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.

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.

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.

[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.

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.

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.

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.

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.

Stachydrine hydrochloride inhibits hepatocellular carcinoma progression via LIF/AMPK axis.

BACKGROUND: Hepatocellular carcinoma (HCC) is not only one of the four highest malignancies, but also the principal reason of cancer-related death worldwide, yet no effective medication for anti-HCC is available. Stachydrine hydrochloride (SH), an alkaloid component in Panzeria alaschanica Kupr, exhibits potent antitumor activity in breast cancer. However, the anti-HCC effects of SH remain unknown. PURPOSE: Our study assessed the therapeutic effect of SH on HCC and tried to clarify the mechanisms by which it ameliorates HCC. No studies involving using SH for anti-HCC activity and molecular mechanism have been reported yet. STUDY DESIGN/METHODS: We examined the cell viability of SH on HCC cells by MTT assay. The effect of SH on cell autophagy in HCC cells was verified by Western blot and Immunofluorescence test. Flow cytometry was performed to assess cell-cycle arrest effects. Cell senescence was detected using ß-Gal staining and Western blot, respectively. An inhibitor or siRNA of autophagy, i.e., CQ and si LC-3B, were applied to confirm the role of autophagy acted in the anti-cancer function of SH. Protein expression in signaling pathways was detected by Western blot. Besides, molecular docking combined with cellular thermal shift assay (CETSA) was used for analysis. Patient-derived xenograft (PDX) model were built to explore the inhibitory effect of SH in HCC in vivo. RESULTS: In vitro studies showed that SH possessed an anti-HCC effect by inducing autophagy, cell-cycle arrest and promoting cell senescence. Specifically, SH induced autophagy with p62 and LC-3B expression. Flow cytometry analysis revealed that SH caused an obvious cell-cycle arrest, accompanied by the decrease and increase in Cyclin D1 and p27 levels, respectively. Additionally, SH induced cell senescence with the induction of p21 in HCC cell lines. Mechanistically, SH treatment down-regulated the LIF and up-regulated p-AMPK. Moreover, PDX model in NSG mice was conducted to support the results in vitro. CONCLUSION: This study is the first to report the inhibitory function of SH in HCC, which may be due to the induction of autophagy and senescence. This study provides novel insights into the anti-HCC efficacy of SH and it might be a potential lead compound for further development of drug candidates for HCC.

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.

Remote Sensing Scene Classification via Multi-Branch Local Attention Network.

Remote sensing scene classification (RSSC) is a hotspot and play very important role in the field of remote sensing image interpretation in recent years. With the recent development of the convolutional neural networks, a significant breakthrough has been made in the classification of remote sensing scenes. Many objects form complex and diverse scenes through spatial combination and association, which makes it difficult to classify remote sensing image scenes. The problem of insufficient differentiation of feature representations extracted by Convolutional Neural Networks (CNNs) still exists, which is mainly due to the characteristics of similarity for inter-class images and diversity for intra-class images. In this paper, we propose a remote sensing image scene classification method via Multi-Branch Local Attention Network (MBLANet), where Convolutional Local Attention Module (CLAM) is embedded into all down-sampling blocks and residual blocks of ResNet backbone. CLAM contains two submodules, Convolutional Channel Attention Module (CCAM) and Local Spatial Attention Module (LSAM). The two submodules are placed in parallel to obtain both channel and spatial attentions, which helps to emphasize the main target in the complex background and improve the ability of feature representation. Extensive experiments on three benchmark datasets show that our method is better than state-of-the-art methods.

Centipeda minima Extract Attenuates Dextran Sodium Sulfate-Induced Acute Colitis in Mice by Inhibiting Macrophage Activation and Monocyte Chemotaxis.

Inflammatory bowel disease (IBD) is an idiopathic inflammatory disease affecting the gastrointestinal tract. IBD is characterized by courses of relapse and remission, and remains incurable. Although multiple factors are related to the pathogenesis of IBD, disruption of intestinal mucosa homeostasis has been proposed to be a major contributor to IBD, and abnormal activation of immune cells is key for initiation of the inflammatory response. Macrophages are the most abundant immune cells in the intestine. Once activated, they are responsible for secretion of pro-inflammatory cytokines and chemokines to attract circulating monocytes to inflammatory sites, exacerbating the inflammatory response, and leading to tissue damage. Therefore, the suppression of activated macrophages, cytokine/chemokine production, and subsequent monocyte chemotaxis possesses great potential for the treatment of IBD. In our study, we have demonstrated the inhibitory effect of Centipeda minima total extract (CME) on the activation of NF-κB, STAT3, and MAPK signaling in LPS-stimulated RAW264.7 macrophages. In addition, we identified the significant suppressive effect of CME on CCL8 expression in activated macrophages, which potentially contributed to inhibition of monocyte chemotaxis. In the DSS-induced acute colitis mouse model, we have demonstrated the suppressive effect of CME on intestinal macrophage infiltration and its ameliorative effect in IBD. Altogether, we have provided evidence of the therapeutic effect of CME in IBD and the potential of CME for the treatment of IBD.

Biologically Active Constituents from Plants of the Genus Xanthium.

Herbaceous annual plants of the genus Xanthium are widely distributed throughout the world and have been employed medicinally for millennia. This contribution aims to provide a systematic overview of the diverse structural classes of Xanthium secondary metabolites, as well as their pharmacological potential. On searching in various reference databases with a combination of three keywords "Xanthium", "Phytochemistry", and "Pharmacology", relevant publications have been obtained subsequently. From the 1950s to the present, phytochemical investigations have focused mainly on 15 Xanthium species, from which 300 compounds have been isolated and structurally resolved, primarily using NMR spectroscopic methodology. Xanthium constituents represent several secondary metabolite types, including simple phenols, sulfur and nitrogen-containing compounds, lignans, sterols, flavonoids, quinones, coumarins, and fatty acids, with terpenoids being the most common of these. Among the 174 terpenoids characterized, xanthanolide sesquiterpenoids are abundant, and most of the compounds isolated containing sulfur were found to be new in Nature. The ethnomedical uses of Xanthium crude extracts are supported by the in vitro and in vivo effects of their constituents, such as cytotoxicity, antioxidant, antibacterial, antifungal, antidiabetes, and hepatoprotective activities. Toxicological results suggest that Xanthium plant extracts are generally safe for use. In the future, additional phytochemical investigations, along with further assessments of the biological profiles and mechanism of action studies of the components of Xanthium species, are to be expected.

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.

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.

Brevilin A, a Natural Sesquiterpene Lactone Inhibited the Growth of Triple-Negative Breast Cancer Cells via Akt/mTOR and STAT3 Signaling Pathways.

PURPOSE: Triple-negative breast cancer (TNBC) is a a breast cancer subtype characterized by a lack of estrogen receptor, progesterone receptor and human epidermal growth receptor 2 and is associated with poorer prognoses when compared to other breast cancers. Thus, novel anti-cancer agents with high efficacy are urgently needed. Brevilin A (BA), a natural sesquiterpene lactone, has been reported to exhibit anti-cancer effects. However, the effects of BA on TNBC have not yet been demonstrated. In this study, we investigated the anti-TNBC effects and the underlying mechanism of BA, in vitro and in vivo. METHODS: Two TNBC cell lines and a xenograft mouse model were employed to assess the effects of BA. Cell viability was detected by MTT assay. Cell cycle status and apoptosis were evaluated by flow cytometry. Cell migration was measured by wound-healing assay. Protein expression was measured by Western blotting analysis. The in vivo anti-cancer activity of BA was assessed in orthotopic tumor xenograft mice. RESULTS: BA significantly inhibited the growth of TNBC cells in a dose- and time-dependent manner via induction of cell cycle arrest at G2/M phase arrest and apoptosis. BA also inhibited tumor cell migration. BA significantly downregulated the expression of Akt, mTOR, Stat3 and their phosphorylation, and thus inhibiting the activation of the Akt/mTOR and STAT3 signaling pathways. Furthermore, oral administration of BA at 25 or 50 mg/kg leads to significant inhibition of tumor growth and proliferation in tumor xenograft model mice. CONCLUSION: BA significantly inhibited the growth and migration of TNBC cells, and induced cell cycle arrest and apoptosis. These inhibitory effects were associated with the suppression of the Akt/mTOR and Stat3 signal pathways. Based on our findings, BA possesses a promising candidate for development as an anti-cancer therapeutic drug against TNBC.

Synthesis and Evaluation of Novel Anticancer Compounds Derived from the Natural Product Brevilin A.

Cancer is the second leading cause of death globally, responsible for an estimated 9.6 million deaths in 2018, and this burden continues to increase. Therefore, there is a clear and urgent need for novel drugs with increased efficacy for the treatment of different cancers. Previous research has demonstrated that brevilin A (BA) exerts anticancer activity in various cancers, including human multiple myeloma, breast cancer, lung cancer, and colon carcinoma, suggesting the anticancer potential present in the chemical scaffold of BA. Here, we designed and synthesized a small library of 12 novel BA derivatives and evaluated the biological anticancer effects of the compounds in various cancer cell lines. The results of this structure-activity relationship study demonstrated that BA derivatives BA-9 and BA-10 possessed significantly improved anticancer activity toward lung, colon, and breast cancer cell lines. BA-9 and BA-10 could more effectively reduce cancer cell viability and induce DNA damage, cell-cycle arrest, and apoptosis when compared with BA. Our findings represent a significant step forward in the development of novel anticancer entities.

Anti-cancer Activity of Centipeda minima Extract in Triple Negative Breast Cancer via Inhibition of AKT, NF-κB, and STAT3 Signaling Pathways.

Breast cancer is the most commonly diagnosed cancer in females worldwide. Estimates from the World Health Organization (WHO) International Agency for Research on Cancer, suggest that globally, there were around 2.1 million new breast cancer cases and 627,000 deaths due to breast cancer in 2018. Among the subtypes of breast cancer, triple negative breast cancer (TNBC) is the most aggressive and carries the poorest prognosis, largest recurrence, and lowest survival rate. Major treatment options for TNBC patients are mainly constrained to chemotherapy, which can be accompanied by severe side effects. Therefore, development of novel and effective anti-cancer drugs for the treatment of TNBC are urgently required. Centipeda minima is a well-known traditional Chinese herbal medicine that has historically been used to treat rhinitis, sinusitis, relieve pain, and reduce swelling. Recent studies have shown that Centipeda minima exhibited efficacy against certain cancers, however, to date, no studies have been conducted on its effects in breast cancer. Here, we aimed to investigate the anti-cancer activity of the total extract of Centipeda minima (CME), and its underlying mechanism, in TNBC. In MDA-MB-231, we found that CME could significantly reduce cell viability and proliferation, induce apoptosis and inhibit cancer cell migration and invasion, in a dose and time-dependent manner. We showed that CME may potentially act via inhibition of multiple signaling pathways, including the EGFR, PI3K/AKT/mTOR, NF-κB, and STAT3 pathways. Treatment with CME also led to in vitro downregulation of MMP-9 activity and inhibition of metastasis. Further, we demonstrated that CME could significantly reduce tumor burden in MDA-MB-231 xenograft mice, without any appreciable side effects. Based on our findings, CME is a promising candidate for development as a therapeutic with high efficacy against TNBC.

Liver Transcriptomic Reveals Novel Pathways of Empagliflozin Associated With Type 2 Diabetic Rats.

The hypoglycaemic target of empagliflozin (EMP), as a novel inhibitor of sodium-glucose cotransporter (SGLT2), is clear. However, recent studies have shown that EMP also has an important role in lipid metabolism and cardiovascular diseases. The liver plays an important role in the development of type 2 diabetes (T2D), although whether EMP affects liver glucose metabolism is currently not reported. This study was designed to evaluate the effect of EMP on hepatic glucose metabolism in T2D and the underlying mechanism. A model of T2D was established by a high-fat and glucose diet (HFD) combined with streptozotocin (30 mg/kg) in male Wistar rats. Serum samples were collected to measure biochemical indicators, and liver samples were extracted for RNA-seq assay. Quantitative real-time PCR (qPCR) was used to further verify the gene expression levels detected by the RNA-seq assay. The EMP group showed significantly decreased blood glucose, triglyceride, cholesterol, non-esterified fatty acid and low-density lipoprotein cholesterol levels, and increased high-density lipoprotein cholesterol levels in serum compared with the type 2 diabetes model (MOD) group. Furthermore, EMP decreased the levels of inflammatory factors IL-1ß, IL-6, and IL-8 in the serum compared to the MOD. Liver transcriptome analysis showed EMP affects a large number of upregulated and downregulated genes. Some of these genes are novel and involve in the metal ion binding pathway and the negative regulation of transcription from the RNA polymerase II promoter pathway, which are also closely related to glucolipid metabolism and insulin signaling. Our study provides new knowledge about the mechanism through which SGLT inhibitor can offer beneficial effects in T2D and especially in the hepatic metabolism. These genes found in this study also laid a solid foundation for further research on the new roles and mechanisms of EMP.

The JAK2/STAT3 pathway is involved in the anti-melanoma effects of brevilin A.

AIMS: Melanoma is lethal. Constitutively active signal transducer and activator of transcription 3 (STAT3) has been proposed as a pathogenic factor and a therapeutic target of melanoma. Brevilin A, a sesquiterpene lactone isolated from Centipeda minima (L.) A. Br. et Aschers., has been shown to exert antineoplastic effects and inhibit the STAT3 pathway in nasopharyngeal, lung, prostate and breast cancer cells. This study aimed to determine whether brevilin A has anti-melanoma effects, and whether STAT3 signaling is involved in the effects. MAIN METHODS: A mouse A375 xenograft model, as well as A375 and A2058 cell models were employed to assess the in vivo and in vitro anti-melanoma effects of brevilin A. A375 cells stably expressing STAT3C, a constitutively active STAT3 mutant, were used to determine the role of STAT3 signaling in brevilin A's anti-melanoma effects. KEY FINDINGS: Intraperitoneal injection of brevilin A dose-dependently inhibited melanoma growth in mice and suppressed STAT3 phosphorylation in the tumors. In cultured cells, brevilin A reduced cell viability, induced apoptosis, suppressed migration and invasion, decreased protein levels of phospho-JAK2 (Y1007/1008) and phospho-STAT3 (Tyr705), and restrained STAT3 nuclear localization. STAT3 over-activation diminished brevilin A's effects on cell viability and migration. Collectively, brevilin A exerts anti-melanoma effects and these effects are at least in part attributed to the inhibition of the JAK2/STAT3 pathway. SIGNIFICANCE: Our findings provide a pharmacological basis for developing brevilin A as a new phytotherapeutic agent against melanoma.