In Vitro and In Vivo Anti-Cancer Activity of Lasiokaurin in a Triple-Negative Breast Cancer Model.

Due to its intricate heterogeneity, high invasiveness, and poor prognosis, triple-negative breast cancer (TNBC) stands out as the most formidable subtype of breast cancer. At present, chemotherapy remains the prevailing treatment modality for TNBC, primarily due to its lack of estrogen receptors (ERs), progesterone receptors (PRs), and human epidermal growth receptor 2 (HER2). However, clinical chemotherapy for TNBC is marked by its limited efficacy and a pronounced incidence of adverse effects. Consequently, there is a pressing need for novel drugs to treat TNBC. Given the rich repository of diverse natural compounds in traditional Chinese medicine, identifying potential anti-TNBC agents is a viable strategy. This study investigated lasiokaurin (LAS), a natural diterpenoid abundantly present in Isodon plants, revealing its significant anti-TNBC activity both in vitro and in vivo. Notably, LAS treatment induced cell cycle arrest, apoptosis, and DNA damage in TNBC cells, while concurrently inhibiting cell metastasis. In addition, LAS effectively inhibited the activation of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway and signal transducer and activator of transcription 3 (STAT3), thus establishing its potential for multitarget therapy against TNBC. Furthermore, LAS demonstrated its ability to reduce tumor growth in a xenograft mouse model without exerting detrimental effects on the body weight or vital organs, confirming its safe applicability for TNBC treatment. Overall, this study shows that LAS is a potent candidate for treating TNBC.

Natural Prenylated Xanthones as Potential Inhibitors of PI3k/Akt/mTOR Pathway in Triple Negative Breast Cancer Cells.

Three prenylated xanthones, garcinone E (1: ), bannaxanthone D (2: ) and bannanxanthone E (3: ) were isolated from the leaves of Garcinia mckeaniana Graib. Their structures were elucidated by spectral methods and compared with literature data. To evaluate their anti-proliferative effects in tumor cells, firstly, cisplatin was used as a positive control and the effects of compound 1:  - 3: were determined by performing MTT assay in MDA-MB-231, CNE-2 and A549 cancer cells. The results showed compound 1:  - 3: exhibited stronger inhibitory effect than cisplatin in MDA-MB-231. Further effects of compound 1:  - 3: in TNBC MDA-MB-231 and MDA-MB-468 cells were examined by performing cell cycle and apoptosis assays. The results indicated that compound 1:  - 3: had ability to arrest cell cycle at G2/M phase and induce apoptosis. Furthermore, compound 2: significantly down-regulated PI3K, Akt and mTOR levels in both total proteins and phosphorylated form, which is its potential anti-cancer mechanism. These findings indicated that those prenylated xanthones might serve as promising leading compounds for the development of anticancer drug for TNBC.

Arnicolide D Inhibits Triple Negative Breast Cancer Cell Proliferation by Suppression of Akt/mTOR and STAT3 Signaling Pathways.

Triple-Negative Breast Cancer (TNBC) is a most dangerous breast cancer subtype. The naturally occurring sesquiterpene lactone, arnicolide D (AD), has proven effective against a variety of tumors, however, the inhibitory effects of AD against TNBC and the underlying mechanisms remain unclear. In the present study, two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and an MDA-MB-231 xenograft mouse model were employed to investigate the anti-TNBC effects of AD in vitro and in vivo. Cell viability was assessed by MTT assay. Cell cycle arrest and apoptosis were analyzed by flow cytometry. Protein levels were determined by immunoblotting. In vitro studies demonstrated that AD significantly decreased cell viability, and induced G2/M cell cycle arrest and apoptosis. In vivo assays showed that oral administration of 25 or 50 mg/kg AD for 22 days led to a reduction of tumor weights by 24.7% or 41.0%, without appreciable side effects. Mechanistically, AD inhibited the activation of Akt/mTOR and STAT3 signaling pathways. Based on our findings, AD is a promising candidate for development as an adjunctive therapeutic drug for TNBC.

Robust Building Extraction for High Spatial Resolution Remote Sensing Images with Self-Attention Network.

Building extraction from high spatial resolution remote sensing images is a hot spot in the field of remote sensing applications and computer vision. This paper presents a semantic segmentation model, which is a supervised method, named Pyramid Self-Attention Network (PISANet). Its structure is simple, because it contains only two parts: one is the backbone of the network, which is used to learn the local features (short distance context information around the pixel) of buildings from the image; the other part is the pyramid self-attention module, which is used to obtain the global features (long distance context information with other pixels in the image) and the comprehensive features (includes color, texture, geometric and high-level semantic feature) of the building. The network is an end-to-end approach. In the training stage, the input is the remote sensing image and corresponding label, and the output is probability map (the probability that each pixel is or is not building). In the prediction stage, the input is the remote sensing image, and the output is the extraction result of the building. The complexity of the network structure was reduced so that it is easy to implement. The proposed PISANet was tested on two datasets. The result shows that the overall accuracy reached 94.50 and 96.15%, the intersection-over-union reached 77.45 and 87.97%, and F1 index reached 87.27 and 93.55%, respectively. In experiments on different datasets, PISANet obtained high overall accuracy, low error rate and improved integrity of individual buildings.

Total Synthesis-Enabled Systematic Structure-Activity Relationship Study for Development of a Bioactive Alkyne-Tagged Derivative of Neolaxiflorin L.

Neolaxiflorin L (NL) is a low-abundant Isodon 7,20-epoxy- ent-kuarenoid and was found to be a promising anticancer drug candidate in our previous study. In order to study its structure-activity relationship (SAR), a diversity-oriented synthetic route toward two libraries of (±)-NL analogs, including analogs containing different functionalities in the same 7,20-epoxy- ent-kuarene skeleton and analogs with skeletal changes, has been developed. The results of this total synthesis-enabled SAR successfully led to a bioactive alkyne-tagged NL derivative, which could be a useful probe for proteomics studies.

Arnicolide D, from the herb Centipeda minima, Is a Therapeutic Candidate against Nasopharyngeal Carcinoma.

Nasopharyngeal carcinoma (NPC) is a high morbidity and mortality cancer with an obvious racial and geographic bias, particularly endemic to Southeast China. Our previous studies demonstrated that Centipeda minima extract (CME) exhibited anti-cancer effects in human NPC cell lines. Arnicolide C and arnicolide D are sesquiterpene lactones isolated from Centipeda minima. In this study, for the first time, we investigated their anti-NPC effects and further explored the related molecular mechanisms. The effects of both arnicolide C and arnicolide D were tested in NPC cells CNE-1, CNE-2, SUNE-1, HONE1, and C666-1. The results showed that the two compounds inhibited NPC cell viability in a concentration- and time-dependent manner. As the inhibitory effect of arnicolide D was the more pronounced of the two, our following studies focused on this compound. Arnicolide D could induce cell cycle arrest at G2/M, and induce cell apoptosis. The molecular mechanism of cell cycle regulation and apoptosis induction was investigated, and the results showed that arnicolide D could downregulate cyclin D3, cdc2, p-PI3K, p-AKT, p-mTOR, and p-STAT3, and upregulate cleaved PARP, cleaved caspase 9, and Bax. Regulation of cyclin B1, cdk6, and Bcl-2 expression by arnicolide D showed dynamic changes according to dose and time. Taken together, arnicolide D modulated the cell cycle, activated the caspase signaling pathway, and inhibited the PI3K/AKT/mTOR and STAT3 signaling pathways. These findings provide a solid base of evidence for arnicolide D as a lead compound for further development, and act as proof for the viability of drug development from traditional Chinese medicines.

Comparative Evaluation of Chemical Profiles of Pyrrosiae Folium Originating from Three Pyrrosia Species by HPLC-DAD Combined with Multivariate Statistical Analysis.

Pyrrosiae Folium (PF) is a commonly used Chinese herb medicine originating from three Pyrrosia species for the treatment of urinary infection and urolithiasis. According to Chinese medicine practice, different specie origins led to some variations in the therapeutic effects of PF. To ensure the safety and efficacy of PF in clinical practice, it is necessary to establish a reliable and integrative method to distinguish PF occurring from the three species. In the present paper, a HPLC-DAD method was developed and applied to simultaneously analyze five major compounds in PF. Afterwards, multivariate statistical analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) were applied for specie discrimination and integrative quality evaluation based on quantitative data. The chemical determination and pattern recognition results of 35 batches of PF samples indicated that PF samples from three species showed different chemical profiles and could be discriminated clearly. In conclusion, the present method is rapid and reliable for the quality assessment and species discrimination of PF.

Enhanced Intestinal Permeability of Bufalin by a Novel Bufalin-Peptide-Dendrimer Inclusion through Caco-2 Cell Monolayer.

Bufalin (BFL) has excellent physiological activities such as defending tumors, improving cardiac function, and so on. However, due to its poor water-solubility and bioavailability, the clinical application of BFL remains limited. In order to improve bioavailability of BFL, in our previous research, a novel peptide-dendrimer (PD) was synthesized and applied to encapsulate BFL. In the present study, we investigate the absorption property and mechanism of BFL in free form and BFL-peptide-dendrimer inclusion (BPDI) delivery system by using the Caco-2 cell monolayer model in vitro. The apparent permeability coefficient (Papp) values of BFL in free or BPDI form were over 1.0 × 10-6 cm/s. Meanwhile, their almost equal bi-directional transport and linear transport percentage with time and concentration course indicated that BFL in both forms was absorbed mainly through passive diffusion. The most important result is that the Papp values of BFL increased about three-fold more BPDI than those of its free form, which indicated the intestinal permeability of BFL could be improved while BFL was encapsulated in BPDI form. Therefore, PD encapsulation may be a potential delivery system to increase the bioavailability of BFL.

Global detection and semi-quantification of Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus by a non-targeted multiple reaction monitoring approach.

Methods based on triple quadrupole tandem mass spectrometry have been widely used and reported as highly selective and sensitive methods for quantifying substances of herbal medicines. However, most of them were limited to targeted components, due to the difficulties to optimize the multiple reaction monitoring transitions without authentic standards. This study proposed a novel strategy for non-targeted optimization of multiple reaction monitoring method based on the diagnostic ion guided family classifications, tandem mass spectrometry database establishment, and transitions and collision energy screening. Applying this strategy, 59 Fritillaria alkaloids in Fritillariae Ussuriensis Bulbus have been classified, and 51 of these Fritillaria alkaloids were successfully detected by the optimal multiple reaction monitoring method. For semi-quantification, the easy-to-obtain Fritillaria alkaloids of each type, such as verticinone for cevanine type and peimisine for jervine type, were used as the reference standards to calibrate the other Fritillaria alkaloids in the same type. The method was demonstrated a good linearity (R(2) > 0.998) with satisfactory accuracy and precision, and the lower limits of quantification of verticinone and peimisine were estimated to be 0.076 and 0.216 pg, respectively. In addition, the results suggested that the proposed strategy might obtained high quality metabolomics data in discrimination of Fritillaria unibracteata and Fritillaria ussuriensis.

Quantitative and Qualitative Analysis of Flavonoids and Phenolic Acids in Snow Chrysanthemum (Coreopsis tinctoria Nutt.) by HPLC-DAD and UPLC-ESI-QTOF-MS.

A simple, accurate and reliable high performance liquid chromatography coupled with photodiode array detection (HPLC-DAD) method was developed and then successfully applied for simultaneous quantitative analysis of eight compounds, including chlorogenic acid (1), (R/S)-flavanomarein (2), butin-7-O-ß-d-glucopyranoside (3), isookanin (4), taxifolin (5), 5,7,3',5'-tetrahydroxyflavanone-7-O-ß-d-glucopyranoside (6), marein (7) and okanin (8), in 23 batches of snow chrysanthemum of different seed provenance and from various habitats. The results showed total contents of the eight compounds in the samples with seed provenance from Keliyang (Xinjiang, China), are higher than in samples from the other five provenances by 52.47%, 15.53%, 19.78%, 21.17% and 5.06%, respectively, which demonstrated that provenance has a great influence on the constituents in snow chrysanthemum. Meanwhile, an ultra performance liquid chromatography coupled with electrospray ionization and quadrupole time-of-flight-mass spectrometry (UPLC-ESI-QTOF-MS) was also employed to rapidly separate and identify flavonoids and phenolic acids in snow chrysanthemum from Keliyang. As a result, a total of 30 constituents, including 26 flavonoids and four phenolic acids, were identified or tentatively identified based on the exact mass information, the fragmentation characteristics, and retention times of eight reference standards. This work may provide an efficient approach to comprehensively evaluate the quality of snow chrysanthemum.

Enhancement of nitrogen cycling and functional microbial flora by artificial inoculation of biological soil crusts in sandy soils of highway slopes.

Biological soil crusts (BSCs) are common in arid and semi-arid ecosystems and enhance soil stability and fertility. Highway slopes severely deplete the soil ecological structure and soil nutrients, hindering plant survival. The construction of highway slope BSCs under human intervention is critical to ensure the long-term stable operation of the slope ecosystem. This study investigated the variation rules and interaction mechanisms between soil nutrients and microbial communities in the subsoil BSCs on highway slopes. Bacterial 16S rRNA high-throughput sequencing was employed to investigate the dynamic compositional changes in the microbial community and perform critical metabolic predictive analyses of functional bacteria. This study revealed that the total soil nitrogen increased significantly from 0.557 to 0.864 g/kg after artificial inoculation with desert Phormidium tenue and Scytonema javanicum. Actinobacteria (44-48%) and Proteobacteria (28-31%) were the dominant phyla in all samples. The abundance of Cyanobacteria, Cytophagaceae, and Chitinophagaceae increased significantly after inoculation. PICRUST analysis showed that the main metabolic pathways of soil microorganisms on highway slopes included cofactor and vitamin, nucleotide, and amino acid metabolisms. These findings suggest that the artificial inoculation with Phormidium tenue and Scytonema javanicum could alter soil microbial distribution to promote soil development on highway slopes toward nutrient accumulation.

Arnicolide D induces endoplasmic reticulum stress-mediated oncosis via ATF4 and CHOP in hepatocellular carcinoma cells.

Endoplasmic reticulum (ER) stress can trigger various cell death mechanisms beyond apoptosis, providing promise in cancer treatment. Oncosis, characterized by cellular swelling and increased membrane permeability, represents a non-apoptotic form of cell death. In our study, we discovered that Arnicolide D (AD), a natural sesquiterpene lactone compound, induces ER stress-mediated oncosis in hepatocellular carcinoma (HCC) cells, and this process is reactive oxygen species (ROS)-dependent. Furthermore, we identified the activation of the PERK-eIF2α-ATF4-CHOP pathway during ER stress as a pivotal factor in AD-induced oncosis. Notably, the protein synthesis inhibitor cycloheximide (CHX) was found to effectively reverse AD-induced oncosis, suggesting ATF4 and CHOP may hold crucial roles in the induction of oncosis by AD. These proteins play a vital part in promoting protein synthesis during ER stress, ultimately leading to cell death. Subsequent studies, in where we individually or simultaneously knocked down ATF4 and CHOP in HCC cells, provided further confirmation of their indispensable roles in AD-induced oncosis. Moreover, additional animal experiments not only substantiated AD's ability to inhibit HCC tumor growth but also solidified the essential role of ER stress-mediated and ROS-dependent oncosis in AD's therapeutic potential. In summary, our research findings strongly indicate that AD holds promise as a therapeutic agent for HCC by its ability to induce oncosis.

Fingerprint analysis and simultaneous determination of phenolic compounds in extracts of Curculiginis Rhizoma by HPLC-diode array detector.

Curculiginis Rhizoma (Curculigo orchioides GAERTN.) is a well-known Chinese herbal medicine, as well as an important Rasayana drug in India. Current criteria of quality control on this herb are to quantitatively analyze single compound curculigoside, which fail to comprehensively evaluate quality of this herb. In this paper, a simple and reliable HPLC coupled with diode array detector (DAD) method was developed to evaluate the quality of Curculiginis Rhizoma through establishing chromatographic fingerprint and simultaneously quantitating four phenolic compounds, orcinol glucoside, orcinol, 2,6-dimethoxybenzoic acid and curculigoside. The fingerprint displayed eleven common peaks, and the similarity index of different samples was in a range of 0.890-0.977. Validation of the method was acceptable, with 96.03-102.82% accuracy in recovery test and inter and intra-day precisions were less than 2%. This developed method by having a combination of chromatographic fingerprint and quantitation analysis could be applied to the quality control of Curculiginis Rhizoma.

Two new antioxidant diarylheptanoids from the fruits of Alpinia oxyphylla.

Two new diarylheptanoids, 1-(3',5'-dihydroxy-4'-methoxyphenyl)-7-phenyl-3-heptanone (1) and 1-(2',4'-dihydroxy-3'-methoxyphenyl)-7-(4″-methoxyphenyl)-3-heptanone (2), along with known diarylheptanoid yakuchinone A (3), and five flavanoids, tectochrysin (4), chrysin (5), izalpinin (6), kaempferol 7, 4'-dimethyl ether (7), and kaempferide (8) were isolated from the fruits of Alpinia oxyphylla Miq. Their structures were determined by means of spectroscopic methods. Antioxidant activities of all the isolated compounds were evaluated using a 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Compounds 1-3 and 6-8 exhibited potent antioxidant activities in the DPPH assay.

Recent advances in natural compounds inducing non-apoptotic cell death for anticancer drug resistance.

The induction of cell death is recognized as a potent strategy for cancer treatment. Apoptosis is an extensively studied form of cell death, and multiple anticancer drugs exert their therapeutic effects by inducing it. Nonetheless, apoptosis evasion is a hallmark of cancer, rendering cancer cells resistant to chemotherapy drugs. Consequently, there is a growing interest in exploring novel non-apoptotic forms of cell death, such as ferroptosis, necroptosis, pyroptosis, and paraptosis. Natural compounds with anticancer properties have garnered significant attention due to their advantages, including a reduced risk of drug resistance. Over the past two decades, numerous natural compounds have been discovered to exert anticancer and anti-resistance effects by triggering these four non-apoptotic cell death mechanisms. This review primarily focuses on these four non-apoptotic cell death mechanisms and their recent advancements in overcoming drug resistance in cancer treatment. Meanwhile, it highlights the role of natural compounds in effectively addressing cancer drug resistance through the induction of these forms of non-apoptotic cell death.

Model Compression Based on Differentiable Network Channel Pruning.

Although neural networks have achieved great success in various fields, applications on mobile devices are limited by the computational and storage costs required for large models. The model compression (neural network pruning) technology can significantly reduce network parameters and improve computational efficiency. In this article, we propose a differentiable network channel pruning (DNCP) method for model compression. Unlike existing methods that require sampling and evaluation of a large number of substructures, our method can efficiently search for optimal substructure that meets resource constraints (e.g., FLOPs) through gradient descent. Specifically, we assign a learnable probability to each possible number of channels in each layer of the network, relax the selection of a particular number of channels to a softmax over all possible numbers of channels, and optimize the learnable probability in an end-to-end manner through gradient descent. After the network parameters are optimized, we prune the network according to the learnable probability to obtain the optimal substructure. To demonstrate the effectiveness and efficiency of DNCP, experiments are conducted with ResNet and MobileNet V2 on CIFAR, Tiny ImageNet, and ImageNet datasets.

Dual identity of tumor-associated macrophage in regulated cell death and oncotherapy.

Tumor-associated macrophage (TAM) affects the intrinsic properties of tumor cells and the tumor microenvironment (TME), which can stimulate tumor cell proliferation, migration, and genetic instability, and macrophage diversity includes the diversity of tumors with different functional characteristics. Macrophages are now a central drug target in various diseases, especially in the TME, which, as "tumor promoters" and "immunosuppressors", have different responsibilities during tumor development and accompany by significant dynamic alterations in various subpopulations. Remodelling immunosuppression of TME and promotion of pre-existing antitumor immune responses is critical by altering TAM polarization, which is relevant to the efficacy of immunotherapy, and uncovering the exact mechanism of action of TAMs and identifying their specific targets is vital to optimizing current immunotherapies. Hence, this review aims to reveal the triadic interactions of macrophages with programmed death and oncotherapy, and to integrate certain relationships in cancer treatment.

[Photodegradation of Plastic Blends in Seawater and Its Risk to the Marine Environment].

The production and use of plastic blends have been gradually increasing owing to their versatility and low cost. However, the photodegradation of plastic blends in seawater and the potential risk to the marine environment are still not well understood. In this study, plastic blends including polypropylene/thermoplastic starch blends(PP/TPS) and polylactic acid/poly(butylene adipate-co-terephthalate)/thermoplastic starch blends(PLA/PBAT/TPS) were investigated. The corresponding neat polymers, namely polypropylene(PP) and polylactic acid(PLA), were set as control groups. We investigated the formation of MPs and the changes in the physicochemical properties of plastic blends after photodegradation in seawater. The size distribution of MPs indicated that PP/TPS and PLA/PBAT/TPS were more likely to produce small-sized particles after photodegradation than PP and PLA owing to their poorer mechanical properties and lower resistance to UV irradiation. Noticeable surface morphology alterations, including cracks and wrinkles, were observed for plastic blends following photodegradation, whereas PP and PLA were relatively resistant. After photodegradation, the ATR-FTIR spectrum of PP/TPS and PLA/PBAT/TPS showed a significant decrease in the characteristic bands of thermoplastic starch(TPS), indicating the degradation of their starch fractions. The C 1s spectra demonstrated that aged plastic blends contained fewer -OH groups than the pristine MPs did, further confirming the photodegradation of TPS. These results indicate that PP/TPS and PLA/PBAT/TPS had a higher degree of photodegradation than PP and PLA and thereby generated more small-sized MPs. In summary, plastic blends may pose a higher risk to the marine environment than neat polymers, and caution should be taken in the production and use of plastic blends.

Investigations of Fish Assemblages Using Two Methods in Three Terminal Reservoirs of the East Route of South-to-North Water Transfer Project, China.

The terminal reservoirs of water transfer projects directly supply water for domestic, agricultural, and industrial applications, and the water quality of these reservoirs produce crucial effects on the achievement of project targets. Typically, fish assemblages are monitored as indicators of reservoir water quality, and can also be regulated for its improvement. In the present study, we compared traditional fish landing (TFL) and environmental DNA (eDNA) metabarcoding methods for monitoring fish assemblages in three terminal reservoirs of the East Route of the South-to-North Water Transfer Project, China. Results of TFL and eDNA showed similar assemblage structures and patterns of diversity and spatial distribution with obvious differences in fish composition across three examined reservoirs. Demersal and small fish were dominant in all reservoirs. In addition, a strong association between water transfer distance and assemblages and distribution of non-native fish was found. Our findings highlight the necessity of the fish assemblage monitoring and managing for water quality and revealed the impact of water diversion distance on the structure of fish assemblages and dispersal of alien species along the water transfer project.

Simultaneous determination of eight anthraquinones in Semen Cassiae by HPLC-DAD.

INTRODUCTION: Semen Cassiae (SC), a traditional Chinese herbal medicine for the treatment of various diseases, is known to contain active anthraquinone ingredients. However, since the content of some anthraquinones is too low, previous analytical methods only allow the quantitation of a few anthraquinones or a hydrolysis step has to be included in the sample preparation. A rapid and accurate method to examine the content of as many anthraquinones as possible in SC would be desirable. OBJECTIVE: To develop a rapid, sensitive and accurate high-performance liquid chromatography-diode array detection (HPLC- DAD) method to simultaneously quantify eight major anthraquinones (obtusifolin-2-glucoside, aurantio-obtusin, aloe- emodin, rhein, obtusifolin, emodin, chrysophanol and physcion) in SC. METHODOLOGY: The separation of anthraquinones was achieved on a C18-column with a gradient elution using acetonitrile and 0.1% phosphoric acid. The detection wavelength was 278 nm and the analysis finished within 25 min. RESULTS: The limits of detection of these compounds ranged from 0.07 to 0.15 µg/mL while the limits of quantitation ranged from 0.24 to 0.51 µg/mL. All calibration curves showed good linearities (r² > 0.999) within the test ranges. This validated method was successfully used to analyse 22 batches of SC samples collected from various geographical locations. CONCLUSION: The method was validated to be simple, rapid, accurate and reliable to simultaneously determine eight major anthraquinones in SC. Meanwhile, a more specific anthraquinone, obtusifolin, was proposed to serve as a marker for SC, replacing chrysophanol.