Effects of electric field and light on resistivity switching of Eu0.7Sr0.3MnO3 thin films.

Based on the excellent piezoelectric properties of 0.7Pb(Mg1/3Nb2/3)O3-0.3PbTiO3 (PMN-PT) single crystals, a hole-doped manganite film/PMN-PT heterostructure has been constructed to achieve electric-field and light co-control of physical properties. Here, we report the resistivity switching behavior of Eu0.7Sr0.3MnO3/PMN-PT(111) multiferroic heterostructures under different in-plane reading currents, temperatures, light stimuli and electric fields, and discuss the underlying coupling mechanisms of resistivity change. The transition from the electric-field induced lattice strain effect to polarization current effect can be controlled effectively by decreasing the in-plane reading current at room temperature. With the decrease of temperature, the interfacial charge effect dominates over the lattice strain effect due to the reduced charge carrier density. In addition, light stimulus can lead to the delocalization of eg carriers, and thus enhance the lattice strain effect and suppress the interfacial charge effect. This work helps to understand essential physics of magnetoelectric coupling and also provides a potential method to realize energy-efficient multi-field control of manganite thin films.

Research progress on bioleaching recovery technology of spent lithium-ion batteries.

Bioleaching of lithium-ion batteries is a microbially catalyzed process. Under the action of redox, acid leaching and complexation in the presence of microorganisms, the valuable metals in the cathode material enter the liquid phase as ions and are subsequently recovered from the succeeding process. This technique has the advantages of being inexpensive, environmentally friendly and having simple needs. However, it is still in development and has not yet commercialized. In this paper, the technology is fully discussed based on numerous excellent studies. The contents include commonly utilized microorganisms, bioleaching mechanism, microbial stress response and metabolic activation, enhancement strategies, leaching characteristics and interfacial phenomena, process evaluation, and a critical discussion of recent research breakthroughs. They give readers with comprehensive and in-depth understanding on the bioleaching of lithium-ion batteries and help to improve the technology's industrialization. Researchers can make new explorations from the potential research directions and methods presented in this work to make biotechnology better serve resource recovery and social development.

Cultivated human intestinal fungus Candida metapsilosis M2006B attenuates colitis by secreting acyclic sesquiterpenoids as FXR agonists.

OBJECTIVE: Dysbiosis of the intestinal fungal community has been observed in inflammatory bowel disease (IBD); however, its potential role in IBD development and prevention remains unclear. Here, we explored the biological effects and molecular mechanisms of intestinal fungi isolated from human faeces on colitis in mice. DESIGN: Intestinal fungal strains with differential abundance in IBD were cultivated in human faeces and their effects on various mouse models of experimental colitis were evaluated. In addition, the bioactive metabolites secreted by the target fungus were accurately identified and their pharmacological effects and potential molecular targets were investigated in vitro and in vivo. RESULTS: The abundance of Candida spp was significantly higher in patients with IBD. After large-scale human intestinal fungal cultivation and functional analysis, Candida metapsilosis M2006B significantly attenuated various models of experimental colitis in wild-type, antibiotic-treated, germ-free, and IL10-/- mice by activating farnesoid X receptor (FXR). Among the seven acyclic sesquiterpenoids (F1-F7) identified as major secondary metabolites of M2006B, F4 and F5 attenuated colitis in mice by acting as novel FXR agonists. The therapeutic effects of M2006B and its metabolites on colitis via specific FXR activation were confirmed in Fxr -/- mice. CONCLUSION: This study revealed that C. metapsilosis M2006B significantly attenuated colitis in mice and identified two acyclic sesquiterpenoids (F4 and F5) as major active metabolites of M2006B. Notably, these metabolites were able to effectively treat experimental colitis by selectively activating FXR. Together, this study demonstrates that M2006B could be a beneficial intestinal fungus for treating and preventing IBD.

A strategy for the rapid discovery and validation of active diterpenoids as quality markers in different habitats of Langdu using ultrahigh-performance liquid chromatography-tandem mass spectrometry with multivariate statistical analysis.

Langdu, known as a traditional Chinese medicine, was identified as the roots of species of Euphorbia ebracteolata Hayata and Euphorbia fischeriana Steud, displaying anti-tuberculosis activity. To clarify the potent quality markers of Langdu, this research first developed a fast and sensitive ultrahigh-performance liquid chromatography-tandem mass spectrometry method for the quantification of 13 diterpenoids in Langdu. The developed method was further applied in the analyses of 12 authentic E. ebracteolata and E. fischeriana samples collected in northern and southeastern China. Then, the anti-tuberculosis evaluation of 12 batches of Langdu samples was performed in vitro. Finally, partial least squares discrimination analysis was used in the discrimination of E. ebracteolata and E. fischeriana from different origins and processing methods. Jolkinolide A (1), jolkinolide E (3), yuexiandajisu D (6), and ebractenone A (11) were identified as key, potent diterpenoids for the quality control of E. ebracteolata Hayata and E. fischeriana Steud. The present study established a qualitative chemical analysis method for Langdu (E. ebracteolata and E. fischeriana) and suggested the key bioactive components that will improve qualitative control methodology for this important medicine.

Synthesis and biological evaluation of selenogefitinib for reducing bleomycin-induced pulmonary fibrosis.

Selenium has demonstrated effectiveness in the reduction of oxidative stress and inflammation in vitro and in vivo, both of which are key indicators of the pathogenesis of pulmonary fibrosis. Gefitinib, an FDA-approved EGFR inhibitor, effectively reverses the deterioration of bleomycin-induced pulmonary fibrosis. Based on this, we proposed introducing a selenium atom into the structure of gefitinib, resulting in the generation of selenogefitinib. Compared to gefitinib, selenogefitinib was significantly less hepatotoxic and cytotoxic in cells. The results of the H&E staining of lung tissue validated that Selenogefitinib effectively protected the structure of the alveolar tissue and mitigated the infiltration of inflammatory cells in bleomycin-induced pulmonary fibrosis models. The reduction in the deposition of collagen fibers in lung tissue determined by Masson staining and hydroxyproline (HYP) content also corroborated the efficacy of selenogefitinib in the treatment of pulmonary fibrosis. Furthermore, Selenogefitinib decreased the levels of pro-inflammatory markers IL-4, IL-6, and TNF-α more significantly than gefitinib, which indicated that it exhibited a higher anti-inflammatory activity. In addition, the presence of selenium manifested a greater reduction in oxidative stress based on the decrease in the levels of MDA in mice blood. These results suggested that Selenogefitinib may be a potential candidate for the treatment of IPF.

Alisma genus: Phytochemical constituents, biosynthesis, and biological activities.

The genus Alisma contains 11 species distributed worldwide, of which at least two species (A. orientale [Sam.] Juzep. and A. plantago-aquatica Linn.) have been used as common herbal medicines. Secondary metabolites obtained from the genus Alisma are considered to be the material basis for the various biological functions and medicinal applications. In this review, we mainly focused on the recent investigations of secondary metabolites from plants of the genus Alisma and their biological activities, with the highlighting on the diversity of the chemical structures, the biosynthesis of interesting secondary metabolites, the biological activities, and the relationships between structures and bioactivities.

Aromatic rosane diterpenoids from the roots of Euphorbia ebracteolata and their inhibitory effects against lipase.

The bioactive chemical constituents of Euphorbia ebracteolata have been investigated in the present work using various techniques. On the basis of chromatographic methods, such as silica gel, RP C-18 column chromatography, five novel rosane type diterpenoids with an aromatic A-ring (1-5) have been isolated from the roots of Euphorbia ebracteolata. Their structures were elucidated by widely spectroscopic data, including HRESI-MS, 1D and 2D NMR. Additionally, the inhibitory effects on lipase of these isolated diterpenoids were evaluated in vitro. Compound 1 as a new diterpenoid displayed significant inhibitory effect on lipase (IC50 = 1.0 µM). And, the inhibitory kinetics has been studied fully, which determined a competitive inhibition model for compound 1 on the enzymatic activity of lipase (Ki = 1.8 µM).

Inula japonica ameliorated bleomycin-induced pulmonary fibrosis via inhibiting soluble epoxide hydrolase.

Pulmonary fibrosis is a progressive, irreversible, and fatal fibrotic lung disease with a high mortality and morbidity, and commonly nonresponsive to conventional therapy. Inula japonica Thunb. is a traditional Chinese medicine, known as "Xuan Fu Hua" in Chinese, and has been widely applied to relieve cough and dyspnea and eliminate retained phlegm with a long history. In this study, we aimed to evaluate the anti-fibrosis effect and action mechanism of I. japonica extract (IJE) for the treatment of bleomycin (BLM)-induced pulmonary fibrosis in mice. IJE treatment significantly restored BLM-induced alterations in body weight loss and lung function decline, decreased the collagen deposition induced by BLM in lung tissues, and inhibited fibrotic and inflammatory factors, such as α-SMA, TGF-ß1, TNF-α, IL-6, COX-2, NF-κB, and GSK3ß, in a dose-dependent manner. We found that IJE could enhance the concentration of 8,9-epoxyeicosatrienoic acid (8,9-EET) and decrease concentrations of 8,9-dihydroxyeicosatrienoic acid (8,9-DHET), 11,12-DHET, and 14,15-DHET in BLM-induced mice. Meanwhile, IJE suppressed protein and mRNA expression levels of soluble epoxide hydrolase (sEH), and significantly displayed the inhibition of sEH activity with an IC50 value of 0.98 µg/mL. Our results indicated that IJE exerted remarkable anti-fibrosis effect on BLM-induced pulmonary fibrosis in mice via inhibiting sEH activity, resulting in the regulation of GSK3ß signaling pathway. Our findings revealed the underlying action mechanism of I. japonica, and suggested that I. japonica could be regarded as a candidate resource for the treatment of pulmonary fibrosis.

ß-Glucuronidase- and OATP2B1-mediated drug interaction of scutellarin in Dengzhan Xixin Injection: A formulation aspect.

Scutellarin is the major and active constituent of Dengzhan Xixin Injection (DZXX), a traditional Chinese medicine prepared from the aqueous extract of Erigeron breviscapus and widely used for the treatment of various cerebrovascular diseases in clinic. In present study, the possible pharmacokinetic differences of scutellarin after intravenous administration of scutellarin alone or DZXX were explored. Additional, the potential roles of ß-glucuronidase (GLU) and OATP2B1 in drug-drug interaction (DDI) between scutellarin and constituents of DZXX were further evaluated in vitro. The plasma concentration, urinary and biliary excretion of scutellarin in rats after administration of DZXX, were significantly higher than those received scutellarin, while pharmacokinetic profile of Apigenin 7-O-glucuronide (AG) in rats was similar no matter AG or DZXX group. Furthermore, higher concentration in brain and plasma, however, lower level of scutellarin in intestine were observed after intravenous administration of DZXX. Finally, AG and caffeoylquinic acid esters were found to significantly inhibit GLU and OATP2B1 in vitro, which might explain, at least in part, the pharmacokinetic DDI between scutellarin and other chemical constituents in DZXX. The findings provided deep insight into the prescription-formulating principle in DZXX for treating the cerebrovascular diseases.

Gambogic acid attenuates liver fibrosis by inhibiting the PI3K/AKT and MAPK signaling pathways via inhibiting HSP90.

Gambogic acid (GA), a major ingredient of Garcinia hanburryi, is known to have diverse biological effects. The present study was designed to evaluate the anti-fibrotic effects of GA on hepatic fibrosis and reveal its underlying mechanism. We investigated the anti-fibrotic effect of GA on dimethylnitrosamine and bile duct ligation induced liver fibrosis in rats in vivo. The rat and human hepatic stellate cell lines (HSCs) lines were chose to evaluate the effect of GA in vitro. Our results indicated that GA could significantly ameliorate liver fibrosis associated with improving serum markers, decrease in extracellular matrix accumulation and HSCs activation in vivo. GA significantly inhibited the proliferation of HSC cells and induced the cell cycle arrest at the G1 phase. Moreover, GA triggered autophagy at early time point and subsequent initiates mitochondrial mediated apoptotic pathway resulting in HSC cell death. The mechanism of GA was related to inhibit heat shock protein 90 (HSP90) and degradation of the client proteins inducing PI3K/AKT and MAPK signaling pathways inhibition. This study demonstrated that GA effectively ameliorated liver fibrosis in vitro and in vivo, which provided new insights into the application of GA for liver fibrosis.

Ebracpenes A and B, Unusual Ring C- seco and Ring D-aromatic Nor-Triterpenoids, from Euphorbia ebracteolata and Lipase Inhibitory Evaluation.

Two unusual ring C- seco and ring D-aromatic nor-triterpenoids, ebracpenes A (1) and B (2), were obtained from Euphorbia ebracteolata roots and elucidated by widely spectroscopic data analyses, such as 1D, 2D NMR, HRESIMS, and X-ray crystallography analysis. Compound 2 showed a significant inhibitory activity on lipase (IC50 = 0.89 µM as well as the Ki determined to be 0.69 µM). Enzyme kinetics analysis and molecular docking experiments revealed that compound 2 was a competitive inhibitor, binding to the active site of lipase.

Uncarialins A-I, Monoterpenoid Indole Alkaloids from Uncaria rhynchophylla as Natural Agonists of the 5-HT1A Receptor.

Nine new monoterpenoid indole alkaloids, uncarialins A-I (1-9), were isolated from Uncaria rhynchophylla as well as 14 known analogues (10-23). Their structures were determined by HRESIMS, 1D and 2D NMR, and experimental and calculated electronic circular dichroism data. Compounds 5, 7, 15, and 22 displayed significant agonistic effects against the 5-HT1A receptor with EC50 values of 2.2 ± 0.1, 0.1 ± 0.1, 1.6 ± 0.3, and 2.0 ± 0.5 µM, respectively. The mechanisms of action of these four compounds with the 5-HT1A receptor were investigated by molecular docking, and the results suggested that amino acid residues Asp116, Thr196, Asn386, and Tyr390 played critical roles in the observed activity of the above-mentioned compounds.

Demethylbellidifolin isolated from Swertia bimaculate against human carboxylesterase 2: Kinetics and interaction mechanism merged with docking simulations.

In this study, forty-nine kinds of traditional Chinese medicines (TCMs) were evaluated for their inhibitory activities against human carboxylesterase 2 (HCE 2) using a human liver microsome (HLM) system. Swertia bimaculata showed significant inhibition on HCE 2 at 10 µg/mL among forty-nine kinds of TCMs. The extract of Swertia bimaculata was separated by preparative HPLC to afford demethylbellidifolin (1) identified by MS, 1H NMR, and 13C NMR spectra. Demethylbellidifolin (1) was assayed for its inhibitory HCE 2 effect by HCE 2-mediated DDAB hydrolysis, and its potential IC50 value was 3.12 ±â€¯0.64 µM. Demethylbellidifolin (1) was assigned as a mixed-type competitive inhibitor with the inhibiton constant Ki value of 6.87 µM by Lineweaver-Burk and slope plots. Living cell imaging was conducted to corroborate its inhibitory HCE 2 activity. Molecular docking indicated potential interactions of demethylbellidifolin (1) with HCE 2 through two hydrogen bonds of the C-3 and C-5 hydroxy groups with amino acid residues Glu227 and Ser228 in the catalytic cavity, respectively.

Dihydroartemisinin and doxorubicin co-loaded Soluplus®-TPGS mixed micelles: formulation characterization, cellular uptake, and pharmacodynamic studies.

Clinically, co-delivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. This study was aimed at integrating the merits of combination chemotherapy and mixed micellar technology and demonstrating the anticancer potential of doxorubicin (DOX) and dihydroartemisinin (DHA) co-loaded Soluplus®-TPGS mixed micellar system. In this study, physiochemically stable multidrug loaded mixed micelles were successfully prepared, encapsulation efficiencies of DOX and DHA were as high as 90%, and the average diameter of the micelles was 64.27 nm. The cellular uptake of DOX from the mixed micelles increased by 1.3 and 1.2 times for MCF-7 and MCF-7/ADR cell lines, respectively. The micelles were more cytotoxic than free DHA-DOX. Surprisingly, the co-loaded mixed micelles exhibited higher antitumor activity, while the systemic toxicity was reduced during the treatment. Therefore, the DOX and DHA mixed micelle might be a potential, effective, and less toxic drug-delivery system for cancer therapy.

Highly Specific near-Infrared Fluorescent Probe for the Real-Time Detection of ß-Glucuronidase in Various Living Cells and Animals.

ß-Glucuronidase (GLU) is an important biomarker for primary cancers and intestinal metabolism of drugs or endogenous substances; however, an effective optical probe for near-infrared (NIR) monitoring in vivo is still lacking. Herein, we design an enzyme-activated off-on NIR fluorescent probe, HC-glu, based on a hemicyanine keleton, which is conjugated with a d-glucuronic acid residue via a glycosidic bond, for the fluorescent quantification and trapping of endogenous GLU activity in vitro and in vivo. The newly developed NIR probe exhibited prominent features including prominent selectivity, high sensitivity, and ultrahigh imaging resolution. It has been successfully used to detect and image endogenous GLU in various hepatoma carcinoma cells, tumor tissues, and tumor-bearing mouse models, for cancer diagnosis and therapy. Moreover, it could detect the in vivo activity of GLU in the intestinal tracts of animals including mice and zebrafish, where GLU performs a vital biological function and is mainly distributed. It could also evaluate real intestinal distribution and real-time variations of GLU in development and growth, all of which are very helpful to guide rational drug use in the clinic. Our results fully demonstrated that HC-glu may serve as a promising tool for evaluating the biological function and process of GLU in living systems.

Uncaria rhynchophylla Ameliorates Parkinson's Disease by Inhibiting HSP90 Expression: Insights from Quantitative Proteomics.

BACKGROUND/AIMS: Uncaria rhynchophylla, known as "Gou-teng", is a traditional Chinese medicine (TCM) used to extinguish wind, clear heat, arrest convulsions, and pacify the liver. Although U. rhynchophylla has a long history of being often used to treat central nervous system (CNS) diseases, its efficacy and potential mechanism are still uncertain. This study investigated neuroprotective effect and the underlying mechanism of U. rhynchophylla extract (URE) in MPP+-induced SH-SY5Y cells and MPTP-induced mice. METHODS: MPP+-induced SH-SY5Y cells and MPTP-induced mice were used to established Parkinson's disease (PD) models. Quantitative proteomics and bioinformatics were used to uncover proteomics changes of URE. Western blotting was used to validate main differentially expressed proteins and test HSP90 client proteins (apoptosis-related, autophagy-related, MAPKs, PI3K, and AKT proteins). Flow cytometry and JC-1 staining assay were further used to confirm the effect of URE on MPP+-induced apoptosis in SH-SY5Y cells. Gait analysis was used to detect the behavioral changes in MPTP-induced mice. The levels of dopamine (DA) and their metabolites were examined in striatum (STR) by HPLC-EC. The positive expression of tyrosine hydroxylase (TH) was detected by immunohischemical staining and Western blotting. RESULTS: URE dose-dependently increased the cell viability in MPP+-induced SH-SY5Y cells. Quantitative proteomics and bioinformatics results confirmed that HSP90 was an important differentially expressed protein of URE. URE inhibited the expression of HSP90, which further reversed MPP+-induced cell apoptosis and autophagy by increasing the expressions of Bcl-2, Cyclin D1, p-ERK, p-PI3K p85, PI3K p110α, p-AKT, and LC3-I and decreasing cleaved caspase 3, Bax, p-JNK, p-p38, and LC3-II. URE also markedly decreased the apoptotic ratio and elevated mitochondrial transmembrane potential (DΨm). Furthermore, URE treatment ameliorated behavioral impairments, increased the contents of DA and its metabolites and elevated the positive expressions of TH in SN and STR as well as the TH protein. CONCLUSIONS: URE possessed the neuroprotective effect in vivo and in vitro, regulated MAPK and PI3K-AKT signal pathways, and inhibited the expression of HSP90. U. rhynchophylla has potentials as therapeutic agent in PD treatment.

Diterpenoids from the roots of Euphorbia ebracteolata and their anti-tuberculosis effects.

Euphorbia ebracteolata was a natural medicine for the treatment of tuberculosis. The present work has performed the investigation of bioactive chemical substances from the roots of E. ebracteolata. Using various chromatographic techniques, 15 compounds were obtained from the roots of E. ebracteolata. On the basis of widely spectroscopic data analyses, the isolated compounds were determined to be diterpenoids, including rosane derivatives (1-12), isopimarane (13), abietane (14), and lathyrane (15), among which compounds 1-4, and 9 were undescribed previously. The inhibitory effects of isolated diterpenoids against Mycobacterium tuberculosis were evaluated using an Alamar blue cell viability assay. And two rosane-type diterpenoids 3 and 8 displayed moderate inhibitory effects on with the MIC values of 18 µg/mL and 25 µg/mL, respectively. For the potential inhibitor 3, the inhibitory effect against the target enzyme GlmU was evaluated, which displayed a moderate inhibitory effect with the IC50 12.5 µg/mL. Therefore, the diterpenoids from the roots of E. ebracteolata displayed anti-tuberculosis effects, which would be pay more attentions for the anti-tuberculosis agents.

Cytotoxic ent-Abietane-type diterpenoids from the roots of Euphorbia ebracteolata.

Euphoroids A-C (1-3), three new ent-abietane-type diterpenoids, together with ten known analogues (4-13) were obtained from the roots of Euphorbia ebracteolata. The structures of these compounds were determined by extensive spectroscopic data analysis, including UV, HRESIMS, 1D-, and 2D-NMR data. The inhibitory effects of compounds 1-13 on human cancer cells were determined using the MTT assay. The results revealed that new compounds 2 and 3 showed moderate cytotoxic activities against human cancer cell lines. Especially, compound 3 displayed selective cytotoxic effect agains cancer cell lines.

Unusual ent-atisane type diterpenoids with 2-oxopropyl skeleton from the roots of Euphorbia ebracteolata and their antiviral activity against human rhinovirus 3 and enterovirus 71.

Two novel ent-atisane type diterpenoids possessing the extra unusal 2-oxopropyl moiety (1 and 2) and four known analogues have been isolated from the roots of Euphorbia ebracteolata. The structures and absolute configurations of these compounds were determined by extensive spectroscopic data analysis, including 2D NMR, single-crystal X-ray crystallography, 13C NMR calculation, and electronic circular dichroism spectra calculation. Compounds 1 and 2 are the first examples of natural products with ent-atisane type diterpenoids possessing 2-oxopropyl skeleton. Compounds 2, 3, 5, and 6 show antiviral activities against human rhinovirus 3, with IC50 values of 25.27-90.35 µM. Compounds 5 and 6 showed moderate antiviral activities against EV71 at a concentration of 100 µM.