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Background: Lung cancer has been considered as a serious problem for the public health system. NSCLC is the main type of lung cancer, and finding improved treatments for NSCLC is a pressing concern. In this study, we have explored the efficacy of isotoosendanin (ITSN) for the treatment of NSCLC, and also explored the potential underlying mechanisms., Methods: NSCLC cells were cultured, and colony formation, cell cycle as well as apoptosis assays have been conducted for investigating the biological functions of ITSN on NSCLC cells. Furthermore, target genes of ITSN have been predicted via PharmMapper and SuperPred database, subsequently validated using the drug affinity responsive target stability (DARTS) approach, a cellular thermal shift assay (CETSA) as well as surface plasmon resonance (SPR) analysis. Additionally, ubiquitination experiments have been conducted for the level of ubiquitination of the NSCLC cells. Finally, a nude mouse xenograft model has been established for evaluating the anti-tumor effects of ITSN in vivo., Results: ITSN has shown anti-NSCLC activities both in vitro and in vivo. Mechanistically, ITSN interacts with SHP-2 through enhancing its stability and decreases the level of ubiquitination. Notably, ITSN may regulate the behaviors of NSCLC cells via affecting the JAK/STAT3 signaling, and finally, the anti-tumor effects of ITSN was partially reversed by the application of SHP-2 inhibitor or siRNA of SHP-2., Conclusions: ITSN may exert its anti-tumor effects by directly targeting SHP-2, increasing its stability and minimizing its ubiquitination. These results imply that ITSN could be a revolutionary component for treating NSCLC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier GmbH. All rights reserved.)

Since Tang dynasty in China, the fresh leaves of Vaccinium bracteatum (VBL) have been applied as natural pigment to produce black rice. However, detailed information on its biosynthetic mechanism still remained unclear. Following rice dyeing capacity assay, vaccinoside, one of iridoid glycosides, was identified as the key active compound. Increased methodical research demonstrated vaccinoside as a distinct bifunctional precursor, which could be catalyzed by polyphenol oxidase or β-glucosidase independently, followed by reaction with 15 amino acids to give blue pigments (VBPs; λmax 581-590 nm) of different hues. Two synthetic pathways of VBPs were proposed, using multiple techniques such as HPLC, HPSEC, UV-Vis spectrum and colorimeter as analysis tools. Black rice was interpreted to be prepared by cooking, using vaccinoside, intrinsic enzymes from fresh VBL and rice protein in combination. These findings promote the understanding of VBP formation mechanisms and provide an efficient method of producing novel Vaccinium blue pigments., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Tumor-derived exosome PD-L1 exhaustsTcells and permits tumor cells to evade immune surveillance; thus, the inhibition of ExoPD-L1 secretion can significantly enhance the clinical efficacy of PD-L1 antibody. In this study, we combined exosome membrane, apoA1 and phospholipid into biomimetic exosome vesicles (apoA1-bExo) which were then incubated with cholesterol modified siRNA to generate apoA1-bExo containing siRNA (apoA1-bExo/siRNA). Thepreparedvesicleswere uniformandsphericalin size and could be loaded effectively with siRNA to protect from nuclease degradation. Compared with bExo/siRNA, apoA1-bExo/siRNA showed stronger tumor targeting, tissue permeability, intracellular accumulation efficiency and antitumor efficiency. A portion of apoA1-bExo/siRNA transport siRNA occurred through the endosome-Golgi-ER pathway similar to bExo/siRNA, but mostly occurred directly through selective uptake pathways mediated by the SR-B1 receptor. apoA1-bExo/siRNA successfully achieved silencing efficiency at the transcription and protein levels (96.78 % and 94.07 %, respectively) and reduced the secretion of ExoPD-L1 from HepG2 cells to 15.92 % of that in the PBS group, thus enhancing the killing activity of co-cultured T cells on HepG2 cells. In addition, relevant pharmacodynamic indices were positively correlated with delivery efficiency and the modification of apoA1 could significantly enhance the intracellular accumulation of siRNA, thus exhibiting stronger activity than bExo/siRNA. Moreover, in addition to curing mice of their implanted tumors, blocking ExoPD-L1 secretion in combination with αPD-1 promoted the infiltration of durable antitumor hCD8 + T cells and hCD45 + T cells into tumor in a immune system-tumor dual humanized mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

This study investigated the performance and mechanisms of intermittent aeration to regulate gaseous emission and humification during food waste digestate composting. In addition to continuous aeration, three intermittent aeration regimes were conducted with the on-off interval ratio at 3:1, 2:1, and 1:1 within each 30 min, respectively. Results showed that intermittent aeration regimes reduced gaseous emission and enhanced humification during composting. In particular, intermittent aeration with the on/off ratio of 1:1 was more effective to reduce organic mineralization than other regimes, which alleviated the emission of nitrous oxide and ammonia by 63.1% and 75.7% in comparison with continuous aeration, respectively. In addition, this aeration regime also enhanced the content of humic acid by 24.1%. Further analysis demonstrated that prolonging aeration-off intervals could enrich facultative bacteria (e.g. Atopobium and Clostridium) from digestate and inhibit the proliferation of several aerobic bacteria (e.g. Caldicoprobacter and Marinimicrobium) to retard organic mineralization for humification., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Mountain Zizania latifolia is produced at scale in China, and the edible swollen culm is exported to many countries, but little attention has been paid to its functional components. In this work, microwave-assisted enzymatic extraction (MAEE) is used for the first time to extract polysaccharides from mountain Z. latifolia swollen culm (PMZL). MAEE conditions optimized by Box-Behnken design-response surface methodology were as follows: 2.4% cellulase, microwaving for 6.0 min at 607 W, with a liquid-to-solid ratio of 63:1 ml g -1 . Under these conditions, a notably high yield of 60.43% ± 1.12% for PMZL was achieved, which was significantly higher (p < 0.01) than from plain-grown varieties. PMZL are naturally occurring sulfated polysaccharide-protein complexes containing 8.46% ± 0.18% proteins and 7.86% ± 0.73% sulfates. PMZL comprises mannose, glucosamine, rhamnose, glucose, galactose, and arabinose at molar ratios of 3.80:2.68:1.00:17.41:5.12:2.91, with a weight-average molecular weight of 1569,219 Da and a number-average molecular weight of 364,088 Da. The surface morphology of PMZL is composed of tightly packed oval particles, and this kind of promising polysaccharides preferentially scavenges reactive nitrogen species. PRACTICAL APPLICATION: Due to global warming, the land available for planting vegetables is likely to expand to higher areas, so greater attention should now be paid to mountain-grown vegetables. This study provides an efficient way to obtain novel polysaccharides from mountain Zizania latifolia using microwave-assisted enzymatic extraction with a remarkably high yield of 60.4%. This promising source of natural carbohydrates has potential uses in pharmaceutical, nutraceutical, functional foods, cosmetics, and functional materials industries., (© 2022 Institute of Food Technologists.)

Introduction: Numerous research works have shown that serum Gal-deficient (Gd) IgA1 levels are increased in IgA nephropathy (IgAN) patients and these levels are a dangerous risk factor for IgAN. A relationship between the gut microbiota and IgAN has been reported. Whether the gut microbiota participates in the pathogenesis of IgAN was still controversial., Methods: We evaluated changes in the gut flora and the levels of Gd-IgA1 in IgAN patients and healthy controls (HCs). We investigated the Gd-IgA1 levels in both blood and urine specimens. C57BL/6 mice were given a broad-spectrum antibiotic cocktail to deplete the endogenous gut flora. We established a model of IgAN in pseudosterile mice and investigated the expression of the markers of intestinal permeability, inflammation, and local immune responses., Results: Studies have shown that the levels of certain gut flora differ between IgAN patients and HCs. Moreover, elevated Gd-IgA1 levels were found in both the serum and urine. Interestingly, Coprococcus, Dorea, Bifidobacterium, Blautia, and Lactococcus, selected from 10 candidate biomarkers to predict risk in IgAN patients according to random forest analysis, were inversely associated with urinary Gd-IgA1 levels. Notably, the urine level of Gd-IgA1 could best distinguish IgAN patients from HCs. Additionally, the degree of kidney damage in pseudosterile mice with IgAN was more severe than that in mice with IgAN. Furthermore, the markers of intestinal permeability were significantly elevated in pseudosterile IgAN mice. Moreover, the inflammation responses (TLR4, MyD88, and NF-κB in intestinal and renal tissues; TNF-α and IL-6 in serum) and local immune responses (BAFF and APRIL in intestinal tissue) were upregulated in pseudosterile IgAN mice., Conclusions: The urine Gd-IgA1 level may be as a biomarker for the early screening of potential IgAN, and gut microbiota dysbiosis was demonstrated in IgAN, which might involve the dysfunction of the mucosal barrier, inflammation, and local immune responses., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Rheumatoid arthritis (RA) is an essential cause of labor loss and disability for people worldwide. Acanthopanax senticosus polysaccharide (ASPS) is one of the most important active components from A. senticosus, which exhibits various pharmacological activities such as antioxidation and immunomodulation. However, no studies have reported the application of ASPS in treating RA. This study aims to investigate the therapeutic effect of ASPS on RA and reveal its underlying mechanism. The potential therapeutic effect of ASPS against RA is initially verified in this study using the collagen-induced arthritis model. Moreover, the protective benefits of ASPS are transmitted through the fecal microbiota and blocked by simultaneous antibiotic cocktail treatment, indicating that gut microbiota may be correlated with ASPS. The 16S rRNA sequencing using feces samples and untargeted UPLC-MS metabolomics using serum samples further reveal that ASPS reprograms the arthritic progression triggered dysbiosis, enhances the expression of γ-glutamylcysteine (GGC) synthetase, and enriches the serum concentration of GGC. Furthermore, metabolites GGC is found to be able to effectively interrupt NLRP3 inflammasome activation via inhibiting ASC nucleation and therefore attenuate inflammatory arthritis. Taken together, this work highlights ASPS's therapeutic potential against RA, which mainly exhibits its effects via modulating gut microbiota and regulating GGC production., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Sagittaria trifolia tuber is an aquatic vegetable. In this work, microwave-assisted enzymatic extraction (MEE) was used to extract S. trifolia tuber polysaccharides (STTPs). Optimum conditions were complex enzyme of 2 %, liquid-to-solid ratio of 43 : 1 mL g -1 , microwave power of 506 W, and time of 8 min, under which STTPs yield was 36.22±0.69 %, higher than those of other methods. STTPs were sulfated polysaccharides with sulfur valence of S 6+ . STTPs comprised mannose, glucose, galactose, and arabinose at a mole ratio of 3.69 : 19.33 : 6.21 : 1.00, molecular weights of 3606 kDa and 149.6 kDa, particle size of 220 nm, and zeta potential of -5.02 mV. The surface of STTPs was full of bumps and holes, and abundant in O1s and non-functionalized C1s. STTPs would scavenge reactive oxygen species with advantage. It would provide an efficient MEE method to obtain antioxidant STTPs, also a clue for extracting polysaccharides from starch-rich crops., (© 2022 Wiley-VHCA AG, Zurich, Switzerland.)

Infantile hemangioma (IH) is a common benign endothelial cell tumor in infants and young children, sometimes accompanied by potential complications, and may develop into malignant tumors. Hemangioma endothelial cells (HemECs) are one of the main components of IH. Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially anti-tumor, but its high toxicity, poor water solubility, and serious gastrointestinal side effects limit its clinical application. In this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of podophyllotoxin through esterification reactions. The cytotoxicity of these compounds was evaluated on HemECs. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, measurement of reactive oxygen species (ROS) levels flow cytometry, and Western blot analysis. We found that eight of the compounds were more potent than PPT. Of these, compound V-31 was the most active (IC 50  = 0.079 ± 0.0049 µM). Further research indicated that compound V-31 inhibited its proliferation and migration, increased the level of ROS in cells, and induced apoptosis by downregulating p-PI3K, p-Akt, and Bcl-2, and upregulating cleaved caspase-3 and Bax. Our research provides the first insight into the application of PPT derivatives in HemECs, may provide an effective medicine for IH treatment., (© 2022 John Wiley & Sons A/S.)

Background: Lung cancer is the leading cause of cancer-associated death worldwide and is classified into non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). NSCLC accounts for approximately 80%-85% of all lung cancer cases. Chenodeoxycholic acid (CDCA), a primary bile acid, has been reported to inhibit carcinoma cell proliferation. Here, we aimed to determine the effects and mechanism of action of CDCA against lung adenocarcinoma (LUAD)., Methods: Western blotting and quantitative real-time polymerase chain reaction were used to evaluate the protein and mRNA expression levels in LUAD cell lines, respectively. Cell Counting Kit-8 and clone formation assays were performed to evaluate the proliferation ability of different cell types in vitro. Tumor cell motility was evaluated using Transwell assays. The transcriptional profile of A549 cells treated with CDCA was determined through RNA sequencing analysis. A xenograft model was established to evaluate the effects of CDCA on LUAD progression in vivo., Results: CDCA inhibited LUAD cell proliferation, migration, and invasion. Furthermore, it promoted apoptosis in LUAD cells. Mechanistically, CDCA inhibited the integrin α5β1 signaling pathway in LUAD cells by inhibiting the expression of the α5 and β1 subunits of integrin and phosphorylated FAK. Moreover, CDCA induced an increase in the levels of p53, a downstream gene of the integrin α5β1/FAK pathway. In addition, CDCA significantly decreased tumor volume in mice without inducing significant toxicity., Conclusions: Our findings indicate that CDCA attenuates LUAD pathogenesis in vitro and in vivo via the integrin α5β1/FAK/p53 axis., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

This study evaluated the humification and maturation of kitchen waste during indoor composting by individual households. In total, 50 households were randomly selected to participate in this study using kitchen waste of their own for indoor composting using a standard 20 L sealed composter. Garden waste was also collected from their local communities and used as the bulking agent. Both effective microorganisms and lime were inoculated at 1% (wet weight) of raw composting materials to facilitate the composting initiation. Results from this study demonstrate for the first time that ordinary residents could correctly follow the instruction to operate indoor composting at household level to manage urban kitchen waste at source. Overall, 30 households provided valid and complete data to show an increase (to ~50 °C) and then decrease in temperature in response to the decline of biodegradable organic substances during indoor composting. The compost physiochemical characteristics varied significantly toward maturation with an increase in seed germination index to above 50% for most households. Furthermore, organic humification occurred continuously during indoor composting as indicated by the enhanced content of humic substances, degree of polymerization, and spectroscopic characteristics., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Overcoming blood-brain barrier (BBB) to improve brain bioavailability of therapeutic drug remains an ongoing concern. Prodrug is one of the most reliable approaches for delivering agents with low-level BBB permeability into the brain. The well-known antioxidant capacities of cysteine (Cys) and its vital role in glutathione (GSH) synthesis indicate that Cys-based prodrug could potentiate therapeutic drugs against oxidative stress-related neurodegenerative disorders. Moreover, prodrug with Cys moiety could be recognized by the excitatory amino acid transporter 3 (EAAT3) that is highly expressed at the BBB and transports drug into the brain. In this review, we summarized the strategies of crossing BBB, properties of EAAT3 and its natural substrates, Cys and its donors, and Cys donor-based brain-targeting prodrugs by referring to recent investigations. Moreover, the challenges that we are faced with and future research orientations were also addressed and proposed. It is hoped that present review will provide evidence for the pursuit of novel Cys donor-based brain-targeting prodrug., Competing Interests: The authors declare that there are no conflicts of interest in this article., (Copyright © 2022 Gaoyang Ni et al.)

A rich of 3,4- seco -lupane triterpenoids (3,4-SLT), including chiisanoside (CSS), divaroside (DVS), sessiloside-A1 (SSA), chiisanogenin (CSG), sessiligenin (SSG), were isolated from the ethanol extract of the leaves of Eleutherococcus sessiliflorus (LES). The present study was performed to explore the cytotoxic and anti-tumor effects of the isolated five ones, as well as potential molecular mechanisms. The results of a CCK-8 assay demonstrated that these 3,4-SLT can inhibit the growth of HepG2 cells, and SSG showed the most significant cytotoxicity. Hoechst 33258 fluorescence staining and Annexin V-FITC/PI staining indicated that 3,4-SLT in LES can induce HepG2 cell apoptosis effectively. The AutoDock Vina program was used to simulate molecular docking of drugs and targets to discuss possible pharmacological mechanisms. Besides, western blot and qRT-PCR results indicated that SSG can inhibit PI3K/AKT signaling pathway through controlling multi-targets. This study suggested that 3,4-SLT might become a new research hotspot for antineoplastic drugs.

Eleocharis dulcis, an aquatic plant belonging to Cyperaceae family, is indigenous to Asia, and also occurs in tropical Africa and Australia. The edible corm part of E. dulcis is a commonly consumed aquatic vegetable with a planting area of 44.46 × 10 3 hm 2 in China. This work aims to explore the potential of E. dulcis corm for use as a new food source for sufficient nutrients and health benefits by reviewing its nutrients, phytochemicals, functions, processing and food products. Eleocharis dulcis corm contains starches, dietary fibers, non-starch polysaccharides, proteins, amino acids, phenolics, sterols, puchiin, saponins, minerals and vitamins. Among them, phenolics including flavonoids and quinones could be the major bioconstituents that largely contribute to antioxidant, anti-inflammatory, antibacterial, antitumor, hepatoprotective, neuroprotective and hypolipidemic functions. Peel wastes of E. dulcis corm tend to be enriched in phenolics to a much higher extent than the edible pulp. Fresh-cut E. dulcis corm can be consumed as a ready-to-eat food or processed into juice for beverage production, and anti-browning processing is a key to prolonging shelf life. Present food products of E. dulcis corm are centered on various fruit and vegetable beverages, and suffer from single categories and inadequate development. In brief, underutilized E. dulcis corm possesses great potential for use as a new food source for sufficient nutrients and health benefits. © 2021 Society of Chemical Industry., (© 2021 Society of Chemical Industry.)

Background and Purpose: Panaxynol (PAL, PubChem CID: 5281149) is a common natural minor component in Umbelliferae plants, such as Radix Saposhnikoviae Divaricatae. Modern pharmacology studies show that PAL has nutritional value and anti-inflammatory and other pharmaceutical activities. Therefore, the scientific hypothesis of PAL in the treatment of rheumatoid arthritis was put forward, and the hypothesis was further verified by Fibroblast-like synovial cells (RA-FLS) and Collagen Induced Arthritis (CIA) rats models., Experimental Method: CIA method was used to establish a rat arthritis model. After extracting RA-FLS, flow cytometry and immunofluorescence were used to explore the effect of PAL on the apoptosis and proliferation of RA-FLS. Wound healing and transwell experiment explored the effect of PAL on the migration and invasion of RA-FLS. Western blot analysis explored the inner mechanism of the effect of PAL on RA-FLS. At the same time, it also explored the role of PAL in CIA rats, including pathological section detection and western blot analysis., Main Results: PAL can promote the apoptosis and inhibit the proliferation, migration and invasion of RA-FLS. PAL can also reduce joint swelling in CIA rats, reduce pannus formation and inflammatory infiltration in the joints. Western blot analysis showed that PAL mainly played a role through the TLR4/NF-κB signaling pathway., Conclusion: The results of in vivo and in vitro experiments show that PAL can effectively alleviate the condition of RA, and may be a potential drug for the treatment of RA., (Copyright © 2021. Published by Elsevier B.V.)

Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially its anti-tumor effects. To improve the cytotoxicity and selective effect of PPT, in this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of PPT. The cytotoxicity of these compounds was evaluated with PC-3M, HemECs, A549, MCF-7 and HepG2 cells. We observed that the proliferation of PC-3M cells was inhibited by all 20 ester derivatives in the largest degree, comparing to the other cell lines. Comparing to PPT (IC 50  = 234.90 ± 20.7 nM), eight derivatives had better performance in inhabiting proliferation of PC-3M cells, six of them belong to Boc-amino acid ester derivatives, and the derivative named V-05 (IC 50  = 1.28 ± 0.1 nM) had the strongest inhibitation effect. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, flow cytometry and western blot analysis. We found that V-05 were able to inhibit PC-3M cells proliferation and migration, and induced apoptosis by downregualting p-PI3K, p-Akt and Bcl-2, and upregulating Cleaved caspase-3 and Bax. Our research provides the first insight for the application of PPT derivatives in PC-3M cells, which may offer information to the effective medicine development for human prostate cancer treatment., (Copyright © 2021. Published by Elsevier Ltd.)

Lung cancer is recognized as the leading cause of cancer-related death worldwide, with non-small cell lung cancer (NSCLC) being the predominant subtype, accounting for approximately 85% of lung cancer cases. Although great efforts have been made to treat lung cancer, no proven method has been found thus far. Considering β, β-dimethyl-acryl-alkannin (ALCAP2), a natural small-molecule compound isolated from the root of Lithospermum erythrorhizon. We found that lung adenocarcinoma (LUAD) cell proliferation and metastasis can be significantly inhibited after treatment with ALCAP2 in vitro, as it can induce cell apoptosis and arrest the cell cycle. ALCAP2 also significantly suppressed the volume of tumours in mice without inducing obvious toxicity in vivo. Mechanistically, we revealed that ALCAP2-treated cells can suppress the nuclear translocation of β-catenin by upregulating the E3 ligase NEDD4L, facilitating the binding of ubiquitin to β-catenin and eventually affecting the wnt-triggered transcription of genes such as survivin, cyclin D1, and MMP9. As a result, our findings suggest that targeting the oncogene β-catenin with ALCAP2 can inhibit the proliferation and metastasis of LUAD cells, and therefore, ALCAP2 may be a new drug candidate for use in LUAD therapeutics., (© 2021. The Author(s).)

Sagittaria trifolia is an aquatic plant that is distributed worldwide. The edible tuber part of S. trifolia is a very common and popular vegetable in China. The aim of the present review is to discuss the discovery of nutraceuticals from S. trifolia tuber by reviewing its major constituents, food processing, food products, and health-promoting benefits. Sagittaria trifolia tuber comprises a series of nutritional and bioactive constituents, including dietary fibers, amino acids, minerals, starches, non-starch polysaccharides, diterpenoids, colchicine, phenols, and organic acids. Food processing affects its flavor, biocomponents, and bioactivity. Numerous S. trifolia tuber-based food products and nutraceuticals have been developed, but new categories of products and the anticipated functions still need to be explored. The non-starch polysaccharides could be the central ingredients that contribute to the plant's antioxidant, hepatoprotective, hypoglycemic, lipid-regulating, and immunostimulatory properties. Of these, antioxidant and hepatoprotective effects have been thoroughly investigated. Procedures for the extraction and purification of polysaccharides influence their health-promoting actions. Overall, S. trifolia tuber is an underutilized aquatic vegetable species that is an emerging subject for nutraceutical research. © 2020 Society of Chemical Industry., (© 2020 Society of Chemical Industry.)

Ginsenosides (20S)-Rg3 and (20R)-Rg3 are famous rare ginsenosides from red ginseng, and their configurations in C-20 are different. This study aimed to investigate the protective mechanism of ginsenosides (20S)-Rg3 and (20R)-Rg3 on H 2 O 2 -induced H9C2 cells and compare their activity. The results showed that the ginsenosides (20S)-Rg3 and (20R)-Rg3 could increase the cell activity and the levels of GSH-Px, SOD and CAT, and decrease activities of LDH, MDA and ROS. Further studies showed that ginsenosides (20S)-Rg3 and (20R)-Rg3 could prevent oxidative stress injury of H9C2 cells by H 2 O 2 through the Keap-1/Nrf2/HO-1 pathway. But the ML385 counteracts these effects. Interestingly, among these results, ginsenoside (20R)-Rg3 was superior to (20S)-Rg3, indicating that ginsenoside (20R)-Rg3 have a stronger effect of antioxidative stress. This study reflected that ginsenoside (20R)-Rg3 could be used as a potential Nrf2 activator and a safe effective Chinese herbal monomer in the treatment of cardiovascular disease., (© 2021 Wiley-VHCA AG, Zurich, Switzerland.)

A rich of 3,4-seco-lupane triterpenoids including chiisanoside (CSS), divaroside (DVS), sessiloside-A1 (SSA) and chiisanogenin (CSG) were isolated from the ethanol extract of the leaves of Acanthopanax sessiliflorus. On the basis of previous studies, this article focused on four important components of 3,4-seco-lupane triterpenoids in Acanthopanax sessiliflorus leaves and explored their protective effects against aconitine-induced cardiomyocyte injury and their molecular mechanisms. The results showed that pretreatment with 3,4-seco-lupane triterpenoids could effectively increase cell viability, reduce CK-MB and LDH activities, reduce ROS production, maintain calcium concentration balance, and inhibit apoptosis, with divaroside having the best effect. In addition, Western blot results showed that divaroside down-regulated Cleaved caspase-3 and Bax and up-regulated Bcl-2 expression through activating the PI3 K/AKT pathway. However, the LY294002 inhibitor reversed this situation. This suggests that 3,4-seco-lupane triterpenoids may be a new hotspot for potential myocardial protective drugs research., (© 2020 Wiley-VHCA AG, Zurich, Switzerland.)

ε-Viniferin (VNF), a naturally occurring oligostilbene (a resveratrol dimer), is mainly found in grapes and red wines. However, unlike resveratrol, the biological activity of VNF has not been widely studied. This study was conducted to investigate the beneficial effects of VNF on hyperglycemia and hyperlipidemia and further to reveal the underlying mechanism. The ameliorative effects of VNF in high-fat-diet and streptozotocin-induced type 2 diabetic rats were assessed physiologically, biochemically and histologically after oral administration of VNF (30 mg kg-1 and 60 mg kg-1) for 8 weeks. Western blotting and immunohistochemistry experiments were performed to determine the effects of VNF on the AMPK phosphorylation levels in the livers of diabetic rats. Molecular docking and molecular dynamics simulation were further performed to study the molecular-level interaction between VNF and AMPK. Meanwhile, the protective effects of VNF on the liver and kidney were also evaluated. The results showed that the VNF treatment caused a significant decrease in the concentrations of fasting blood glucose (FBG), total cholesterol (TC), triglyceride (TG), and low density lipoprotein-cholesterol (LDL-C), and improved the glucose tolerance of diabetic rats. In addition, the liver and kidney damage indices such as alanine aminotransferase (ALT), aspartate aminotransaminase (AST), creatinine (CR), and blood urea nitrogen (BUN) were also lowered and improved. Moreover, VNF could increase the AMPK activation and attenuate histopathological changes in the liver of diabetic rats. The molecular docking and molecular dynamics simulation results revealed for the first time that VNF bound to the hinge region between the α- and β-units of AMPK and interacted with the active site of AMPK. In conclusion, VNF can effectively improve hyperglycemia and hyperlipidemia and exhibit protective effects on the liver and kidney functions. The underlying mechanism of VNF in hyperglycemia and hyperlipidemia may be related to the activation of AMPK in vivo. Our findings indicate that VNF is a potentially useful natural agent for the treatment of metabolic diseases, especially type 2 diabetes and hyperlipidemia.

Oviductus ranae is an animal-based traditional Chinese material widely used as tonics in China for hundreds of years. Various bioactive components are present in OR including proteins, amino acids, steroids, fatty acids, phospholipids, nucleosides, vitamins, hydantoins, and mineral elements. These constituents exert a myriad of biological functions such as immunomodulatory, antioxidant, antifatigue, antiaging, estrogen-like, hepatoprotective, hypolipidemic, antiosteoporotic, antidepressant, antitumor, antitussive, expectorant, anti-inflammatory, and antiasthmatic activities. Unlike other traditional Chinese crude drugs recorded in Chinese Pharmacopoeia, OR is seldom prescribed as medicine but often consumed as nutraceuticals to optimize health. In this review, the traditional uses, bioactive constituents, biological functions, and safety properties of OR as functional foods in China were summarized and discussed. It is expected that this review will provide useful information for anyone who is interested in OR.

Since the incidence rate of malignant melanoma is increasing annually, development of drugs against melanoma cell metastasis has become more urgent. Luteolin, a naturally occurring flavonoid, is abundant in our daily dietary intake and exhibits a wide spectrum of pharmacological properties. However, the potential anti-cancer role of luteolin in melanoma cells has not been fully investigated. In this study, we have explored whether luteolin inhibits the migration and invasion of A375 human melanoma cells and further elucidated the underlying anti-cancer molecular mechanism of luteolin in melanoma cells. A proliferation assay, flow cytometry and an apoptosis assay were applied to detect the effect of luteolin on the growth and apoptosis of A375 cells. Wound healing assay and transwell invasion assay were used to explore the impact of luteolin on the migration and invasion of A375 cells. Real-time quantitative PCR, western blot and immunofluorescence analysis were used to investigate the effects of luteolin on the expressions of MMP-2, MMP-9 and PI3K/AKT1 in A375 cells. A xenograft tumor animal model was used to investigate the anti-cancer effect of luteolin on the growth of the A375 cells in vivo. Our data indicated that luteolin significantly inhibited the proliferation, migration and invasion of A375 cells and induced the apoptosis of A375 cells in a concentration-dependent manner. Moreover, luteolin reduced the expressions of MMP-2 and MMP-9 and increased the expression of TIMP-1 and TIMP-2. Furthermore, luteolin significantly inhibited the tumor growth of A375 cells in a xenograft mouse model. The immunofluorescence and immunoblotting assays indicated that luteolin inhibited the phosphorylation of AKT1 and PI3K. In conclusion, both in vivo and in vitro studies showed that luteolin inhibited the proliferation and induced the apoptosis of A375 human melanoma cells by reducing the expressions of MMP-2 and MMP-9 through the PI3K/AKT pathway. Overall, luteolin can be considered as a promising anti-cancer agent for the treatment of human melanoma.

Increasing evidence has suggested that microRNAs (miRNAs; miRs) are extensively involved in the progression of chondrosarcoma (CHS). However, few studies have investigated the functional role of miR-525 in CHS tissues and cells. In the present study, it was discovered that miR-525 levels were decreased in CHS tissues and cells. Dual luciferase assays indicated that F-spondin 1 (SPON1) is a target gene of microRNA (miR)-525. In addition, miR-525 overexpression suppressed SW1353 cell migration and invasion and enhanced SW1353 cell apoptosis. Increased SPON1 expression levels were identified in CHS tissues and cell lines. Furthermore, miR-525 overexpression significantly suppressed the activation of focal adhesion kinase (FAK)/Src/phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (Akt) signaling in CHS cells; this suppression led to SPON1 silencing. In comparison, the SPON1 knockdown-mediated inactivation of FAK/Src/PI3K/Akt signaling was inhibited by inhibiting miR-525. In summary, the present study revealed that decreased miR-525 levels could enhance CHS malignancy as decreased miR-525 binding to the 3' untranslated region of SPON1 activates FAK/Src/PI3K/Akt signaling.

The current study mainly aims to evaluate the expression pattern and underlying mechanism of upstream stimulating factor 1 (USF1) in the muscle tissues of knee osteoarthritis (KOA) patients. In accordance with previous findings, our data showed that muscle strength was significantly decreased in KOA patients compared with controls. Furthermore, several inflammatory factors, including tumor necrosis factor α (TNFα), IL-8, IL-6 and MCP-1, were associated with reduced muscle strength in KOA patients. Not surprisingly, NF-κB signaling was significantly activated in the muscle tissues of KOA patients compared with control individuals. Furthermore, we showed that USF1 was increased in the muscles of KOA patients compared with controls. More importantly, overexpression of USF1 in primary human skeletal muscle cells significantly increased the activation of NF-κB signaling as well as the levels of pro-inflammatory factors. In summary, we showed novel data that the upregulation of USF1 promoted NF-κB activation-induced inflammatory responses in muscle tissues of KOA patients.

Recent studies suggest that cytokines and microRNAs play a key role in the destruction of cartilage matrix in osteoarthritis (OA) tissues. In the current study, we focused on miR-204, which has never been explored in OA. We found that the level of miR-204 was markedly reduced in the OA cartilage tissues compared with that of normal control. Real time PCR analysis demonstrated that the level of miR-204 was markedly decreased after IL-1β treatment for 3, 6, 12 h in the normal chondrocytes and OA chondrocytes, respectively. Furthermore, overexpression of miR-204 markedly suppressed the protein levels of IL-1β, COX-2 and IL6 in human OA chondrocytes and chondrogenic SW1353 cells. Dual luciferase reporter assay demonstrated that miR-204 significantly suppressed the relative luciferase activity of pmirGLO-IL-1β-3'UTR, indicating that IL-1β was a target gene of miR-204. More importantly, treatment with IL-1β significantly enhanced the protein levels of IL-1β, COX-2 and IL6. However, overexpression of miR-204 could partially abolish such effects. In conclusion, our data demonstrate that reduced miR-204 expression enhances the destruction of the cartilage tissues among OA patients mainly through targeting IL-1β.

Beneficial actions of EGb 761 against ischemia/reperfusion (I/R) injury in lung, brain and renal ischemia have been described. However, the relationship between EGb 761 and signal molecules in myocardial ischemia reperfusion has not been well elucidated. In this study, we investigated the effects and mechanism of EGb 761 preconditioning on anti-myocardial I/R injuries in vivo . Meanwhile, their potential anti-oxidative stress and anti-inflammation effect were assessed. Hemodynamic parameters were monitored as left ventricular systolic pressure, LV end-diastolic pressure and maximal rate of increase and decrease of left ventricular pressure (dP/dtmax). The oxidative stress indicators and inflammatory factors were also evaluated. Western blot method was used for analysis of toll-like receptor 4 (TLR4), p-TLR4, nuclear factor-κB (NF-κB), p-NF-κB p65, Bax and Bcl-2 protein expressions. EGb 761 significantly improved cardiac function, decreased levels of creatine kinase, aspartate aminotransferase and lactate dehydrogenase. EGb 761 also restrained the oxidative stress related to myocardial ischemia injury as evidenced by decreased malondialdehyde, superoxide dismutase, catalase, glutathione-peroxidase, glutathione reductase activity. Meanwhile, the inflammatory cascade was inhibited as evidenced by decreased cytokines such as tumor necrosis factor-α, interleukin-6 and interleukin-1β. Our results still showed that EGb 761 pretreatment significantly decrease the level of cleaved Bax, and increase the level of Bcl-2 in rats subjected to I/R injury. Simultaneously, the expressions of myocardial TLR4 and NF-κB were significantly decreased. It can be concluded that EGb 761 pretreatment was protected against myocardium I/R injury by decreasing oxidative stress, repressing inflammatory cascade in vivo and inhibiting TLR4/NF-κB pathway., Competing Interests: CONFLICTS OF INTEREST Authors declare that they have not any conflicts of interest.

Objectives: To study the structure of a small GTPaseRhoA in complex with PDZRhoGEF and the inhibitor HL47, and to provide an easier template for R&D of RhoA inhibitor., Results: Our initial attempts to obtain a binary complex of RhoA with the inhibitor HL47 were unsuccessful probably due to the presence of GDP. By targeting a ternary complex involving the RhoA-specific guanine nucleotide exchange factor PDZRhoGEF, we eliminated GDP and obtained a 2.3 Å structure of the RhoA-PDZRhoGEF-inhibitor HL47 ternary complex., Conclusion: This structure provides a new template for target-based pharmaceutical design against RhoA.

Background: The aim of this experimental study was to evaluate the effect of intra-articular injection of Deoxycholic acid (DCA) on articular cartilage and subchondral bone following induction of knee Osteoarthritis (OA) in a rat model., Methods: Twenty-four Sprague Dawley rats were randomized divided into 4 groups (n = 6). Eighteen of the 24 rats underwent surgical destabilization of the medial meniscus on the right knee joints to induce OA, were divided into 3 groups: DCA 30 mg/kg group, DCA 120 mg/kg group and OA group. The rats in DCA-treated groups were given intra-articular injections of DCA (30 mg/kg or 120 mg/kg) in the operated knees once per 3 days for 42 days. The rats in OA group given intra-articular injections of vehicle alone in the operated knees under the same conditions. The remaining 6 rats (sham-operation group) received sham operations on the right knee joints. 45 days postoperatively, all of the animals were euthanized for macroscopic, histological and radiographic analysis to evaluate the effect of DCA on OA and to determine its potential mechanisms., Results: The results showed that DCA attenuated the severity of OA by reducing macroscopic observation sores for femoral condyles and histological sores for articular cartilage. DCA also significantly decreased bone destruction and erosion of joint evaluated by radiographic examination. Furthermore, DCA could markedly reduce the release of MMP-1, MMP-3 and IL-1β in serum., Conclusions: Intra-articular injection of DCA is beneficial for knee OA. It might repair and protect OA cartilage by delaying cartilage degeneration and impairing the function of inflammatory mediators. These findings highlight DCA might be a useful therapeutic agent for OA.

RhoA, a member of the Rho GTPases, is involved in a variety of cellular functions and could be a suitable therapeutic target for the treatment of cardiovascular diseases. However, few small-molecule RhoA inhibitors have been reported. Based on our previously reported lead compounds, 32 new 2-substituted quinoline (or quinoxaline) derivatives were synthesized and tested in biological assays. Six compounds showed high RhoA inhibitory activities, with IC50 values of 1.17-1.84 μM. Among these, (E)-3-(3-(ethyl(quinolin-2-yl)amino)phenyl)acrylic acid (26 b) and (E)-3-(3-(butyl(quinolin-2-yl)amino)phenyl)acrylic acid (26 d) demonstrated noticeable vasorelaxation effects against phenylephrine-induced contraction in thoracic aorta artery rings, and compound 26 b had good water solubility and showed significant in vivo efficacy, which was similar to that of 5-(1,4-diazepane-1-sulfonyl)isoquinoline (fasudil) in a subarachnoid hemorrhage-cardiovascular model. To the best of our knowledge, compound 26 b is the first example of a small- molecule RhoA inhibitor with potent in vivo efficacy, which could serve as a good lead for designing cardiovascular agents., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Rheumatoid arthritis is the most common arthritis and is mainly characterized by symmetric polyarticular joint disorders. Eleutheroside E (EE), a principal active constituent of Acanthopanax senticosus, is reported to have anti-inflammatory effect by inhibiting NF-κB activities. However, the effects of EE on rheumatoid arthritis (RA) severity are largely unknown. The purpose of this study was to indicate whether EE could ameliorate arthritis and reduce inflammatory cytokine release in collagen-induced arthritis (CIA) mice. The results showed that EE attenuated the severity of arthritis by reducing the mean arthritis score and arthritis incidence. EE also significantly decreased the inflammatory cell infiltration, pannus formation, cartilage damage, and bone erosion of CIA mice. Furthermore, EE caused a marked decrease of the production of TNF-α and IL-6 in vivo and in vitro. These observations identify a novel function of EE that results in inhibition of cytokine release, highlighting EE was a potential therapeutic agent for RA.

Two new ceramides, (3S,4S,5R)-3-octadecanoylamino-4-hydroxy-5-dodecane-2,3,4,5-tetrahydrofuran (1) and (3S,4S,5R)-3-[(2R)-2-hydroxyhexacosanoylamino]-4-hydroxy-5-[(4E)-dodecane-4-ene]-2,3,4,5-tetrahydrofuran (2), together with eight known compounds, eleutheroside A (3), eleutheroside B (4), eleutheroside E (5), 7-hydroxy-6-methoxy-coumarin (6), 6,7-dimethoxycoumarin (7), 5α,8α-epidioxyergosta-6,22-dien-3-ol (8), stigmasterol (9) and rutin (10), were isolated from the fruit pulp of Acanthopanax senticosus (Rupr. et Maxim) Harms. Their structures were elucidated by means of physicochemical properties and spectroscopic methods (1D, 2D NMR and MS).

Mice with chronic graft-versus-host disease (cGVHD) induced by transferring parental BALB/C lymphocytes into (C57BL/6 × BALB/C) F1 (CBF1) hybrids, develop a syndrome characterized by B-cell hyperactivity, autoantibody production, and immune complex-mediated glomerulonephritis. In this model, we evaluated the role of leflunomide on the development of lupus nephritis in system autoimmunity. Daily administration of leflunomide (15 mg/kg/d) from 2 weeks after cGVHD induction can dramatically reduce the production of autoantibodies and immune complex deposition in the kidney, leading to relieved kidney damage and reduced mortality. The therapeutic effect of leflunomide on the lupus-prone mice was partially due to the inhibition of TLR9 signaling pathway, which was an important component of innate immune system.

Background and Aims: Th1/Th2-like cytokine mRNA levels in non-cancerous hepatic tissues from patients with hepatocellular carcinoma (HCC) are associated with metastases and recurrence. This study evaluated the prognostic values of intratumoral and peritumoral Th1/Th2 cytokine protein levels in patients with HCC after curative resection., Methods: Two independent cohorts (A and B) of 453 patients with HCC were enrolled. Twelve Th1/Th2 cytokines in tumour and peritumoral hepatic tissues from cohort A (n=192) were quantified with enzyme-linked immunosorbent assays. This cohort was split into training and test sets which were used to identify and verify the prognostic cytokines. The prognostic values of identified cytokines were further validated in cohort B (n=261) using tissue microarray and immunohistochemical staining., Results: In the training set, higher interleukin (IL)-2 and IL-15 levels in peritumoral liver tissues, but not in tumour tissues, were significantly associated with a decreased incidence of recurrence of intrahepatic tumour and a prolonged overall survival. This association was verified in the testing set and further validated in patients in cohort B. Importantly, this correlation remained significant in patients with early HCC. Univariate and multivariate analyses indicated that the prognostic performance of peritumoral IL-2 (HR for recurrence=0.4, 95% CI 0.3 to 0.6, p<0.0001; HR for death=0.6, 95% CI 0.4 to 0.8, p=0.005) and IL-15 (HR for recurrence=0.7, 95% CI 0.5 to 0.95, p=0.025) was independent of other clinicopathological factors., Conclusion: Peritumoral IL-2 and IL-15 levels are useful for stratifying patients, even those with early-stage HCC, into subgroups with different prognoses after curative resection.

The title compound, [Ni(2)(C(9)H(6)O(4))(2)(C(12)H(8)N(2))(2)(H(2)O)(2)], is isostructural with the Zn(II) analogue. Each Ni(II) atom is coordinated in a distorted octa-hedral geometry by three O atoms from two homophthalate anions, one aqua O atom and two 1,10-phenanthroline N atoms. The two Ni(II) atoms are linked by two bridging homophthalate dianions into a centrosymmetric dinuclear unit. The dinuclear units are linked into one-dimensional ladder-like chains along [100] by O-H⋯O hydrogen bonds between the coordinated water mol-ecules and one of the O atoms of the carboxyl-atomethyl group.