Comprehensive investigations of 2-phenylethanol production by the filamentous fungus Annulohypoxylon stygium.

2-Phenylethanol (2-PE) is an aromatic compound with a rose-like fragrance that is widely used in food and other industries. Yeasts have been implicated in the biosynthesis of 2-PE; however, few studies have reported the involvement of filamentous fungi. In this study, 2-PE was detected in Annulohypoxylon stygium mycelia grown in both potato dextrose broth (PDB) and sawdust medium. Among the 27 A. stygium strains investigated in this study, the strain "Jinjiling" (strain S20) showed the highest production of 2-PE. Under optimal culture conditions, the concentration of 2-PE was 2.33 g/L. Each of the key genes in Saccharomyces cerevisiae shikimate and Ehrlich pathways was found to have homologous genes in A. stygium. Upon the addition of L-phenylalanine to the medium, there was an upregulation of all key genes in the Ehrlich pathway of A. stygium, which was consistent with that of S. cerevisiae. A. stygium as an associated fungus provides nutrition for the growth of Tremella fuciformis and most spent composts of T. fuciformis contain pure A. stygium mycelium. Our study on the high-efficiency biosynthesis of 2-PE in A. stygium offers a sustainable solution by utilizing the spent compost of T. fuciformis and provides an alternative option for the production of natural 2-PE. KEY POINTS: • Annulohypoxylon stygium can produce high concentration of 2-phenylethanol. • The pathways of 2-PE biosynthesis in Annulohypoxylon stygium were analyzed. • Spent compost of Tremella fuciformis is a potential source for 2-phenylethanol.

Ultrasonic-responsive piezoelectric stimulation enhances sonodynamic therapy for HER2-positive breast cancer.

INTRODUCTION: Breast cancer ranks second as the most common malignancy globally, after lung cancer. Among the various subtypes of breast cancer, HER2 positive breast cancer (HER2 BC)poses a particularly challenging prognosis due to its heightened invasiveness and metastatic potential. The objective of this study was to construct a composite piezoelectric nanoparticle based on poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) for imaging and treatment of HER2 BC. METHOD: By reshaping the crystal structure of P(VDF-TrFE) piezoelectric nanoparticles, improving hydrophilicity, and incorporating imaging capabilities, we developed piezoelectric composite nanoparticles (PGd@tNBs) that integrate imaging and therapeutic functions. The in vitro characterization encompassed the assessment of piezoelectric properties, hydrophilicity, imaging performance, and therapeutic efficacy of these particles. The targeting and therapeutic effectiveness of PGd@tNBs particles were further validated in the SK-BR3 cell line and subsequently confirmed in HER2-positive tumor-bearing mice. RESULTS: The nanoparticle demonstrated excellent biocompatibility and impressive multimodal imaging performance. Magnetic resonance imaging (MRI) observations revealed significant accumulation of PGd@tNBs particles in the HER2 positive tumor, exhibiting superior contrast-enhanced ultrasound performance compared to traditional ultrasound contrast agents, and small animal in vivo imaging showed that PGd@tNBs particles were primarily excreted through respiration and urinary metabolism. Piezoforce Microscopy characterization highlighted the outstanding piezoelectric properties of PGd@tNBs particles. Upon targeted binding to HER2-BC, ultrasound stimulation influenced the cell membrane potential, leading to reversible electroporation. This, in turn, affected the balance of calcium ions inside and outside the cells and the mitochondrial membrane potential. Following ingestion by cells, PGd@tNBs, when exposed to ultrasound, triggered the generation of reactive oxygen species (ROS), resulting in the consumption of glutathione and superoxide dismutase and achieving sonodynamic therapy. Notably, repeated ultrasound stimulation, post PGd@tNBs particles binding and entry into cells, increased ROS production and elevated the apoptosis rate by approximately 45%. CONCLUSION: In conclusion, the PGd@tNBs particles developed exhibit outstanding imaging and therapeutic efficacy, holding potential for precise diagnosis and personalized treatment of HER2 BC.

Disordered Convolution Region of P(VDF-TrFE) Piezoelectric Nanoparticles: The Core of Sono-Piezo Dynamic Therapy.

The recent focus on P(VDF-TrFE) material in biomedical engineering stems from its outstanding mechanical properties and biocompatibility. However, its application in sono-piezo dynamic therapy (SPDT) has been relatively unexplored. In this study, we developed composite piezoelectric nanoparticles (rPGd NPs@RGD) based on recrystallized P(VDF-TrFE) particles, which offer dual capabilities of MRI imaging and targeted treatment for brain gliomas. SEM observations of P(VDF-TrFE) particles in the disordered convolution region (DCR) revealed recrystallization, representing the polymer chain structure and particle polarity. In comparison to nonrecrystallized nanoparticles, rPGd NPs@RGD exhibited remarkable stability and biocompatibility. Under ultrasound excitation, they generated significantly higher levels of reactive oxygen species, effectively inhibiting tumor cell proliferation, invasion, and migration. rPGd NPs@RGD demonstrated excellent MRI imaging capabilities and antitumor activity in U87 tumor-bearing mice. This study highlights the remarkable SPDT abilities of the developed nanoparticles, attributed to the microscopic morphological changes in the DCR that increase the nanoparticle's polarity and thus boost its potential for SPDT. This research opens new possibilities for utilizing P(VDF-TrFE) materials in advanced biomedical applications.

Decorin inhibits the formation of hard nodules after microwave ablation by inhibiting the TGF-ß1/SMAD and MAPK signaling pathways: in a Bama miniature pig model of mammary gland hyperplasia.

BACKGROUND: Benign breast lesions are often associated with hard nodule formation after microwave ablation (MWA), which persists for a long time and causes problems in patients. The aim of this study was to evaluate the efficacy of decorin in the treatment of hard nodule formation and its potential mechanism of action. METHODS: Using a Bama miniature pig model of mammary gland hyperplasia, immunohistochemistry, Masson's trichrome and western blotting were firstly applied to compare the extent of fibrosis and activation of key members of the TGF-ß1/SMAD and MAPK signaling pathways of hard nodule in the control and MWA groups, and then the extent of fibrosis and expression of signaling pathways in hard nodule were examined after application of decorin. RESULTS: The results showed that the MWA group had increased levels of TGF-ß1, p-SMAD2/3, p-ERK1/2, and collagen I proteins and increased fibrosis at 2 weeks, 4 weeks, and 3 months after MWA. After decorin treatment, the expression levels of each protein were significantly downregulated, and the degree of fibrosis was reduced at 2 weeks, 4 weeks, and 3 months after MWA compared with the MWA group. CONCLUSION: In conclusion, these results suggest that activation of TGF-ß1 may play an important role in hard nodule formation and that decorin may reduce hard nodule formation after MWA in a model of mammary gland hyperplasia by inhibiting the TGF-ß1/SMAD and MAPK signaling pathways.

Genes related to osmoregulation and antioxidation play important roles in the response of Trollius chinensis seedlings to saline-alkali stress.

Saline-alkali stress is one of the main abiotic stress factors affecting plant growth and development. Trollius chinensis is a perennial herbal medicinal plant with high values for garden application. However, its response and tolerance to saline-alkali stress is unclear. In this study, we mixed four salts (NaCl: Na2SO4: NaHCO3: Na2CO3) with a concentration ratio of 1:9:9:1, and applied low (40 and 80 mM) and high (120 and 160 mM) saline-alkali stress to analyze osmotic regulation substances, antioxidant systems and the gene expression of T. chinensis. Along with higher saline-alkali stress, the leaf relative water content (RWC) started to decrease only from high stress, while the malondialdehyde (MDA) content in leaves decreased continuously, and the contents of proline (Pro), soluble sugar (SS) and soluble protein (SP) increased compared with control. The activities of antioxidant enzymes and the contents of non-enzymatic antioxidants were increased positively with the accumulation of superoxide anion (O2 •-) and hydrogen peroxide (H2O2). For instance, the ascorbic acid-glutathione (AsA-GSH) cycle was enhanced in T. chinensis seedling leaves subject to saline-alkali stress. Principal Component Analysis (PCA) indicates that MDA, Pro, SS, SP, H2O2, O2 •-, and GSH are important indexes to evaluate the response and tolerance of T. chinensis to saline-alkali stress. Through RNA-Seq, a total of 474 differentially expressed genes (DEGs) were found in plant under low saline-alkaline stress (40 mM, MSA1) vs. control. Among them, 364 genes were up-regulated and 110 genes were down-regulated. DEGs were extensively enriched in carbohydrate transport, transferase activity, zeatin biosynthesis, ABC transporters, and spliceosome. The transcription factor family MYB, BZIP, WRKY, and NAC were related to its saline-alkali tolerance. In addition, some DEGs encode key enzymes in the processes of osmoregulation and antioxidation, including betaine aldehyde dehydrogenase (BADH), inositol monophosphatase (IMP), chloroperoxidase (CPO), thioredoxin (Trx), and germin-like protein (GLPs) were found. Overall, these findings provide new insights into the physiological changes and molecular mechanism of T. chinensis to saline-alkali stress and lay a foundation for application of T. chinensis in saline-alkali environment.

Comparison of Pharmacokinetic Similarity, Immunogenicity, and Safety of Ustekinumab and BAT2206 in Healthy Chinese Male Subjects in a Double-Blind, Randomized, Single-Dose, Parallel-Group Phase I Trial.

OBJECTIVE: We aimed to evaluate the similarity of BAT2206 to its originator, ustekinumab, including pharmacokinetic profiles, immunogenicity, and safety in healthy Chinese male subjects. METHODS: This was a double-blinded, randomized, single-dose, parallel-group clinical trial, in which 270 healthy male subjects were enrolled to receive a single subcutaneous injection (45 mg) of either BAT2206 or ustekinumab (European Union or USA) at a 1:1:1 ratio. The pairwise pharmacokinetic similarities and the safety and immunogenicity of both drugs were evaluated and compared. RESULTS: The results showed that the 90% confidence interval of the geometric mean ratio for primary pharmacokinetic parameters (maximum plasma concentration and area under the plasma concentration-time curve from time zero to infinity) among BAT2206 and ustekinumab (USA or European Union sourced) groups were all within the predefined equivalent interval of 80-125%. Furthermore, all the groups had similar incidences of treatment-emergent adverse events, in which the majority of cases belonged to Common Terminology Criteria for the Classification of Adverse Events Grade 1 or 2. Anti-drug antibodies were detected in 54 (20.1%) subjects, namely 24 (26.7%), 13 (14.8%), and 17 (18.9%) patients in the BAT2206, ustekinumab (European Union), and ustekinumab (USA) groups, respectively. In contrast, the incidences of positive neutralizing antibodies were similar among the three groups. CONCLUSIONS: Pharmacokinetic similarity between BAT2206 and ustekinumab (USA or European Union sourced) was confirmed. The three groups had similar safety profiles, and the investigational drugs were well tolerated by subjects. CLINICAL TRIAL REGISTRATION: This study was registered with ClinicalTrials.gov (NCT04371185).

First-In-Human Study on Pharmacokinetics, Safety, and Tolerability of Single and Multiple Escalating Doses of Hepenofovir, a Novel Hepatic Targeting Prodrug of Tenofovir in Healthy Chinese Subjects.

Objective: Hepenofovir, a novel hepatic targeting prodrug of tenofovir, has been developed for the treatment of chronic hepatitis B (CHB). This is a first-in-human study to evaluate the pharmacokinetics (PK) and tolerability of single and multiple escalating doses of hepenofovir in healthy Chinese subjects. Methods: This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (25-200 mg) study under fasted conditions comprising a food-effect investigation (200 mg) and a multiple-ascending-dose (MAD) (25 mg) study under fasted conditions. Results: Hepenofovir was well tolerated in healthy Chinese subjects. There was no significant difference in adverse reaction rates between hepenofovir and placebo groups. Hepenofovir was rapidly absorbed and metabolized into tenofovir after dosing. In healthy participants, the median Tmax of hepenofovir and tenofovir was 0.33-0.50 h and 0.62-0.75 h, respectively, and their mean half-life was 2.5-12.3 h and 49.7-53.8 h, respectively. Systemic exposure to tenofovir increased in proportion to the dose. The mean accumulation indexes of hepenofovir and tenofovir were 1.1 vs. 1.8. Moreover, food could reduce the Cmax of both hepenofovir and tenofovir, but did not affect their area under the curve (AUC). Conclusions: Hepenofovir has shown a favorable safety and PK profile, which support the further evaluation of its safety and efficacy in CHB patients. Clinical trial registration number: The trial is registered at Chinese Clinical Trial website (http://www.chinadrugtrials.org.cn/index.html # CTR20191953).

Dual-responsive nanodroplets combined with ultrasound-targeted microbubble destruction suppress tumor growth and metastasis via autophagy blockade.

The inhibition of autophagy is a feasible clinical strategy in tumor therapy. Traditional autophagy inhibitors are limited in clinical tumor therapy due to nonspecific biodistribution, systemic toxicity and limited antitumor effect. Herein, the autophagy inhibitor hydroxychloroquine (HCQ)-loaded nanodroplets (NDs) are synthesized to overcome these drawbacks. HCQ-NDs are endowed with endogenous pH- and exogenous ultrasound-responsive drug release and contrast enhanced ultrasound imaging performance. The combined application of ultrasound-targeted microbubble destruction (UTMD) and HCQ-NDs can severely break the homeostasis of tumor cells, simultaneously releasing HCQ rapidly to block autophagic flux and thus abolish the cytoprotective function. This strategy presents strong synergistic antitumor efficacy with the tumor growth inhibition value of 80.02% and synchronously inhibits tumor lung metastasis by inhibition of MMP2 and MMP9 production, eventually leading to tumor suppression. In addition, HCQ-NDs show excellent tumor-targeting, biocompatibility, biosafety and contrast-enhanced ultrasound imaging properties. Based on the above findings, this combined strategy rationally regulates the autophagic process of tumor cells and could be instructive for the design of clinical treatment modalities.

A randomized, double-blind, placebo-controlled, single, and multiple dose-escalation Phase I clinical trial to investigate the safety, pharmacokinetic, and pharmacodynamic profiles of oral S086, a novel angiotensin receptor-neprilysin inhibitor, in healthy Chinese volunteers.

BACKGROUND: This study evaluated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of single ascending doses (SAD) and multiple ascending doses (MAD) of S086 in healthy Chinese volunteers. RESEARCH DESIGN AND METHODS: This randomized, double-blind, placebo-controlled, Phase I clinical trial enrolled 113 subjects, including 65 subjects in the SAD (60-1080 mg) study and 48 subjects in the MAD study (180-720 mg). The safety, PK (sacubitril, LBQ657, and EXP3174) and PD (MAD study: blood pressure, pulse) of S086 were assessed. RESULTS: There were no deaths, serious adverse events, or discontinuations due to TEAEs, and there were no significant safety concerns associated with S086. PK parameters for sacubitril, LBQ657, and EXP3174 increased in a dose-dependent manner after single oral doses of S086. Plasma concentrations of sacubitril, LBQ657, and EXP3174 were maintained at steady state within 5 days of once-daily oral administration of S086. In the MAD study, S086 administration was associated with a dose-dependent decrease in mean diastolic and systolic blood pressure compared to baseline. CONCLUSIONS: The safety and PK profile profiles of S086 support the use of S086 240 mg once daily in a future Phase II study in patients with heart failure. TRIAL REGISTRATION: The trial is registered at chinadrugtrials.org.cn (CT.gov identifier: CTR20182350 and CTR20182351).

Safety, tolerability, pharmacodynamics, and pharmacokinetics of CJC-1134-PC in healthy Chinese subjects and type-2 diabetic subjects.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) mimetics are widely used for treating type 2 diabetes (T2D) with pleiotropic effects on heart and kidneys. The safety/tolerability and pharmacokinetics/pharmacodynamics ((PK/PD) of CJC-1134-PC (a long-acting GLP-1) were investigated in Chinese. METHOD: Two randomized, double-blind, placebo-controlled phase I studies were conducted. Study A: 30 healthy subjects received (subcutaneously injected) a single dose (2 mg) or titrate doses (2 + 3 and 2 + 3 + 4 mg at weekly intervals) of CJC-1134-PC. Study B: 49 T2D subjects received 10 weekly doses (1, 2, 3, and 4 mg). RESULT: CJC-1134-PC was well tolerated with gastrointestinal (GI) side effects. Higher doses increased the adverse events risk. CJC-1134-PC was steadily absorbed, with maximum plasma concentrations(Cmax) occurring at 36-72 h and 48 h after administration in healthy and T2D subjects, respectively. The steady-state exposures in T2D subjects increased more than the dose-proportionality(1-3 mg). The mean t1/2 ranged from 111.6 to 127.6 h. After four- five weeks of targeting doses, steady state was reached in T2D subjects with apparent accumulation effect. At week 11 for T2D subjects, HbA1c mean baseline change was significantly different than that of the placebo, and the fasting plasma glucose (FPG) was not significantly altered. CONCLUSION: The safety and PK/PD profiles of weekly CJC-1134-PC doses support Phase II studies with guidance on optimal-dose selection. Clinical trial registration: ChiCTR-IPC-15007190.

Hydrogeochemistry Evidence for Impacts of Chemical Acidic Wastewater on Karst Aquifer in Dawu Water Source Area, Northern China.

The study of the hydrochemical characteristics and the water-rock interaction of karst groundwater is very important for the rational exploitation of karst groundwater and its pollution control. In this paper, the systematic clustering method was used to analyze the hydrochemical characteristics of different types of groundwater, combined with hydrochemical graphic analysis and correlation analysis to explore the impact of chemical acidic wastewater on the evolution of karst aquifer in the Dawu water source area, northern China. The results show that the chemical acid wastewater, sourcing from discharges/spillages from the local chemical industries, has different degrees of pollution impact on karst groundwater, causing the total hardness of all karst groundwater and the total dissolved solids, Cl- and SO42- in nearly half of the karst groundwater to exceed the quality indexes of class III water in China's standard for groundwater quality (GB/T 14848-2017). Hydrochloric acid and sulfuric acid in the wastewater can be buffered by the dissolution of carbonate rocks, resulting in a nearly neutral pH (pH-buffering effect) and an increase in Ca2+, Mg2+, Sr, Cl- and SO42- concentrations in karst groundwater.

Safety, Tolerability, and Pharmacokinetics of the Novel Hepatitis B Virus Capsid Assembly Modulator GST-HG141 in Healthy Chinese Subjects: a First-in-Human Single- and Multiple-Dose Escalation Trial.

Hepatitis B virus capsid assembly modulators (HBV CAMs) are promising, clinically validated therapeutic agents for the treatment of chronic hepatitis B (CHB). The safety, tolerability, and pharmacokinetic (PK) profiles of GST-HG141, a novel HBV CAM, were evaluated in healthy Chinese volunteers. This phase Ia study included two parts: a double-blinded, randomized, placebo-controlled single-ascending-dose (SAD) (50, 100, 200, 300, 400, or 500 mg) study comprising a food-effect investigation (300 mg) and a multiple-ascending-dose (MAD) (100 or 200 mg twice daily) study. GST-HG141 reached the maximum plasma concentration (Cmax) at 1.25 to 3.00 h (median Tmax). The exposure exhibited a linear increase, while the mean half-life (t1/2) ranged from 13.096 h to 22.121 h. The exposure of GST-HG141 (300 mg) was higher after food intake by about 2.4-fold. In the MAD study, steady state was reached at around day 5, and the mean trough steady-state concentrations were 423 and 588 ng/ml for 50- and 100-mg cohorts, respectively. The ratios of GST-HG141 accumulation were <1.5. GST-HG141 was well tolerated in healthy Chinese subjects. The rates of adverse events in the GST-HG141 cohort did not differ from those of the placebo cohort. GST-HG141 was tolerated in healthy Chinese subjects. The safety and PK profiles of GST-HG141 support the further evaluation of its efficacy in individuals with CHB. (This study has been registered in ClinicalTrials.gov under identifier NCT04536337.).

A Biosimilarity Study Between QX001S and Ustekinumab in Healthy Chinese Male Subjects.

Objective: To evaluate the tolerance, variability, and pharmacokinetics (PK) of QX001S, a biosimilar for ustekinumab, in healthy Chinese men. Methods: One hundred and seventy-eight healthy men were recruited in this randomized, double-blind, single-dose, two-arm, parallel study, and received 45 mg of QX001S or ustekinumab in a single subcutaneous injection. PK, immunogenicity, and tolerance were evaluated in all participants for a period of 113°days. Results: The similarity between the two drugs was determined by comparing the baseline characteristics for each drug. The PK parameters were similar in the two groups: QX001S (n = 89) and ustekinumab (n = 88). The 90% confidence intervals (CIs) for the geometric mean ratio (GMR) of QX001S to the reference (ustekinumab) for the maximum observable serum concentration (C max ), area under the curve (AUC) from zero to the final quantifiable concentration (AUC0-t), and AUC from zero to infinity (AUC0-∞) were 100.90-118.68%, 98.71-115.26%, and 98.49-115.81%, respectively, which were within the predefined bioequivalence limit of 80.00-125.00%. High inter-subject variability (ranging from 32.0 to 33.5%) was observed. A total of 17 participants (19.1%) in the QX001S group and 36 (40.9%) in the ustekinumab group developed anti-drug antibodies (ADA) after administration. Nevertheless, the ADA did not affect the outcomes of the bioequivalence tests. Adverse reactions were recorded in 38 individuals injected with QX001S and 37 injected with ustekinumab. The most common adverse reactions were upper respiratory infection and elevated alanine aminotransferase. Conclusions: Our study ratified pharmacokinetic biosimilarity between QX001 S and ustekinumab, with high variability between subjects.

Pharmacokinetics, Pharmacodynamics, Safety, Tolerability, and Immunogenicity of the QX002N anti-IL-17 Monoclonal Antibody: A Phase I, Randomized, Double-Blind, Single Ascending Dose Study in Healthy Chinese Volunteers.

Background: The innovative injection of interleukin 17 A (IL-17A) monoclonal antibody QX002N is being developed to treat active ankylosing spondylitis and plaque psoriasis in adults. Objective: This study investigated the pharmacokinetics (PKs), pharmacodynamics (PDs) safety, tolerability, and immunogenicity of single ascending subcutaneous injections of QX002N in healthy Chinese volunteers. Methods: A total of 65 healthy subjects were enrolled in a randomized, double-blind, placebo-controlled, single ascending dose phase I study (10-320 mg). Ten subjects were allocated to each cohort (containing 8 subjects treated with QX002N and 2 with placebo), except cohort 1 (only 4 subjects treated with QX002N and 1 with placebo). The studies on PKs, PDs, tolerability, and immunogenicity of QX002N were performed. Results: Our study showed that QX002N injection was well tolerated, without deaths, serious adverse events, or discontinuations due to treatment-emergent adverse events (TEAEs). Neither more frequency nor high severity of the drug-related adverse reaction was observed with increasing QX002N dose. The TEAEs in all subjects were considered Grades 1-2 (CTCAE 5.0) except for one case of Grade 3 (hypertriglyceridemia). Tmax of QX002N was obtained from 168 to 240 h across the dose range after administration. The Cmax and area under the curve of QX002N increased in proportion to dose, and showed linear PKs. Anti-drug antibody positivity was detected in one (1.9%) subject after drug administration. Conclusion: QX002N was well tolerated in our study. Based on the PKs and safety results of QX002N, 80 mg is recommended as the effective dose for a future phase Ib study. Clinical Trial Registration: https://www.chinadrugtrials.org.cn/, identifier ChiCTR1900023040.

Biosorption of copper, zinc, cadmium and chromium ions from aqueous solution by natural foxtail millet shell.

The industrial effluents discharge including heavy metals drain into the river, which has given rise to many problems of hazarding aquatic ecosystems and human health. Biosorption serves as the adsorption of heavy metals onto a natural adsorbent, it is becoming a potential alternative for toxic metals removal from industrial effluents in the last decades. The objectives of present research were to investigate the biosorption behaviors and the mechanisms of copper (Cu), zinc (Zn), cadmium (Cd) and chromium (Cr) ions, respectively onto foxtail millet shell as a new natural biosorbent in aqueous solution. The effects of pH (2.0-6.0), contact time (5.0-240.0 min), initial metal ions concentration (25.0-300.0 mg/L), particle size (0.25-2.0 mm) and biosorbent dosage (1.0-6.0 g/L) on the adsorption efficiency of the target metals using foxtail millet shell were evaluated in batch experiments. The models of isotherms and kinetics were used to assess the removal behaviors of Cu, Zn, Cd and Cr ions from aqueous solution by foxtail millet shell. The results showed that the best fitting equilibrium isotherm models for Cu, Zn, Cd and Cr ions were Freundlich (Cu and Zn) and Langmuir (Cd and Cr), respectively under the proper adsorption conditions. The maximum biosorption capacities were 11.89, 10.59, 12.48 and 11.70 mg g-1 of Cu, Zn, Cd and Cr, respectively by terms of Langmuir model. The kinetics of biosoption the target metal ions processes were best explained by pseudo-second-order kinetic model. Furthermore, pseudo-second-order and intraparticle diffusion models were cooperative mechanism during the whole biosorption. In addition, the pores on the surface of the shell were covered and then became smooth after biosorption through Scanning electron microscope (SEM) revealed, which demonstrated that the target metal ions were adsorbed by foxtail millet shell. The results of Energy dispersive spectrometer (EDS) further gave evidences that Cu, Zn, Cd and Cr ions were adsorbed onto surface of the adsorbent, respectively. Analysis of Fourier transform infrared spectroscopy (FTIR) demonstrated that various functional groups, such as C-H, C˭O, C˭C, C-O, O-S-O and Si-O groups were engaged in the interaction between foxtail millet shell and Cu, Zn, Cd and Cr ions. This paper provided evidences that foxtail millet shell was a potential and efficient biosorbent on removal of Cu, Zn, Cd and Cr ions from aqueous solutions, due to its high biosorption availability, capacity and low cost.

Characteristics of multiple Fano resonances in waveguide-coupled surface plasmon resonance sensors based on waveguide theory.

We observe and analyze multiple Fano resonances and the plasmon-induced transparency (PIT) arising from waveguidecoupled surface plasmon resonance in a metal-dielectric Kretschmann configuration. It is shown that the simulation results for designed structures agree well with those of the dispersion relation of waveguide theory. We demonstrate that the coupling between the surface plasmon polariton mode and multi-order planar waveguide modes leads to multiple Fano resonances and PIT. The obtained results show that the number of Fano resonances and the linewidth of resonances depend on two structural parameters, the Parylene C and SiO2 layers, respectively. For the sensing action of Fano resonance, the figure of merit for the sensitivity by intensity is estimated to be 44 times higher than that of conventional surface plasmon resonance sensors. Our research reveals the potential advantage of sensors with high sensitivity based on coupling between the SPP mode and multi-order PWG modes.

Coherent noise reduction in digital holographic microscopy by averaging multiple holograms recorded with a multimode laser.

In digital holographic microscopy (DHM), it is undesirable to observe coherent noise in the reconstructed images. The sources of the noise are mainly the parasitic interference fringes caused by multiple reflections and the speckle pattern caused by the optical scattering on the object surface. Here we propose a noise reduction approach in DHM by averaging multiple holograms recorded with a multimode laser. Based on the periodicity of the temporal coherence of a multimode semiconductor laser, we acquire a series of holograms by changing the optical path length difference between the reference beam and object beam. Because of the use of low coherence light, we can remove the parasitic interference fringes caused by multiple reflections in the holograms. In addition, the coherent noise patterns change in this process due to the different optical paths. Therefore, the coherent noise can be reduced by averaging the multiple reconstructions with uncorrelated noise patterns. Several experiments have been carried out to validate the effectiveness of the proposed approach for coherent noise reduction in DHM. It is shown a remarkable improvement both in amplitude imaging quality and phase measurement accuracy.

The Anti-Inflammatory Effect and Intestinal Barrier Protection of HU210 Differentially Depend on TLR4 Signaling in Dextran Sulfate Sodium-Induced Murine Colitis.

BACKGROUND: Ulcerative colitis (UC) is strongly associated with inflammation and intestinal barrier disorder. The nonselective cannabinoid receptor agonist HU210 has been shown to ameliorate inflamed colon in colitis, but its effects on intestinal barrier function and extraintestinal inflammation are unclear. AIMS: To investigate the effects and the underlying mechanism of HU210 action on the UC in relation to a role of TLR4 and MAP kinase signaling. METHODS: Wild-type (WT) and TLR4 knockout (Tlr4 -/-) mice were exposed to 4% dextran sulfate sodium (DSS) for 7 days. The effects of HU210 on inflammation and intestinal barrier were explored. RESULTS: Upon DSS challenge, mice suffered from bloody stool, colon shortening, intestinal mucosa edema, pro-inflammatory cytokine increase and intestinal barrier destruction with goblet cell depletion, increased intestinal microflora accompanied with elevated plasma lipopolysaccharide, reduced mRNA expression of the intestinal tight junction proteins, and abnormal ratio of CD4+/CD8+ T cells in the intestinal Peyer's patches. Pro-inflammatory cytokines in the plasma and the lung, as well as pulmonary myeloperoxidase activity, indicators of extraintestinal inflammation were increased. Protein expression of p38α and pp38 was up-regulated in the colon of WT mice. Tlr4 -/- mice showed milder colitis. HU210 reversed the intestinal barrier changes in both strains of mice, but alleviated inflammation only in WT mice. CONCLUSIONS: Our study indicates that in experimental colitis, HU210 displays a protective effect on the intestinal barrier function independently of the TLR4 signaling pathway; however, in the extraintestinal tissues, the anti-inflammatory action seems through affecting TLR4-mediated p38 mitogen-activated protein kinase pathway.

Pharmacokinetics, Pharmacodynamics, and Tolerability of Single and Multiple Doses of Trandolapril, an Effective Angiotensin-Converting Enzyme Inhibitor, in Healthy Chinese Subjects.

Trandolapril is the pro-drug of trandolaprilat, a non-sulfhydryl angiotensin-converting enzyme inhibitor. This study was designed to assess the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of single and multiple doses of trandolapril in healthy Chinese subjects. Healthy subjects (six men and six women) were randomized into a single-dose, 3 × 3 crossover study (1-2-4 mg, 2-4-1 mg, and 4-1-2 mg), and a multiple-dose study (2 mg/day, 6 days). Serial blood and urine samples were collected after drug administration and analyzed using a validated LC-MS/MS method, and the trandolapril and trandolaprilat PK parameters were obtained. PD was evaluated by the changes in blood pressure and heart rates after dosing. Tolerability was assessed by monitoring adverse events, vital signs, ECGs, and changes in laboratory tests. In the single-dose study, trandolapril was absorbed rapidly, and peak plasma levels (C max, 1.57, 3.77, and 7.99 ng/mL) and AUCs (1.89, 3.46, and 6.47 ng/mL) were dose-dependent. The AUC0-∞ of trandolaprilat was dose-dependent, but in a non-linear fashion. The cumulative urine excretion of trandolapril and trandolaprilat was 5.51, 6.20, and 7.41 % for three doses, respectively. In the multiple-dose study, steady-state pharmacokinetics was observed; there was no trandolapril accumulation, but there was mild trandolaprilat accumulation (R = 1.67). Trandolapril was well tolerated. The most pronounced reductions in blood pressure were observed at 8 h after administration, which was later than T max. No orthostatic hypotension occurred. The pharmacokinetics and pharmacodynamics following single and multiple oral doses trandolapril in healthy Chinese subjects are similar to those observed in non-Chinese healthy subjects.

Pharmacokinetics and safety profiles of novel diethylstilbestrol orally dissolving film in comparison with diethylstilbestrol capsules in healthy Chinese male subjects.

OBJECTIVE: We compared the pharmacokinetic (PK) profiles of diethylstilbestrol orally dissolving film (DES ODF) and DES-capsule as well as assessing the safety, local tolerability, taste, and disintegration time of DES ODF. MATERIALS AND METHODS: Twelve healthy male volunteers receiving a single administration of 2.0 mg of DES ODF or DES-capsule were included in the study. The tolerability, taste, and time to dissolution of DES ODF were assessed after dosing. Safety assessments included adverse events, hematology and biochemistry tests, urinalysis, vital signs, and electrocardiography. RESULTS: The PK parameters of DES ODF were all greater than those of DEScapsule. The Cmax values were 5.64 ± 1.1 and 3.4 ± 1.93 ng/mL for DES ODF and DES-capsule, respectively. Assessment of bioequivalence was based on the 90% CIs of the treatment ratios of the log-transformed Cmax, AUC0-t, and AUC0-∞ (DES ODF to DES-capsule), with the mean values being 1.93 (141 - 264), 1.24 (98 - 156), and 1.59 (121 - 207), respectively, indicating that DES ODF had a significantly high bioavailability. The mean DES ODF disintegration time was 14 ± 5 minutes. DES ODF was well tolerated and no serious adverse events or clinically relevant changes were observed. CONCLUSIONS: The DES ODF is well tolerated and better absorbed in comparison with DES-capsule.