Paris polyphylla ethanol extract and polyphyllin I ameliorate adenomyosis by inhibiting epithelial-mesenchymal transition.

BACKGROUND: The active ingredients of the Chinese medical herb Paris polyphylla, P. polyphylla ethanol extract (PPE) and polyphyllin I (PPI), potentially inhibit epithelial-mesenchymal transition (EMT) in tumors. However, the roles of these ingredients in inhibiting EMT in adenomyosis (AM) remain to be explored. PURPOSE: The primary goal of the study was to uncover the underlying molecular processes through which PPE and PPI suppress EMT in AM, alongside assessing the safety profiles of these substances. METHODS: To assess the suppressive impact of PPE on adenomyosis-derived cells (AMDCs), we employed Transwell and wound healing assays. The polyphyllins (PPI, PPII, PPVII) contained in PPE were characterized using high-performance liquid chromatography (HPLC). Then, bioinformatics techniques were performed to pinpoint potential PPI targets that could be effective in treating AM. Immunoblotting was used to verify the key proteins and pathways identified via bioinformatics. Furthermore, we examined the efficacy of PPE and PPI in treating Institute of Cancer Research (ICR) mice with AM by observing the morphological and pathological features of the uterus and performing immunohistochemistry. In addition, we assessed safety by evaluating liver, kidney and spleen pathologic features and serum test results. RESULTS: Three major polyphyllins of PPE were revealed by HPLC, and PPI had the highest concentration. In vitro experiments indicated that PPE and PPI effectively prevent AMDCs invasion and migration. Bioinformatics revealed that the primary targets E-cadherin, N-cadherin and TGFß1, as well as the EMT biological process, were enriched in PPI-treated AM. Immunoblotting assays corroborated the hypothesis that PPE and PPI suppress the TGFß1/Smad2/3 pathway in AMDCs to prevent EMT from progressing. Additionally, in vivo studies showed that PPE (3 mg/kg and 6 mg/kg) and PPI (3 mg/kg and 6 mg/kg), successfully suppressed the EMT process through targeting the TGFß1/Smad2/3 signaling pathway. Besides, it was observed that lower doses of PPE (3 mg/kg) and PPI (3 mg/kg) exerted minimal effects on the liver, kidneys, and spleen. CONCLUSIONS: PPE and PPI efficiently impede the development of EMT by inhibiting the TGFß1/Smad2/3 pathway, revealing an alternative pathway for the pharmacological treatment of AM.

Plant polyphenol surfactant construction with strong surface activity and chelation properties as efficient decontamination of UO22+ on cotton fabric.

Chemically synthesized surfactants have promising applications in the treatment of uranium, however, their hazardous environmental effects, non-biodegradability, and numerous drawbacks prevent them from being widely used in practice. Herein, we successfully synthesized a green chelating and foaming integrated surfactant (BTBS) by Mannich reaction and acylation of bayberry tannin for the effective removal of UO22+ from aqueous environments or solid surfaces. The as-prepared surfactant was systematically characterized by FT-IR, showing that the hydrophobic groups were successfully grafted onto tannin. The modified material showed better foaming and emulsifying properties, which proved this method could improve the amphiphilicity of tannin. Moreover, for the first time, a foam fractionation method in conjunction with a tannin-based surfactant was applied for UO22+ removal from water. This surfactant was used as a co-surfactant and could readily remove 90 % of UO22+ (20 mg L-1) from water. The removal of UO22+ could be completed in a short time (30 min), and the maximum adsorption capacity was determined as 175.9 mg g-1. This surfactant can also be used for efficient decontamination of uranium-contaminated cotton cloth with a high removal rate of 94.55 %. In addition, the mechanism studies show that the adsorption of BTBS for UO22+ can be mainly attributed to a chelating mechanism between UO22+ and the adjacent phenolic hydroxyls. The novel biomass-derived BTBS with advantages such as high capture capacity, environmental friendliness, and cost-effectiveness suggests that it plays an important role in the remediation of radionuclide pollution.

Anti-inflammatory effects of extracellular vesicles from Morchella on LPS-stimulated RAW264.7 cells via the ROS-mediated p38 MAPK signaling pathway.

Morchella is a kind of important edible and medicinal fungi, which is rich in polysaccharides, enzymes, fatty acids, amino acids and other active components. Extracellular vesicles (EVs) have a typical membrane structure, and the vesicles contain some specific lipids, miRNAs and proteins, and their can deliver the contents to different cells to change their functions. The present study investigated whether Morchella produce extracellular vesicles and its anti-inflammatory effect on lipopolysaccharide (LPS)-induced RAW246.7 macrophages. The experimental results showed that Morchella produced extracellular vesicles and significantly reduced the production of nitric oxide (NO) and reactive oxygen species (ROS) in a model of LPS-induced inflammation. In addition, the expression of inflammatory factor-related genes such as inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and cyclooxygenase-2 (COX-2) showed dose-dependent inhibition. Morchella extracellular vesicles also can inhibit the inflammatory response induced by LPS by inhibiting the production of ROS and reducing the phosphorylation levels of the p38 MAPK signaling pathway. These results indicate that the Morchella extracellular vesicles can be used as a potential anti-inflammatory substance in the treatment of inflammatory diseases.

Red Cell Distribution Width-To-Lymphocyte Ratio as a New Prognostic Predictor in HBV-Associated Decompensated Cirrhosis.

BACKGROUND: Hepatitis B virus-associated decompensated cirrhosis (HBV-DeCi) has a high risk of short-term mortality. However, it is difficult to predict the prognosis of these patients in clinical practice. The present study sought to determine whether red cell distribution width-to-lymphocyte ratio (RLR) is related to adverse outcomes in HBV-DeCi patients. METHODS: One hundred and seventy HBV-DeCi patients were recruited for the study. The patients were divided into survivor and non-survivor groups according to the 30-day mortality. Multivariate logistic analyses and area under the receiver operating characteristic curve (AUROC) values were used to determine the performance of RLR as a prognostic predictor in HBV-DeCi. RESULTS: The 30-day mortality of the HBV-DeCi patients was 13.5% (23/170). RLR was higher in the non-survivor group compared with the survivor group. Multivariate analysis identified RLR as an independent factor for mortality in HBV-DeCi patients. The AUROC analysis demonstrated that RLR can be a reliable prognostic biomarker for HBV-DeCi patients. CONCLUSIONS: RLR could be utilized as a short-term prognostic indicator for HBV-DeCi patients.

D-Dimer-to-Albumin Ratio: A Novel Indicator to Predict Poor Outcomes in Patients with HBV-Associated Decompensated Cirrhosis.

Background: The purpose of the present study was to investigate the impact of D-dimer-to-albumin ratio (DAR) on outcomes in patients with hepatitis B virus-associated decompensated cirrhosis (HBV-DeCi). Methods: A total of 172 HBV-DeCi patients were enrolled. Logistic regression was used to explore the association between DAR and 30-day mortality. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of DAR for predicting mortality. Results: The 30-day mortality was 19.8%. DAR was clearly higher in the nonsurvivors compared with the survivors, and increasing DAR was associated with an increasing risk of death. DAR was independently associated with mortality and its AUC for mortality was equivalent to that for Model for End-Stage Liver Disease score. Conclusions: DAR may be a potential prognostic marker for mortality in HBV-DeCi patients.

Agrimonolide inhibits cancer progression and induces ferroptosis and apoptosis by targeting SCD1 in ovarian cancer cells.

BACKGROUND: Ovarian cancer is a gynaecological tumour has high incidence and mortality rates. Agrimonolide, isolated from Agrimonia pilosa Ledeb, has multiple biomedical activities, including anticancer activity. PURPOSE: Here, we aimed to reveal the function of agrimonolide on ovarian cancer progression. METHODS: MTT assay, colony-formation assay, flow cytometry, transwell assay, scratch test, western immunoblotting, reactive oxygen species (ROS) detection, and ferroptosis analysis were performed to reveal the role and underlying mechanisms of agrimonolide in ovarian cancer cell lines (A2780 and SKOV-3). The effects of agrimonolide on the SKOV-3 xenograft model were also studied. RESULTS: Agrimonolide dose-dependently inhibited proliferation, migration, and invasion and promoted apoptosis in A2780 and SKOV-3 cells. Agrimonolide induced ferroptosis in tumour cells, evidenced by the increased levels of ROS, total iron, and Fe2+ and downregulation of ferroptosis indicators (SLC7A11 and GPX4). The SwissTargetPrediction and Comparative Toxicogenomics Database predicted SCD1 as a target protein for agrimonolide. Molecular Operating Environment software docked agrimonolide in the SCD1 protein, and the binding energy of interaction was -8.21 kcal/mol. The effects of agrimonolide on proliferation, invasion, and induction of apoptosis and ferroptosis were attenuated by SCD1 overexpression in A2780 and SKOV-3 cells. Additionally, agrimonolide attenuated the tumour growth of ovarian cancer in the SKOV-3 xenograft model and significantly downregulated SCD1 in tumour tissues. CONCLUSION: Our study is the first to suggest that agrimonolide acts as a novel apoptosis- and ferroptosis-inducing agent in ovarian cancer cells by targeting SCD1. Agrimonolide may be a novel therapeutic agent for treating ovarian cancer.

Adsorption of Lead (II) from Aqueous Solution with High Efficiency by Hydrothermal Biochar Derived from Honey.

A novel natural honey hydrothermal biochar (HHTB) was prepared using natural honey as raw material. The as-prepared adsorbent was applied to adsorb Pb2+ from aqueous solution and characterized by scanning electron microscopy, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy to investigate the structure and morphology change of the adsorbent before and after Pb2+ adsorption. The influence of the pH, initial Pb2+ concentration, temperature, and contact time on the adsorption of Pb2+ was systematically investigated. The results revealed that the adsorption capacity for Pb2+ is up to 133.2 mg·g-1 at initial pH of 5.0 and adsorption temperature of 298 K. Meanwhile, the adsorption of Pb2+ on HHTB can be well fitted by the pseudo-second-order model and Langmuir isotherm model. The adsorbent had great selectivity for Pb2+ from the aqueous solution containing coexisting ions including Cd2+, Co2+, Cr3+, Cu2+, Ni2+ and Zn2+. Furthermore, the adsorption of Pb2+ on HHTB was attributed to complexation coordination, where it involved hydroxyl and carboxylic groups on HHTB in the process of adsorption of Pb2+.

Advanced X-ray Shielding Materials Enabled by the Coordination of Well-Dispersed High Atomic Number Elements in Natural Leather.

Nowadays, X-rays are playing increasingly important roles in daily life and industrial manufacture, which calls for effective and mobile shielding materials. However, it seems to be a paradox to prepare shielding materials simultaneously achieving excellent X-ray attenuation properties and superior mechanical strength. Here, an advanced leather-based X-ray shielding material containing bismuth and iodine (BiINP-LM) is prepared, and the stable and well-dispersed loading of high-Z element components is enabled by favorable interactions between bismuth iodide and leather, i.e., coordination, hydrogen bonds, and electrostatic attractions. A piece of BiINP-LM with 1.00 mm thickness displays an excellent X-ray attenuation efficiency of more than 90% in the photon energy range below 50 keV and 65% at 83 keV, which averagely exceeds ∼3% than that of the 0.25 mm lead plate and ∼5% than that of the 0.65 mm commercial lead apron. Additionally, the coordination between bismuth and leather provides an enhanced tensile and tear strength of ∼10-fold and 3-fold compared with the lead apron. It is worth mentioning that BiINP-LM also displays extra high water-vapor permeability, which is ∼50-fold more than the lead apron. Overall, this work opens up a new prospect for preparing advanced X-ray shielding materials with both excellent X-ray attenuation and outstanding physiomechanical performances.

Inhibition of glycolysis by a novel EGFR/HER2 inhibitor KU004 suppresses the growth of HER2+ cancer.

Upregulation of glycolysis was often observed in human HER2-overexpressing cancers. In this study, we demonstrated that KU004, a dual novel EGFR/HER2 inhibitor, disrupted cancer cell proliferation via modulation of glycolysis. KU004, inhibited the Warburg effect by suppressing hexokinase II (HK2) expression at the transcriptional and post-translational levels. Further study demonstrated that the downregulation of HKII by KU004 was mainly mediated by the PI3K/Akt signaling pathway. Furthermore, the role of HKII downregulation in KU004-mediated antitumor effect was also confirmed in our in vivo xenograft model. Collectively, these data suggest that multifaceted targeting the aberrant glucose metabolism along with the upstream HER2 may be an effective approach for clinical treatment against HER2+ cancer.

Pyrazinamide-induced hepatotoxicity is alleviated by 4-PBA via inhibition of the PERK-eIF2α-ATF4-CHOP pathway.

Pyrazinamide (PZA)-induced serious liver injury, but the exact mechanism of PZA-induces hepatotoxicity remains controversial. Endoplasmic reticulum (ER) stress-caused cell apoptosis plays a critical role in the development of drug-induced liver injury (DILI). However, the direct connection between PZA toxicity and ER stress is unknown. In this study, we describe the role of ER stress in PZA induced hepatotoxicity in vivo and in vitro. We found that PZA induces apoptosis in HepG2 cells, and causes liver damage in rats, characterized by increased serum ALT, AST and TBA levels. PZA impairs antioxidant defenses, although this effect did not play an important role in resulting liver injury. The ER stress related proteins GRP78, p-PERK, p-eIF2α, ATF4, CHOP and caspase12 were activated after PZA exposure both in vivo and in vitro. Furthermore, as an ER stress inhibitor, sodium 4-phenylbutyrate (4-PBA) could ameliorate PZA toxicity in HepG2 cells and rat liver. These results have potential implications for the pathogenesis of PZA-induced hepatotoxicity in which ER stress especially PERK-eIF2α-ATF4-CHOP pathway participates in hepatocellular injury.

Liver Fatty Acid Binding Protein Deficiency Provokes Oxidative Stress, Inflammation, and Apoptosis-Mediated Hepatotoxicity Induced by Pyrazinamide in Zebrafish Larvae.

Pyrazinamide (PZA) is an essential antitubercular drug, but little is still known about its hepatotoxicity potential. This study examined the effects of PZA exposure on zebrafish (Danio rerio) larvae and the mechanisms underlying its hepatotoxicity. A transgenic line of zebrafish larvae that expressed enhanced green fluorescent protein (EGFP) in the liver was incubated with 1, 2.5, and 5 mM PZA from 72 h postfertilization (hpf). Different endpoints such as mortality, morphology changes in the size and shape of the liver, histological changes, transaminase analysis and apoptosis, markers of oxidative and genetic damage, as well as the expression of certain genes were selected to evaluate PZA-induced hepatotoxicity. Our results confirm the manner of PZA dose-dependent hepatotoxicity. PZA was found to induce marked injury in zebrafish larvae, such as liver atrophy, elevations of transaminase levels, oxidative stress, and hepatocyte apoptosis. To further understand the mechanism behind PZA-induced hepatotoxicity, changes in gene expression levels in zebrafish larvae exposed to PZA for 72 h postexposure (hpe) were determined. The results of this study demonstrated that PZA decreased the expression levels of liver fatty acid binding protein (L-FABP) and its target gene, peroxisome proliferator-activated receptor α (PPAR-α), and provoked more severe oxidative stress and hepatitis via the upregulation of inflammatory cytokines such as tumor necrosis factor alpha (TNF-α) and transforming growth factor ß (TGF-ß). These findings suggest that L-FABP-mediated PPAR-α downregulation appears to be a hepatotoxic response resulting from zebrafish larva liver cell apoptosis, and L-FABP can be used as a biomarker for the early detection of PZA-induced liver damage in zebrafish larvae.

Pyrazinamide Induced Rat Cholestatic Liver Injury through Inhibition of FXR Regulatory Effect on Bile Acid Synthesis and Transport.

Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/ß, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport.

Pyrazinamide induced hepatic injury in rats through inhibiting the PPARα pathway.

Pyrazinamide (PZA) causes serious hepatotoxicity, but little is known about the exact mechanism by which PZA induced liver injury. The peroxisome proliferator-activated receptors alpha (PPARα) is highly expressed in the liver and modulates the intracellular lipidmetabolism. So far, the role of PPARα in the hepatotoxicity of PZA is unknown. In the present study, we described the hepatotoxic effects of PZA and the role of PPARα and its target genes in the downstream pathway including L-Fabp, Lpl, Cpt-1b, Acaa1, Apo-A1 and Me1 in this process. We found PZA induced the liver lipid metabolism disorder and PPARα expressionwas down-regulated which had a significant inverse correlation with liver injury degree. These changeswere ameliorated by fenofibrate, the co-treatment that acts as a PPARα agonist. In contrast, short-termstarvation significantly aggravated the severity of PZA-induced liver injury. In conclusion, this study demonstrated the critical role played by PPARα in PZA-induced hepatotoxicity and provided a better understanding of the molecular mechanisms underlying PZA-induced liver injury. Copyright © 2016 John Wiley & Sons, Ltd.

A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells.

Human epidermal growth factor receptor 2 (HER2) is a validated therapeutic target in cancer therapy, and HER2 protein-tyrosine kinase inhibitors have attracted considerable attention in the field of searching for novel anticancer drug candidates. In this study, we investigated the anticancer effect of KU004, a novel dual EGFR and HER2 inhibitor in vitro and in vivo. In vitro, KU004 preferentially inhibited the growth of HER2-overexpressing breast and gastric cell lines and HER2 expression level significantly correlated with response to KU004. It blocked activation of EGFR, HER2 and downstream Akt and Erk and induced G0/G1 arrest which was associated with downregulation of p53, p21, cyclin D1 and CDK4 along with increase of p27 and dephosphorylation of pRb. Apoptosis occurred in a caspase-dependent manner mainly via the extrinsic apoptotic pathway after KU004 treatment. The in vitro efficacy of KU004 was comparable to that of lapatinib. Moreover, KU004 suppressed the growth of NCI-N87 tumor and induced apoptosis without causing apparent weight loss or obvious toxicity. Tumor volume was significantly smaller in KU004-treated group than that in lapatinib-treated group at comparable dose levels. Taken together, these findings demonstrate KU004 can be expected to be a promising anti-HER2 candidate.

Adsorption chromatography separation of the flavonols kaempferol, quercetin and myricetin using cross-linked collagen fibre as the stationary phase.

BACKGROUND: Kaempferol, quercetin and myricetin are typical flavonols that are most concentrated in many medicinal herbs. However, the separation of these flavonols is very challenging due to their similar molecular structures. In the present investigation, the chromatographic separation of the flavonols kaempferol, quercetin and myricetin was performed using glutaraldehyde cross-linked collagen fibre (GCF) as the stationary phase. RESULTS: Kaempferol, quercetin and myricetin could be completely separated from each other by the GCF column by using gradient elution with different solutions of aqueous ethanol (100% to 70%) and 50% acetone. When the chromatographic separation was carried out at a flow rate of 0.75 bed volume h(-1) with a sample loading of 30 mg 7 g(-1) GCF, the purity of kaempferol, quercetin and myricetin was 98.17%, 93.81% and 81.76%, respectively. The separation resolution was influenced by column length, flow rate and sample loading amount. The separation efficiency of GCF was not obviously reduced after applications had been repeated five times. In the fifth repeated application, the purity of the recovered kaempferol, quercetin and myricetin was still higher than 97%, 94% and 78%, respectively. CONCLUSION: GCF is a promising adsorbent for use as a stationary phase in the chromatographic separation of flavonols from their mixtures.