impacts due to the differences between the contents and the surface. The results can help disinfect eggs and guide antibiotic selection. [ABSTRACT FROM AUTHOR]

In recent decades, freak waves, characterized by their unusual high amplitude, sharp crest, and concentrated energy, have attracted researchers' attention due to their potential threat to marine structures. Green-water loads caused by freak waves can be significant and may lead to local damage to the ship structures. Therefore, this paper focuses on the study of green-water loads and examines the structural responses of ship bow structures under the influence of the green-water loads caused by freak waves. Firstly, a three-dimensional numerical wave tank is established in which the superposition model is used to generate freak waves. Validations on the freak-wave generation, ship motion response and the wave loading are carried out to verify the present solvers. The simulation on the interaction between the freak wave and the ship are conducted to obtain the interaction process and green-water loads. Secondly, a finite element (FEM) model of the ship bow is built, on which the green-water loads are applied to calculate the structural responses. Finally, the displacement and stress of the deck and breakwater structures are analyzed. It is found that green water events caused by freak waves can generate enormous impact forces on the bow deck and breakwater, resulting in severe structural responses and even possible damage to the structures. The local strength of structures under freak waves needs to be considered in practical engineering applications. [ABSTRACT FROM AUTHOR]

Chlorpyrifos (CHL), profenofos (PRO) and cypermethrin (CYP) are widely used in combination to increase crop yields. However, these three pesticides can cause serious harm to human health and do not easily degrade. In this study, a novel visible paper sensor has been prepared successfully and different colorimetric reactions were utilized to detect the three pesticides simultaneously. The sensor was constructed by grafting a zwitterionic polymer onto a cellulose filter (CF) and placing it on a glass surface modified with PDMS. The branch shape was designed to form multiple detection areas, which were modified with specific pesticides and corresponding chromogenic reagents. The as-prepared colorimetric platform exhibited high sensitivity, a short detection time, a good linear response and a low detection limit (LOD) for the three pesticides (chlorpyrifos: y = 46.801 − 1.939x, R2 = 0.983, LOD = 0.235 mg/L; profenofos: y = 40.068 + 42.5x, R2 = 0.988, LOD = 4.891 mg/L; cypermethrin: y = 51.993 + 1.474x, R2 = 0.993, LOD = 4.053 mg/L). The comparison of the results obtained by the proposed paper sensor and those obtained by spectrophotometry further revealed the stability and reliability of the paper sensor. In particular, the color intensity of the interaction between the pesticides and coloring agents could be directly observed by the human eye. The consistency of the colorimetric/optical assay was proven in real target pesticide samples. Thus, this sensing strategy provides a portable, cost-effective, accurate and visualized paper platform, which could be suitable for application in the fruit and vegetable industry for monitoring CHL, PRO and CYP in parallel. [ABSTRACT FROM AUTHOR]

The selection of the optimizer is critical for convergence in the field of on-chip training. As one second moment optimizer, adaptive moment estimation (ADAM) shows a significant advantage compared with non-moment optimizers such as stochastic gradient descent (SGD) and first-moment optimizers such as Momentum. However, ADAM is hard to implement on hardware due to the computationally intensive operations, including square, root extraction, and division. This work proposed Hardware-ADAM (HW-ADAM), an efficient fixed-point accelerator for ADAM highlighting hardware-oriented mathematical optimizations. HW-ADAM has two designs: Efficient-ADAM (E-ADAM) unit reduced the hardware resource consumption by around 90% compared with the related work. E-ADAM achieved a throughput of 2.89 MUOP/s (Million Updating Operation per Second), which is 2.8× of the original ADAM. Fast-ADAM (F-ADAM) unit reduced 91.5% flip-flops, 65.7% look-up tables, and 50% DSPs compared with the related work. The F-ADAM unit achieved a throughput of 16.7 MUOP/s, which is 16.4× of the original ADAM. [ABSTRACT FROM AUTHOR]

The hardware architecture of a deep-neural-network-based feature point extraction method is proposed for the simultaneous localization and mapping (SLAM) in robotic applications, which is named the Feature Point based SLAM Network (FPSNET). Some key techniques are deployed to improve the hardware and power efficiency. The data path is devised to reduce overall off-chip memory accesses. The intermediate data and partial sums resulting in the convolution process are stored in available on-chip memories, and optimized hardware is employed to compute the one-point activation function. Meanwhile, address generation units are used to avoid data overlapping in memories. The proposed FPSNET has been designed in 65 nm CMOS technology with a core area of 8.3 mm2. This work reduces the memory overhead by 50% compared to traditional data storage for activation and overall by 35% for on-chip memories. The synthesis and simulation results show that it achieved a 2.0× higher performance compared with the previous design while achieving a power efficiency of 1.0 TOPS/W, which is 2.4× better than previous work. Compared to other ASIC designs with close peak throughput and power efficiency performance, the presented FPSNET has the smallest chip area (at least 42.4% reduction). [ABSTRACT FROM AUTHOR]

Non-small-cell lung cancer (NSCLC) is a prevalent malignant tumor with high morbidity and mortality rates worldwide. Although surgical resection, adjuvant radiotherapy/chemotherapy, and targeted molecular therapy are the cornerstones of NSCLC treatment, NSCLC is associated with high recurrence rates and drug resistance. This study analyzed the potential targets and pathways of 6-Shogaol (6-SH) in NSCLC, showing that 6-SH binds to heat-shock 60 kDa protein (HSP60) in A549 cells, induces cell apoptosis, and arrests the cell cycle possibly by disrupting the mitochondrial function. HSP60 was identified as the target of 6-SH and 6-SH-induced HSP60 degradation which was mediated by the proteasome. The binding of 6-SH with HSP60 altered its stability, inhibited the ERK, Stat3, PI3K, Akt, and mTOR signaling pathways, and Tax acted synergistically with 6-SH, indicating that 6-SH could be developed as a potential therapeutic agent for an NSCLC treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Boer goat is a world-famous meat-type goat breed that underwent long-term artificial selection from African indigenous animals. The current study displayed the genome-wide selection signature analyses of South African indigenous goat (AF), African Boer (BH), and Australian Boer (AS), to investigate the hereditary basis of artificial selection in different stages. Moreover, the θπ, FST, and XP-CLR methods were used to search for the candidate signatures of positive selection in Boer goats. Ten genes (e.g., BMPR1B, DNER, ITGAL, and KIT) under selection in both groups were identified and are potentially responsible for reproduction, metabolism, growth, and development. This study provided a comprehensive overview of genomic variations in Boer goat, which may provide a basis for further resource protection and improvement of this breed. Boer goats, as kemp in meat-type goats, are selected and bred from African indigenous goats under a long period of artificial selection. Their advantages in multiple economic traits, particularly their plump growth, have attracted worldwide attention. The current study displayed the genome-wide selection signature analyses of South African indigenous goat (AF), African Boer (BH), and Australian Boer (AS) to investigate the hereditary basis of artificial selection in different stages. Four methods (principal component analysis, nucleotide diversity, linkage disequilibrium decay, and neighbor-joining tree) implied the genomic diversity changes with different artificial selection intensities in Boer goats. In addition, the θπ, FST, and XP-CLR methods were used to search for the candidate signatures of positive selection in Boer goats. Consequently, 339 (BH vs. AF) and 295 (AS vs. BH) candidate genes were obtained from SNP data. Especially, 10 genes (e.g., BMPR1B, DNER, ITGAL, and KIT) under selection in both groups were identified. Functional annotation analysis revealed that these genes are potentially responsible for reproduction, metabolism, growth, and development. This study used genome-wide sequencing data to identify inheritance by artificial selection. The results of the current study are valuable for future molecular-assisted breeding and genetic improvement of goats. [ABSTRACT FROM AUTHOR]

A novel rapid and cost-effective pre-processing method for the simultaneous determination of pyrethroid pesticides in vegetables has been developed and validated. The process of pesticide extraction was carried out by the QuEChERS (quick, easy, cheap, effective, rugged and safe) method combined with filtration by filter paper, and cleanup was carried out by the multi-plug-filtration-cleanup (m-PFC) method with no centrifuge program during the whole process. The pre-processing method is optimized for gas chromatography (GC). The process is convenient and time saving, requiring just a few seconds per sample. The recovery rate (70–120%), limit of detection (0.0001–0.007 mg/kg), precision (0.2–9.3%) and accuracy for each analyte were determined in 10 representative vegetables with good results. Finally, the feasibility of the developed method was further confirmed by the successful determination of pyrethroid-pesticide residues in pyrethroid-containing practical samples within the processing method coupled with thin-layer chromatography and a colloidal-gold test strip. [ABSTRACT FROM AUTHOR]

Deltamethrin (DEL) is one of the most commonly used pyrethroid pesticides that can cause serious harms to the ecological environment and human health. Herein, we have developed a paper-based colorimetric sensor impregnated with gold nanoparticles (AuNPs) for on-site determination of DEL pesticide. AuNPs show obvious color change on paper device with the presence of DEL. Measuring the gray intensity of the AuNPs on the reaction zone of the paper sensor allows accurate quantitative analysis. The detection mechanism of DEL on paper sensor was confirmed by UV-Vis spectrophotometry (UV-Vis), Fourier transform infrared spectroscopy (FT-IR), and transmission electron microscope (TEM). Under optimal conditions, the colorimetric sensor exhibited high sensitivity, rapid detection, and low detection limit within the values stipulated by Chinese detection standards (LOD = 0.584 mg/L). Besides, detecting DEL in vegetable and fruit samples also gave satisfying results, which were much consistent with those obtained by spectrophotometry. Overall, this work provided a user-friendly, cost-effective and visualized detection platform, which could be applied to rapidly detect DEL pesticides in the food safety field. [ABSTRACT FROM AUTHOR]

Simple Summary: The follicle development (FD) of a goat is precisely regulated by various noncoding RNAs (ncRNAs), especially by the regulatory mechanism of competing endogenous RNAs (ceRNAs). This study aimed to determine the expression patterns of messenger RNA (mRNA), long noncoding RNA, microRNA, and circular RNA during the FD of Dazhu black goats by whole-transcriptomic sequencing and analyze the regulatory mechanism of the ncRNA and ceRNA regulatory network. The results may lay a foundation for further research on FD and improving the reproductive performance of goats. The follicle development (FD) is an important factor determining litter size in animals. Recent studies have found that noncoding RNAs (ncRNAs) play an important role in FD. In particular, the role of the regulatory mechanism of competing endogenous RNAs (ceRNAs) that drive FD has attracted increasing attention. Therefore, this study explored the genetic basis of goat FD by obtaining the complete follicular transcriptome of Dazu black goats at different developmental stages. Results revealed that 128 messenger RNAs (mRNAs), 4 long noncoding RNAs (lncRNAs), 49 microRNAs (miRNAs), and 290 circular RNAs (circRNAs) were significantly differentially expressed (DE) between large and small follicles. Moreover, DEmRNAs were enriched in many signaling pathways related to FD, as well as GO terms related to molecular binding and enzyme activity. Based on the analysis of the ceRNA network (CRN), 34 nodes (1 DElncRNAs, 10 DEcircRNAs, 14 DEmiRNAs, and 9 DEmRNAs) and 35 interactions (17 DEcircRNAs–DEmRNAs, 2 DElncRNAs–DEmiRNAs, and 16 DEmRNA–DEmiRNAs) implied that the CRN could be involved in the FD of goats. In conclusion, we described gene regulation by DERNAs and lncRNA/circRNA–miRNA–mRNA CRNs in the FD of goats. This study provided insights into the genetic basis of FD in precise transcriptional regulation. [ABSTRACT FROM AUTHOR]

Simple Summary: Previous research found that FATP1 plays an important role in the regulation of fatty acid metabolism and lipid accumulation in pig and chicken, but its function has not been explored in bovine adipocyte yet. In this study, we investigated the effect of FATP1 expression on preadipocyte differentiation in Qinchuan cattle using overexpression and interference assays. Our results reveal that FATP1 overexpression promoted preadipocyte differentiation, lipid droplet formation, and the expression of LPL and PPARγ, while FATP1 interference had the opposite effects on adipocyte differentiation and fat deposition. Following FATP1 overexpression and FATP1 interference in adipocytes, RNA-seq analysis identified that SLPI, STC1, SEMA6A, TNFRSF19, SLN, PTGS2, ADCYP1, FADS2, and SCD genes were differentially expressed. Pathway analysis revealed that the PPAR signaling pathway, AMPK signal pathway, and Insulin signaling pathway were enriched with differentially expressed genes. We propose that the FATP1 gene may affect the beef quality by involving adipocyte differentiation and lipid deposition, and may shed new light on the formation mechanisms of adipose tissues. FATP1 plays an important role in the regulation of fatty acid metabolism and lipid accumulation. In this study, we investigated the patterns of FATP1 expression in various tissues obtained from calf and adult Qinchuan cattle, and in differentiating adipocytes. Next, we investigated the effect of FATP1 expression on preadipocyte differentiation in Qinchuan cattle using overexpression and interference assays. We also identified the differentially expressed genes (DEGs) and pathways associated with FATP1 overexpression/interference. Our results reveal that FATP1 was broadly expressed in heart, kidney, muscle, small intestine, large intestine, and perirenal fat tissues. While FATP1 overexpression promoted preadipocyte differentiation, fat deposition, and the expression of several genes involved in fat metabolism, FATP1 interference had the opposite effects on adipocyte differentiation. Following FATP1 overexpression and FATP1 interference in adipocytes, RNA-seq analysis was performed to identify DEGs related to fat metabolism. The DEGs identified include SLPI, STC1, SEMA6A, TNFRSF19, SLN, PTGS2, ADCYP1, FADS2, and SCD. Pathway analysis revealed that the DEGs were enriched in the PPAR signaling pathway, AMPK signal pathway, and Insulin signaling pathway. Our results provide an in-depth understanding of the function and regulation mechanism of FAPT1 in fat metabolism. [ABSTRACT FROM AUTHOR]

The fabrication and luminescent performance of novel phosphors Na2YMg2V3O12:Dy3+ were investigated by a conventional solid-state reaction method. Under near-UV light, the Na2YMg2V3O12 host self-activated and released a broad emission band (400–700 nm, with a peak at 524 nm) ascribable to charge transfer in the (VO4)3− groups. Meanwhile, the Na2YMg2V3O12:Dy3+ phosphors emitted bright yellow light within both the broad emission band of the (VO4)3- groups and the sharp peaks of the Dy3+ ions at 490, 582, and 663 nm at a quenching concentration of 0.03 mol. The emission of the as-prepared Na2YMg2V3O12:Dy3+ phosphors remained stable at high temperatures. The obtained phosphors, commercial Y2O3:Eu3+ red phosphors, and BaMgAl10O17:Eu2+ blue phosphors were packed into a white light-emitting diode (WLED) device with a near-UV chip. The designed WLED emitted bright white light with good chromaticity coordinates (0.331, 0.361), satisfactory color rendering index (80.2), and proper correlation to a color temperature (7364 K). These results indicate the potential utility of Na2YMg2V3O12:Dy3+ phosphor as a yellow-emitting phosphor in solid-state illumination. [ABSTRACT FROM AUTHOR]

At present, melanoma is a common malignant tumor with the highest mortality rate of all types of skin cancer. Although the first option for treating melanoma is with chemicals, the effects are unsatisfactory and include poor medication response and high resistance. Therefore, developing new medicines or a novel combination approach would be a significant breakthrough. Here, we present cinnamaldehyde (CA) as a potential candidate, which exerted an antitumor effect in melanoma cell lines. Chemical biology methods of target fishing, molecular imaging, and live cell tracing by an alkynyl–CA probe revealed that the α-enolase (ENO1) protein was the target of CA. The covalent binding of CA with ENO1 changed the stability of the ENO1 protein and affected the glycolytic activity. Furthermore, our results demonstrated that dacarbazine (DTIC) showed a high promoting effect with CA for antimelanoma both in vivo and in vitro. The combination improved the DTIC cell cycle arrest in the S phase and markedly impacted melanoma growth. As a covalent inhibitor of ENO1, CA combined with DTIC may be beneficial in patients with drug resistance in antimelanoma therapy. [ABSTRACT FROM AUTHOR]

Lunasin, a bioactive peptide, was originally found in soybeans, and it has exhibited multiple biological functions. On the basis of previous studies, salt stress was found able to induce changes in many polypeptides and translatable mRNA levels in plants. Salt stress was applied to soybean germination, with water treatment as a control group, to evaluate the effects of salt stimulation on lunasin accumulation and activity during soybean germination. Lunasin content gradually increased in the control group during germination, reached the highest level after six hours of imbibition, and then slowly decreased. Under salt exposure, lunasin content showed a similar trend to that of the control group. The lunasin content in salt-treated soybean was significantly higher than that in the control group. Lunasin peptide was purified from soybean after six hours of imbibition and it was then used for function evaluation. Purified lunasin from salt-stress-germinated soybean (6 h-LSGS) exhibited stronger antioxidant activity than lunasin from water-treatment-germinated soybean (6 h-LWGS) and soybean seed without imbibition (DRY). The 6 h-LSGS presented anti-inflammatory activity on LPS-induced macrophage cells (p < 0.05) by suppressing the release of nitric oxide (NO) and proinflammatory cytokines, including IL-1 and IL-6. The gene expression of NOS, IL-1, IL-6, and TNF-α was significantly inhibited by 6 h-LSGS. Further, 6 h-LSGS exhibited superior antiproliferation activity on human breast-cancer cells MDA-MB-231 when compared to 6 h-LWGS and DRY. Overall, this study offers a feasible elicitation strategy for enhancing lunasin accumulation and its properties in soybean for possible use in functional food. [ABSTRACT FROM AUTHOR]

Simple Summary: In this article explore the role of the bovine TP53INP2 gene in adipocyte differentiation and its function in autophagy during the early stage of adipocyte differentiation. In our work we found that a novel, important autophagy related protein TP53INP2 can activate autophagy during the early stage of differentiation in bovine adipocytes and positively regulate adipocyte differentiation by affecting autophagy. Furthermore, we demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) also contributed to the function of TP53INP2 in modulating adipocyte differentiation. The study of the function of bovine TP53INP2 gene on adipocyte differentiation has not been reported, therefore, we have decided to focus on Qinchuan cattle, one of the five important cattle breeds in China. We propose that the TP53INP2 gene may affect the meat quality of Qinchuan cattle by regulating lipid deposition, and may shed new light on the developmental mechanisms of adipose development. Tumor protein p53 inducible nuclear protein 2 (TP53INP2) is a key positive regulator of autophagy, and it has been shown to modulate adipocyte differentiation. However, the molecular mechanism involved in autophagy regulation during adipocyte differentiation has not been clarified. Our experiments were intended to investigate whether TP53INP2 is involved in the regulation of autophagy during bovine adipocyte differentiation and how TP53INP2 affects the differentiation of bovine adipocytes. In our research, using RT-qPCR and Western blot methods, we found that the overexpression of TP53INP2 resulted in the upregulation of adipogenesis and autophagy-related genes, and autophagy flux and the degree of differentiation were detected by LipidTOX™ Deep Red Neutral Lipid staining and dansylcadaverine staining, respectively. The knockdown of TP53INP2 produced results that were the inverse of those produced by the overexpression of TP53INP2. Overall, our results suggested that TP53INP2 can activate autophagy during the early stage of differentiation in bovine adipocytes and positively regulate adipocyte differentiation by affecting autophagy. Additionally, peroxisome proliferator-activated receptor gamma (PPARγ) also contributed to the function of TP53INP2 in modulating adipocyte differentiation. [ABSTRACT FROM AUTHOR]

The demand for flexible and wearable electronic devices with excellent stretchability and sensitivity is increasing, especially for human motion detection. In this work, a simple, low-cost and convenient strategy has been employed to fabricate flexible strain sensor with a composite of carbon black and silver nanoparticles as sensing materials and thermoplastic polyurethane as matrix. The strain sensors thus prepared possesses high stretchability and good sensitivity (gauge factor of 21.12 at 100% tensile strain), excellent static (almost constant resistance variation under 50% strain for 600 s) and dynamic (100 cycles) stability. Compared with bare carbon black-based strain sensor, carbon black/silver nanoparticles composite-based strain sensor shows ~18 times improvement in sensitivity at 100% strain. In addition, we discuss the sensing mechanisms using the disconnection mechanism and tunneling effect which results in high sensitivity of the strain sensor. Due to its good strain-sensing performance, the developed strain sensor is promising in detecting various degrees of human motions such as finger bending, wrist rotation and elbow flexion. [ABSTRACT FROM AUTHOR]

Isoxanthohumol is a unique prenylflavonoid with the highest content in beer. Isoxanthohumol has multiple bioactivities and has recently received considerable attention in the scientific community. Nonetheless; its effect on drug resistant cancer cells has rarely been studied. In this paper; we investigated the synergistic effect of isoxanthohumol and doxorubicin on doxorubicin resistant MCF-7/ADR cells. Our results showed that isoxanthohumol sensitized the cytotoxic effect of doxorubicin on MCF-7/ADR cells via increased proliferation inhibition and apoptosis stimulation. Molecular mechanism studies further demonstrated that isoxanthohumol inhibited ABCB1-mediated doxorubicin efflux; stimulated the ATPase activity of ABCB1 (ATP-binding cassette sub-family B member 1); and acted as an ABCB1 substrate. Molecular docking results suggested that isoxanthohumol bound to the central transmembrane domain of ABCB1 and its binding site overlapped with the doxorubicin binding site. The present studies demonstrated that isoxanthohumol was a competitive ABCB1 inhibitor which reversed ABCB1-mediated doxorubicin resistance in MCF-7/ADR cells; and therefore could be further developed to help with overcoming ABCB1-mediated drug resistance., Competing Interests: The authors declare no conflict of interest.

Ingenol mebutate possesses significant cytotoxicity and is clinically used to treat actinic keratosis. However, ingenol mebutate undergoes acyl migration which affects its bioactivity. Compound 3-O-angeloyl-20-O-acetyl ingenol (AAI, also known as 20-O-acetyl-ingenol-3-angelate or PEP008) is a synthetic derivative of ingenol mebutate. In this work, we report the AAI synthesis details and demonstrate AAI has higher cytotoxicity than ingenol mebutate in a chronic myeloid leukemia K562 cell line. Our data indicate that the increased activity of AAI originates from the improved intracellular stability of AAI rather than the increased binding affinity between AAI and the target protein protein kinase Cδ (PKCδ). AAI inhibits cell proliferation, induces G2/M phase arrest, disrupts the mitochondrial membrane potential, and stimulates apoptosis, as well as necrosis in K562 cells. Similar to ingenol mebutate, AAI activates PKCδ and extracellular signal regulated kinase (ERK), and inactivates protein kinase B (AKT). Furthermore, AAI also inhibits JAK/STAT3 pathway. Altogether, our studies show that ingenol derivative AAI is cytotoxic to K562 cells and modulates PKCδ/ERK, JAK/STAT3, and AKT signaling pathways. Our work suggests that AAI may be a new candidate of chemotherapeutic agent.