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This study aimed to determine the bioavailability and pharmacokinetic parameters of sulfadiazine (SDZ) in channel catfish (Ictalurus punctatus) following oral gavage and intravenous injection. The healthy channel catfish were orally and intravenously administrated with SDZ solution at doses of 50 and 5 mg/kg, respectively. Plasma samples were determined by ultra-performance liquid chromatography with an ultraviolet detector. The results demonstrated that the concentration-time profile of SDZ after oral dosing was best described by a one-compartmental open model with first-order absorption. The absorption half-life (t1/2Kα ), the elimination half-life (t1/2Ke ), and the area under concentration-time profile (AUC0-∞ ) were estimated to be 0.87 h, 29.04 h, and 1311.72 mg.h/L, respectively. After intravenous administration, the concentration-time curve of SDZ conformed to a two-compartmental open model without absorption. The distribution half-life (t1/2α ), the elimination half-life (t1/2β ), the apparent distribution volume (Vss ), the total clearance (CL), and AUC0-∞ were calculated to be 0.19 h, 14.24 h, 0.36 L/kg, 0.018 L/h/kg, and 277.12 mg.h/L, respectively. Finally, the bioavailability was estimated to be 47.33%. This study will provide some useful information for the modification of the dosage form of SDZ in aquaculture, and is partly beneficial for appropriate use of SDZ in the future.

Megakaryocytes (MKs) are the unique non-pathological cells that undergo polyploidization in mammals. The polyploid formation is critical for understanding the MK biology, and transcriptional regulation is involved in the differentiation and maturation of MKs. However, little is known about the functions of transcriptional elongation factors in the MK polyploidization. In this study, we investigated the role of transcription elongation factor EloA in the polyploidy formation during the MK differentiation. We found that EloA was highly expressed in the erythroleukemia cell lines HEL and K562. Knockdown of EloA in HEL cell line was shown to impair the phorbol myristate acetate (PMA) induced polyploidization process, which was used extensively to model megakaryocytic differentiation. Selective over-expression of EloA mutants with Pol II elongation activity partially restored the polyploidization. RNA-sequencing revealed that knockdown of EloA decelerated the transcription of genes enriched in the ERK1/2 cascade pathway. The phosphorylation activity of ERK1/2 decreased upon the EloA inhibition, and the polyploidization process of HEL was hindered when ERK1/2 phosphorylation was inhibited by PD0325901 or SCH772984. This study evidenced a positive role of EloA in HEL polyploidization upon PMA stimulation through enhanced ERK1/2 activity.

The combined effects of degrading bacteria (Paracoccus sp. LXC), humic acid (HA), and soil amendments, including chicken manure, biochar, and wormcast, were investigated through 84 d of incubation ...

Maternal nutrition can influence the composition of human breastmilk by altering the components that are sensitive to maternal diet pattern. Traditional Tibetan maternal diet pattern among native rural lactating women possesses distinct characteristics due to its unique geographical environment and dietary habits. This study investigated maternal diet pattern and human breastmilk composition of Tibetan lactating women through different lactation stages during the first month postpartum in Shigatse. The results indicated that Tibetan maternal diet profile was apparently monotonous, mainly sufficient in Zanba, buttered tea, red meat, and fatty soup, yet insufficient in white meat, eggs, leafy vegetables, and fruits, leading to imperfect maternal nutritional intakes with high‐level carbohydrates and deficient proteins. Distinctions of maternal diet profiles in various degrees can be discovered upon different lactation stages, which brings multiple influences to the composition of human milk. There was significantly weak‐to‐medium correlation of protein contents between maternal diet intakes and human milk, while other macronutrients correlated insignificantly. Micronutrient constituents in human milk, involving functional unsaturated fatty acids and free essential amino acids, were also impacted by maternal diet intakes through different lactation stages. These results show that more systematic and profound research is requisite for the clarification and development of Tibetan maternal diet to offer more enhanced and individualized nutritional recommendations for Tibetan lactating women and infants., This study investigated maternal diet pattern and human breastmilk composition of Tibetan lactating women through different lactation stages during the first month postpartum in Shigatse. Distinctions of maternal diet profiles in various degrees can be discovered upon different lactation stages, which brings multiple influences to the composition of human milk. These results show that more systematic and profound research is requisite for the clarification and development of Tibetan maternal diet to offer more enhanced and individualized nutritional recommendations for Tibetan lactating women and infants.

The purpose of this study was to investigate lipase-catalysis bioprocess in the application of sensory enhancement upon modified skim milk products. Through the comparison of various experimental elements, an optimal lipase-catalysis protocol for flavor rich milk was set, which was to catalyze pasteurized whole milk under the experimental parameters of reaction temperature 55 °C, reaction time 3 h, Lipozyme TLIM 3.0 U/mL, alcohol 135.00 μL/100 mL by a molar ratio of mpropanediol:methanol = 3:2. Then, the acquired flavor rich milk was partially utilized into the preparation of modified skim milk products. The results from volatile compositional analysis showed that high amounts of volatiles could be yielded in modified skim milk products, which can be amounted to 394.39 μg/L, mainly including short-chain fatty acids, fatty acid esters, methyl ketones, alkanes and aldehydes. Descriptive sensory results showed that the advantageous volatile characters of modified skim milk products were intensified and favorable in the sensory traits of milk flavor and mouthfeel, yet with some defects.

Functional dyspepsia (FD) is a common disease of the digestive system and probiotics have been reported to be effective in the treatment of functional gastrointestinal diseases. The aim of this study was to determine the effect of the beverage containing Lactobacillus paracasei LC-37 (LC-37) and its ability to relieve symptoms of FD by a randomized clinical trial. Due to the mechanistic complexity underlying FD, intestinal microbiota and stool metabolomes were also evaluated. The results showed that FD was relieved in participants after treatment with the beverage containing LC-37 for 14 and 28 d. The clinical symptom scores were significantly decreased after these times (abdominal pain and belching were significantly decreased after 14 d and almost absent after 28 d of treatment). Probiotics, such as those containing the Lactobacillus, Lactococcus, and Weissella, significantly increased, and the abundance of harmful bacteria such as Lachnocliostridium significantly decreased. Furthermore, relevant beneficial intestinal metabolites such as pelargonic acid, benzoic acid, and short-chain fatty acids increased, and harmful intestinal metabolites such as hippuric acid decreased. Taken together, these findings suggested that the beverages containing LC-37 can increase the abundance of probiotics and decrease pathogenic bacteria, and thereby improve beneficial intestinal metabolites. Therefore, the beverages containing LC-37 may provide a natural alternative to combat FD.

We report for the first time using zinc hydroxyfluoride (ZnOHF) for efficient NO2 gas detection. The prepared ZnOHF had a unique flower-like architecture self-assembled by nanorods with a diameter of 150 nm and length of 2-3 μm. The sensing performance toward NO2 detection indicated that the prepared ZnOHF exhibited high response (82.71), short response/recovery time (13 s/35 s) to 10 ppm of NO2, and excellent selectivity at 200 °C, greatly outperforming the ZnO raw material. ZnOHF could work in a wide detection window ranging from 100 ppb to 50 ppm, implying its practical application prospects in both industry and daily life. The excellent sensing behavior of ZnOHF originated mainly from the negligible oxygen ions adsorbed on the material surface, which was caused by the higher work function of ZnOHF. Therefore, almost all conduction band electrons can be used in the NO2 gas sensing.

Volatile flavor profile of skim milk relates to product quality and consumer liking. The volatile compositions of different skim milk products are challenging to discriminate due to subtle constituents and inconspicuous peculiarities. This study develops a correlative analysis protocol for the characterization and differentiation of volatile flavor components in various skim milk products via headspace solid-phase micro-extraction gas chromatography–mass spectrometry (HS-SPME–GC–MS) and electronic nose (E-nose) with multivariate statistical analysis. Sixty-two volatile flavor components were identified in six skim milk products, which were paired into pasteurized skim milk, ultra-high-temperature skim milk, and modified skim milk, respectively. Distinguishable variation trends were observed upon the aroma response values of skim milk samples through the solid-state E-nose sensors. The results of principal component analysis, cluster heatmap analysis and Venn diagram analysis showed that significant distinctions in varying degrees among the six skim milk products could be presented in both volatile flavor composition and aroma release distribution. The correlative analysis by partial least squares regression indicated an adequate combination of HS-SPME–GC–MS and E-nose for the differentiation and classification of volatile flavor profiles in skim milk products. These findings provide an insightful perspective for the efficient flavor evaluation of fluid skim milk.

Homologs of PtxS are ubiquitous transcriptional regulators controlling the expression of the glucose dehydrogenase and kgu operon to globally regulate the 2-ketogluconic acid (2KGA) metabolism in Pseudomonas. In the present study, a PtxS from a 2KGA industrial producer Pseudomonas plecoglossicida JUIM01 (PpPtxS) was heterologously expressed in E. coli BL21(DE3), then structurally and functionally characterized. The obtained results showed that PpPtxS was a 36.65-kDa LacI-family transcriptional regulator. 2KGA was the sole effector of PpPtxS. Glucose negatively affected the molecular binding of PpPtxS and 2KGA, and gluconic acid inhibited the PpPtxS-2KGA binding reaction. PpPtxS in water solution mainly existed as a dimer and bound to two molecules of 2KGA. The effector 2KGA mainly bound to the region close to the C-terminal of PpPtxS by interacting with the 299th to the 301st amino acids (Ala, Gln, Pro, Thr, Glu and Arg). PpPtxS specifically recognized and bound to a 14-bp palindrome sequence (5'-TGAAACCGGTTTCA-3') due to its conserved HTH motif at the N-terminal. The characterization of PpPtxS in this study would provide a theoretical guidance for the industrial production of 2KGA.

Reversible phosphorylation has emerged as an important mechanism for regulating 26S proteasome function in health and disease. Over 100 phospho-tyrosine (pTyr) sites of the human proteasome have been detected, and yet their function and regulation remain poorly understood. Here we show that the 19S subunit Rpt2 is phosphorylated at Tyr439, a strictly conserved residue within the C-terminal HbYX motif of Rpt2 that is essential for 26S proteasome assembly. Unexpectedly, we found that Y439 phosphorylation depends on Rpt2 membrane localization mediated by its N-myristoylation. Multiple receptor tyrosine kinases (RTKs) can trigger Rpt2-Y439 phosphorylation by activating Src, a N-myristoylated tyrosine kinase. Src directly phosphorylates Rpt2-Y439 in vitro and negatively regulates 26S proteasome integrity and activity at cellular membranes, which can be reversed by the membrane-associated isoform of protein tyrosine phosphatase non-receptor type 2 (PTPN2). In H1975 lung cancer cells with activated Src, blocking Rpt2-Y439 phosphorylation by the Y439F mutation conferred partial resistance to the Src inhibitor saracatinib both in vitro and in a mouse xenograft tumor model, and caused significant changes of cellular responses to saracatinib at the proteome level. Our study has defined a novel mechanism involved in the spatial regulation of proteasome function and provided new insights into tyrosine kinase inhibitor-based anti-cancer therapies.

The introduction of porous nanofillers into the polyamide selective layer of thin-film composite membranes is a promising strategy towards improved water flux and salt rejection for reverse osmosis...

Promoters and ribosome binding sites (RBSs) are routinely applied in gene expression regulation, but their orthogonality and combinatorial effects have not yet been systematically studied in Corynebacterium glutamicum. Here, 17 core promoters and 29 RBSs in C. glutamicum were characterized, which exhibited 470-fold and 430-fold in transcriptional and translational activity, respectively. By comparing the expression of two reporter genes regulated by multiple RBSs, the RBS efficacy showed significant dependence on the gene context, besides the RBSs' strength, reflecting the poor orthogonality of RBSs. Bicistron-modified RBS (referred as bc-RBS) was adapted to C. glutamicum, which improved RBS reliability. By coupling a series of promoters with RBSs/bc-RBSs, a much broader regulation range that spanned 4 orders of magnitude was observed compared with that of a sole element, and the contribution to gene expression of RBS was more than that of promoter. Finally, promoters and RBSs were applied as built-in elements to fine-tune the gene cluster in the arginine synthesis pathway in C. glutamicum. Compared with the original strain, more arginine (1.61-fold) or citrulline (2.35-fold) was accumulated in a 7 L bioreactor by strains with the gene expression regulation system rationally engineered. We demonstrated that, via combination of well-characterized gene elements, and overall consideration for both transcription and translation, the biosynthesis pathway can be effectively balanced, and the yield of a target metabolite can be further improved.

Our previous study has revealed that Pseudomonas plecoglossicida JUIM01 produced 2-keto- d -gluconic acid (2KGA) and re-utilized 2KGA as an alternative carbon source to support cell growth after complete consumption of glucose. Phosphorylation of intracellular 2KGA to 2-keto-6-phosphogluconic acid by 2-ketogluconate kinase (KguK) was regarded as the first step of 2KGA catabolism in Pseudomonas cytoplasm. In the present study, a kguK gene encoding 2-ketogluconate kinase from P. plecoglossicida JUIM01 was cloned and heterologously expressed in Pichia pastoris. The recombinant KguK showed the highest activity at 30–33 °C and pH 7.7, and high stability at 33 °C. Under the optimal conditions of 30 °C and pH 7.7 with addition of 5 mM Mg2+, the purified and concentrated (~30 folds) KguK had a specific activity of 3649.6 U/g and a Michaelis constant for 2KGA of 8.7 × 10−4 M. Knockout of kguK could retard but not completely inhibit 2KGA catabolism, indicating other existing 2KGA utilization pathway(s). The kguK-knockout P. plecoglossicida significantly reduced 2KGA re-utilization without negative effects on cell growth, glucose consumption or 2KGA production. The outputs demonstrated kguK knockout could be an effective strategy to develop the alternative 2KGA high-producing Pseudomonas strains to avoid the decrease of 2KGA yield caused by its re-utilization.

In this study, a pair of chiral baicalin (BA) derivatives were synthesized by combining BA with phenylalanine methyl ester based on molecular docking technology, namely BAD and BAL. Cell cytotoxicity trails showed that the cell growth inhibitory effects of both BAD and BAL were increased by 8- to 12-fold compared with BA on A549 cells. Flow cytometry showed that the apoptotic rates of 50 μg/mL BA, BAD, and BAL to A549 cells for 48 h were 17.94%, 24.32%, and 39.69%, respectively. Western blotting analysis showed that BAD and BAL could promote Bax, caspase-3, and caspase-9 expression and inhibit Bcl-2 expression by inhibiting the expression of p-Akt. The tumor inhibition rates of BA, BAD, and BAL in nude mice of tumor-bearing experiment lasting for 24 days were 35.01%, 53.30%, and 59.35%, respectively. These results in vitro and in vivo showed that BAL had higher antitumor activity than did BAD and BA, which were related to promotion of the apoptosis of tumor cells by inhibiting the expression of p-Akt on PI3K/Akt pathway. This study provides an experimental basis for the development of a new configuration of BA for the treatment of cancer.

Curcumin (CUR), as a traditional Chinese medicine monomer extracted from the rhizomes of some plants in Ginkgo and Araceae, has shown a wide range of therapeutic and pharmacological activities such as anti-tumor, anti-inflammatory, anti-oxidation, anti-virus, anti-liver fibrosis, anti-atherosclerosis, and anti-Alzheimer's disease. However, some issues significantly affect its biological activity, such as low aqueous solubility, physico-chemical instability, poor bioavailability, and low targeting efficacy. In order to further improve its curative effect, numerous efficient drug delivery systems have been carried out. Among them, physicochemical targeting preparations could improve the properties, targeting ability, and biological activity of CUR. Therefore, in this review, CUR carrier systems are discussed that are driven by physicochemical characteristics of the microenvironment (eg, pH variation of tumorous tissues), affected by external influences like magnetic fields and vehicles formulated with thermo-sensitive materials.

Paclitaxel (PTX) is widely used to treat breast and ovarian cancers, but innate and acquired resistance often compromises its applications. The objective of this study was to screen new-generation taxanes for their efficiency against both PTX-sensitive and PTX-resistant breast cancer cells. From twelve compounds, difluorovinyl-ortataxel (DFV-OTX) displayed potent cytotoxic activities against both PTX-sensitive and PTX-resistant breast cancer cells. Moreover, DFV-OTX effectively induced tubulin/microtubule polymerization and G2/M phase arrest, leading to apoptosis in both PTX-sensitive and PTX-resistant cancer cells. Molecular docking analysis showed that DFV-OTX possesses unique hydrogen-bonding and van der Waals interactions with β-tubulin. LC-MS/MS analysis also demonstrated that the intracellular drug amount of DFV-OTX was lower than that of PTX, which would be critical to overcome PTX-resistance. Furthermore, DFV-OTX exhibited clear efficacy in the MCF-7R and MDA-MB-231R tumor xenografts in mouse models. Taken together, our results demonstrate that the novel taxane, DFV-OTX, can effectively overcome PTX-resistance in MDA-MB-231R cells, wherein the drug resistance was attributed to ABCB1/ABCG2 upregulation and a distinct mode of action in MCF-7R cells. Our results strongly indicate that DFV-OTX is a promising chemotherapeutic agent for the treatment of PTX-resistant cancers.

Background A novel nanoemulsion (CU/FU-LN) was developed as an oral 5-fluorouracil and curcumin co-delivery system for synergistic efficacy against liver cancer. Methods MTT assay, confocal laser scanning microscope, and H&E staining were utilized to establish the efficacy and safety of CU/FU-LN. Results The AUC(0-t) of CU/FU-LN was 8.85-fold and 8.59-fold greater than those of CU and FU, respectively. The IC50 of CU/FU-LN was 4.6-fold and 4.9-fold lower than those of FU and CU in HepG2 cells, respectively. In vivo anti-tumor trials, the tumor inhibition rate was significantly elevated by CU/FU-LN (49.29%), compared 24.84% and 4.72% for FU and CU, respectively. Ki-67 immunohistochemical analysis revealed that CU/FU-LN had an obvious anti-proliferation effect. The IC50 of CU/FU-LN in L02 cells was 1.51-fold and 2.60-fold higher than those of CU and FU, respectively. Certain vital organs in the mice of the CU/FU-LN group showed markedly fewer lesions than those of the CU, FU, and CU+FU groups. The CU/FU-LN treatment caused no significant change in mouse body weight relative to the control group (P > 0.05). Conclusions We successfully prepared a promising co-delivery platform for the synergistic treatment of liver cancer and it has a comparatively enhanced efficacy and mitigated toxicity.

Background: Starch is synthesized during the day for temporary storage in leaves and then degraded during the subsequent night to support plant growth and development. Impairment of starch degradation leads to stunted growth, even senescence and death. The nuclear pore complex is involved in many cellular processes, but its relationship with starch degradation is unclear until now. We previously identified that two Nucleoporin98 (Nup98) genes (Nup98a and Nup98b) redundantly regulate flowering through CONSTANS (CO) independent pathway in Arabidopsis thaliana. The nup98a-1 nup98b-1 double mutant also shows severe senescence phenotypes. Results: We find that Nucleoporin 98 (Nup98) participates in the regulation of sugar metabolism in leaves and in turn involves in senescence regulation in Arabidopsis. We show that Nup98a and Nup98b redundantly function in the different steps of starch degradation and the nup98a-1 nup98b-1 double mutant accumulates more starch than wild type plants and has a severe early senescence phenotype compared to wild type plants. The expression of marker genes related to starch degradation is impaired in the nup98a-1 nup98b-1 double mutant, and marker genes of carbon starvation and senescence express earlier and in higher abundance in the nup98a-1 nup98b-1 double mutant than in wild type plants, suggesting that abnormality of energy metabolism is the main cause of senescence of the nup98a-1 nup98b-1 double mutant. Addition of sucrose to the growth medium rescues early senescence phenotypes of the nup98a-1 nup98b-1 mutant. Conclusions: Our results provide a line of evidence on a novel role of the nuclear pore complex in energy metabolism related to growth and development, in which Nup98 functions in starch degradation conferring growth regulation in Arabidopsis.

The assessment method of iodine nutrition for pregnant women lacks strong evidence-based medicine. The prevalence of iodine deficiency in pregnant women may be overestimated using urinary iodine concentration (UIC). The reference intervals of UIC-to-urinary creatinine concentration ratio (UIC/UCr) were established using a self-sequential longitudinal study of pregnant women with singleton gestation who were recruited using the criteria of the National Academy of Clinical Biochemistry in Dandong City, which is a long-term iodine-replete area. Nine thousand one hundred sixty-four pregnant women in the first trimester from Dalian City, Dandong City, and Shenyang City were included to verify our proposed reference intervals. UIC and concentrations of urinary creatinine, serum iodine, TSH, FT4, TPOAb, and TgAb were measured. The reference intervals of UIC/UCr were 38.63-489.46 μg/g for the first trimester, 58.48-644.03 μg/g for the second trimester, and 56.27-644.93 μg/g for the third trimester. The prevalence of iodine deficiency was 49.50% using UIC as the indicator ( 150 μg/L), while the prevalence was 3.28% using UIC/UCr ( 38.63 μg/g). The prevalence of iodine excess was 3.21% using UIC as the indicator ( 500 μg/L) while the prevalence was 1.45% using UIC/UCr ( 489.46 μg/g). The highest prevalence of overt hypothyroidism and positive thyroid antibodies was in the group with UIC/UCr 38.63 μg/g. In contrast to the place of residence and age, BMI was an influencing factor for UIC/UCr. The reference intervals of UIC/UCr were established. UIC/UCr may eliminate the effect of urine volume and reflect the actual prevalence of iodine deficiency in pregnant women.

The nano-sheet assembled NiO/ZnO microspheres with a diameter of ca. 2 μm have been synthesized via facile hydrothermal method followed by a thermal treatment process. The gas-sensing measurement results show that the sensor using nano-sheet assembled NiO/ZnO microspheres exhibits improved response to sulfur dioxide gas compared with the pure ZnO microspheres sensor. In particular, the sensor with a Ni/Zn molar ratio of 0.5 (0.5 mol% NiO/ZnO) shows high response value (S = 107) and superior selectivity to 10 ppm sulfur dioxide at a low operating temperature of 160 °C and the detection limit of the NiO/ZnO sensor toward sulfur dioxide is down to 1 ppm (S = 6). The enhanced sensing performance is attributed to the formation of p-n heterojunctions on the interface, the catalytic function of NiO and the three-dimensional microspheres composed of the lamellar structure with a large specific surface area. The three-dimensional microspheres provide more active sites for gas adsorption, and the interlayer gap facilitates the diffusion of gas in three-dimensional structure, resulting in high sensitivity and superior selectivity. This work provides a simple method for the synthesis of NiO/ZnO heterojunction microspheres with superior gas-sensing performance, which can be used as a potential material for sulfur dioxide detection.

To further improve the removal ability of layered double hydroxide (LDH) for iodide (I−) anions from wastewater, we prepared hierarchically porous Cu5Mg10Al5-LDH and used as a matrix for in suit growth of Cu/Cu2O on its surface, forming Cu/Cu2O-LDH, which was characterized and applied as an adsorbent. Results displayed high I− saturation uptake capability (137.8 mg/g) of Cu/Cu2O-LDH compared with Cu5Mg10Al5-LDH (26.4 mg/g) even thermal activated LDH (76.1 mg/g). Thermodynamic analysis showed that the reaction between I− anions and Cu/Cu2O-LDH is a spontaneous and exothermic. Uptake kinetics analysis exhibited that adsorption equilibrium can be reached after 265 min. Additionally, the adsorbent showed satisfactory selectivity in the presence of competitive anions (e.g., SO42−), and could achieve good adsorption performance in a wide pH range of 3–8. A cooperative adsorption mechanism was proposed on the basis of the following two aspects: (1) ion exchange between iodide and interlayer anions; (2) the adsorption performance of Cu, Cu(II) and Cu2O for I−. Meanwhile, the difference between the adsorption mechanism of Cu/Cu2O-LDH, Cu5Mg10Al5-LDH and Cu5Mg10Al5-CLDH adsorbents was also elaborated and verified.

An HMPA catalyzed reductive alkylation of ureas and thioureas with trichlorosilane under mild reaction conditions has been developed. Both aldehydes and ketones could be used as efficient alkylation reagents in this method to obtain the desired products in moderate to high yields. A variety of di- and trisubsituted ureas and thioureas were easily prepared by this new reductive alkylation method. This protocol exhibits excellent functional group tolerance, chemoselectivity and practicality.

The 9α-hydroxyandrost-4-ene-3,17-dione (9α−OH-AD) is a key intermediate for synthetizing steroid pharmaceutical compounds. It is bioconverted by Mycobacterium sp. LY-1 from phytosterols. During biotransformation, the low solubility of phytosterols in water limits 9α−OH-AD production. In the present work, polyoxyethylene (10) nonylphenyl ether (TX-40), a nonionic surfactant, was first used to enhance phytosterol solubility during 9α−OH-AD biotransformation. In the presence of 0.7% TX-40, phytosterol solubility was increased 12.1-fold, and the 9α−OH-AD molar yield reached 42.5% at the phytosterols concentration of 15 g/L, an increase of 217.2% over controls. The improvement is sufficient to replace the traditional process of adding soybean oil. Scanning electron microscopy showed that the extracellular membrane-like structure was loosened by TX-40, but cells maintained their integrity. The fatty acid profile of Mycobacterium sp. LY-1 cells revealed that TX-40 altered the composition of the cell membrane and improved its permeability. The transcript levels of key enzymes involved in cell membrane lipid synthesis were downregulated significantly upon TX-40 addition compared with controls. These results demonstrated that the increase in product molar yield by TX-40 was primarily related to easier substrate transportation across the cell membrane of Mycobacterium sp. LY-1.

Background Poly-γ-glutamic acid (γ-PGA) is a natural anionic biopolymer widely used in various fields, including medicine, food, cosmetics, and environmental protection. The γ-PGA synthase complex, CapBCA, is the only polyprotein complex responsible for γ-PGA synthesis. However, systematic and in-depth research on the function of each component involved in γ-PGA synthesis is scarce, which limits enhanced production of γ-PGA. Results To address this limitation, γ-PGA synthase components were localized, and their functions associated with γ-PGA synthesis were investigated in Corynebacterium glutamicum. Bioinformatics analysis and confocal microscopic observations of CapB-sfGFP, CapC-sfGFP, and CapA-sfGFP proteins revealed that γ-PGA synthase components CapB, CapC, and CapA were all localized on the cell membrane. More importantly, γ-PGA was detected only when CapB, CapC, and CapA were expressed in combination in C. glutamicum. Furthermore, enhancement of CapB or CapC transcription levels (from low to high) and maintaining medium-level CapA transcription led to 35.44% and 76.53% increase in γ-PGA yield (γ-PGA yield-to-biomass), respectively. However, maintaining medium-level CapB and CapC transcription, and moderate enhancement of CapA transcription level (from low to medium) led to 35.01% increase in γ-PGA yield, whereas a further increase in CapA expression (from medium to high) led to 10.36% decrease in γ-PGA yield. Notably, CapC had the greatest influence (accounting for 68.24%) on γ-PGA synthesis. Conclusions The present study determined the membrane localization of γ-PGA synthase components, CapB, CapC, and CapA, in C. glutamicum and confirmed the significance of these components in γ-PGA production. Furthermore, CapC was found to have the greatest influence on controlling γ-PGA synthesis. These findings shed light into the effect of γ-PGA synthase component expression on γ-PGA synthesis, and provide insights for further improvement in γ-PGA production.

Tripterygium hypoglaucum (Lévl.) Hutch (THH) is believed to play an important role in health care and disease treatment according to traditional Chinese medicine. Moreover, it is also the representative of medicine with both significant efficacy and potential toxicity. This characteristic causes THH hard for embracing and fearing. In order to verify its prospect for clinic, a wide variety of studies were carried out in the most recent years. However, there has not been any review about THH yet. Therefore, this review summarized its characteristic of components, pharmacological effect, pharmacokinetics and toxicity to comprehensively shed light on the potential clinical application. More than 120 secondary metabolites including terpenoids, alkaloids, glycosides, sugars, organic acids, oleanolic acid, polysaccharides and other components were found in THH based on phytochemical research. All these components might be the pharmacological bases for immunosuppression, anti-inflammatory and anti-tumour effect. In addition, recent studies found that THH and its bioactive compounds also demonstrated remarkable effect on obesity, insulin resistance, fertility and infection of virus. The main mechanism seemed to be closely related to regulation the balance of immune, inflammation, apoptosis and so on in various disease. Furthermore, the study of pharmacokinetics revealed quick elimination of the main component triptolide. The feature of celastrol was also investigated by several models. Finally, the side effect of THH was thought to be the key for its limitation in clinical application. A series of reports indicated that multiple organs or systems including liver, kidney and genital system were involved in the toxicity. Its potential serious problem in liver was paid specific attention in recent years. In summary, considering the significant effect and potential toxicity of THH as well as its components, the combined medication to inhibit the toxicity, maintain effect might be a promising method for clinical conversion. Modern advanced technology such as structure optimization might be another way to reach the efficacy and safety. Thus, THH is still a crucial plant which remains for further investigation.

The endothelial-mesenchymal transition (EndMT) participates in the progression of diabetic retinopathy (DR), but cell-intrinsic factors modulating this process remain elusive. In this study, we explored the role of lysophosphatidic acid (LPA) – producing enzyme, acylglycerol kinase (AGK), in the EndMT of human retinal microvascular endothelial cells (HRECs) under high-glucose (HG) conditions. We found that AGK was significantly elevated in HG-treated cells. In addition, AGK knockdown reversed the HG-induced EndMT in HRECs, which was evidenced by the increased endothelial markers (CD31 and VE-cadherin) and decreased mesenchymal markers (FSP1 and α-SMA). Furthermore, downregulation of AGK inhibited the HG-induced activation of transforming growth factor β (TGF-β)/Notch pathways, whereas exogenous TGF-β1 (10 ng/mL) impeded the inhibitory effects of AGK knockdown on HG-induced EndMT in HRECs. Additionally, the silencing of AGK abolished the HG-induced upregulation of LPA and its receptor, LPA receptor 1 (LPAR1), and overexpression of LPAR1 further rescued the AGK knockdown-mediated inhibition of the EndMT process. In conclusion, we demonstrate that downregulation of AGK suppresses HG-induced EndMT in HRECs through regulating the LPAR1/TGF-β/Notch signaling pathway, indicating that AGK might be a potential therapeutic target for the treatment of DR.

Purpose/Background: Paclitaxel (PTX) has been widely used in the clinic to treat breast cancer. However, its poor water solubility and intolerable toxicity greatly reduce the efficacy and medication safety. In this paper, a curcumin derivative (CUD) synthesized by the research group was used as a carrier to prepare a new type of PTX nanodrug delivery system (CUD-PTX-LN), thereby improving the safety of PTX medication and enhancing the anti-tumor effect.Methods: CUD-PTX-LN was prepared by solid dispersion technology and the dialysis method was adopted to investigate the release behavior of CUD-PTX-LN in vitro. Meanwhile, the dynamic process of nanoparticles in vivo was analyzed by pharmacokinetic experiments. Hemolysis experiment, acute toxicity and cumulative toxicity were conducted in mice to evaluate the safety of CUD-PTX-LN. Subsequently, the anti-tumor activity of CUD-PTX-LN was investigated using in vitro and in vivo breast cancer cell models.Results: The average particle size, PDI, and Zeta potential of CUD-PTX-LN were 238.5 ± 4.79 nm, 0.225 ± 0.011 and -33.8 ± 1.26 mV, respectively. CUD-PTX-LN had an encapsulation efficiency (%EE) of 94.20 ± 0.49% and an achievable drug loading (%DL) of 10.98 ± 0.31%. This nanoparticle was stable for up to half a year when the lyophilized powder was stored at room temperature. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of nanoparticles in comparison to free PTX. CUD-PTX-LN significantly prolonged the half-life and retention time of PTX. The area under the curve (AUC) of CUD-PTX-LN was 14.72 mg/L × h, which was 6 times that of the free PTX group (2.38 mg/L × h). In anti-tumor experiments in vivo, CUD-PTX-LN possessed the advantages of improving the antitumor efficacy and reducing the toxic side effects of drugs. Importantly, CUD-PTX-LN is safer than free PTX in terms of assessing hemolytic, acute and cumulative toxicity.Conclusion: A novel PTX nanodrug delivery system constructed based on CUD as a carrier holds great potential in improving breast cancer treatment.

Mn-doped ZnS quantum dots (QDs) with excellent optical properties have been explored in a wide range of fields. Their potential adverse effects on biological systems and human health should be evaluated before biological application. In the present study, we investigated the effect of Mn-doped ZnS QDs on the intestinal tract and gut microbiota structures at 2 h and 14 days (d) after 14 d repeated oral exposure in mice. Flame atomic absorption spectrophotometry (FAAS), histopathological examination, and transmission electron microscopy (TEM) were used to assess the absorption and toxicity of Mn-doped ZnS QDs on the intestinal tract. The 16S rRNA gene sequencing was used to evaluate the gut microbial communities. Mn-doped ZnS QDs did not accumulate in the duodenum, jejunum, ileum, or colon. The Zn content of feces was not significantly higher than in the control group. No major histological changes were found in these tissues. The intestinal microvilli remained regular, but swelling of mitochondria and endoplasmic reticulum was detected by TEM at 14 d after the last gavage. A total of 2,712 operational taxonomic units (OTUs) were generated. Mn-doped ZnS QDs treatment did not significantly change the α-diversity of Richness, Chao1, Shannon, and Simpson indexes. According to principal component analysis (PCA), Mn-doped ZnS QDs had no effect on the overall structure of the gut microbiota. No significant change occurred at the phylum level, while three genera were downregulated at 2 h and seven changed at 14 d after the last gavage. Our findings revealed that Mn-doped ZnS QDs had a little stimulation of the intestinal tract and gut microbiota, and oral administration may be a safe route for biological application (such as bioimaging and drug delivery).

Copper plays pivotal roles in metabolic homoeostasis, but its potential role in human tumorigenesis is not well defined. Here, it is revealed that copper activates the phosphoinositide 3‐kinase (PI3K)‐protein kinase B (PKB, also termed AKT) oncogenic signaling pathway to facilitate tumorigenesis. Mechanistically, copper binds 3‐phosphoinositide dependent protein kinase 1 (PDK1), in turn promotes PDK1 binding and subsequently activates its downstream substrate AKT to facilitate tumorigenesis. Blocking the copper transporter 1 (CTR1)‐copper axis by either depleting CTR1 or through the use of copper chelators diminishes the AKT signaling and reduces tumorigenesis. In support of an oncogenic role for CTR1, the authors find that CTR1 is abnormally elevated in breast cancer, and is subjected by NEDD4 like E3 ubiquitin protein ligase (Nedd4l)‐mediated negative regulation through ubiquitination and subsequent degradation. Accordingly, Nedd4l displays a tumor suppressive function by suppressing the CTR1‐AKT signaling. Thus, the findings identify a novel regulatory crosstalk between the Nedd4l‐CTR1‐copper axis and the PDK1‐AKT oncogenic signaling, and highlight the therapeutic relevance of targeting the CTR1‐copper node for the treatment of hyperactive AKT‐driven cancers., Besides playing pivotal roles in metabolic homoeostasis, copper also binds PDK1 to activate its downstream AKT kinase, which in turn facilitates tumorigenesis. Meanwhile, the copper transporter 1 (CTR1) is negatively regulated by Nedd4l‐mediated ubiquitination and subsequent degradation, indicating a novel regulatory crosstalk between the Nedd4l‐CTR1‐copper axis and the PDK1‐AKT oncogenic signaling to govern tumorigenesis.

Nanozymes have been widely used in biosensors instead of natural enzymes because of low cost, high stability and ease of storage. However, few works use oxidase-like nanozymes to fabricate electrochemical biosensors. Herein, we proposed a sensitive electrochemical biosensor to detect uracil-DNA glycosylase (UDG) based on the hollow Mn/Ni layered doubled hydroxides (h-Mn/Ni LDHs) as oxidase-like nanozyme. Briefly, the h-Mn/Ni LDHs, which was prepared by a facile hydrothermal method, exhibited excellent oxidase-like activity because the hollow structure provided rich active sites and high specific surface area. Then, the signal probes were constructed by assembling the hairpin DNA (hDNA), single DNA1 and DNA2 on the h-Mn/Ni LDHs, respectively. In the presence of UDG, the uracil bases in the stem of hDNA were specifically excised, generating apyrimidinic (AP) sites and inducing the unwinding of the hDNA. Afterwards, the h-Mn/Ni LDHs@Au-hDNA/DNA1 was connected on the electrode via hybridization between unwinded hDNA and capture DNA (cDNA). Subsequently, the self-linking process allowed the retention of numerous h-Mn/Ni LDHs through simple DNA hybridization to amplify the signal of o-phenylenediamine (o-PD). Unlike many peroxidase-like nanozyme-based electrochemical biosensors, there is no need to add H2O2 during the experimental process, which effectively reduced the background signal as well as improved the stability of the biosensor. As expected, the biosensor exhibited excellent performance with a wide linear range and a low detection limit. This work highlights an appealing opportunity to develop a no H2O2 platform based on h-Mn/Ni LDHs for future application in biological analysis and clinical diagnosis.

Herein, we synthesize the thiophene tetraphenylethene-based conjugated microporous polymer (ThT-CMP) using the tetraphenylethylene derivative [i.e., 1,1,2,2-tetrakis(4-bromophenyl)ethane (TPBE)] and 2,5-thiophenediboronic acid as the precursors. The aggregation of TPBE in the ThT-CMP can induce a strong dual-band bipolar electrochemiluminescence (AIECL) emission at 554 nm (anodic) and 559 nm (cathodic) with tri-n-propylamine (TPrA) and S2O82- as the coreactants, respectively. The anodic and cathodic ECL efficiencies are measured to be 11.49 and 3.82% with respect to the standard of the Ru(bpy)32+/TPrA system, respectively. We further develop a dipolar ECL sensor to sensitively detect rhodamine B (RhB) based on resonance energy transfer. This ECL sensor possesses a large dynamic range and high sensitivity. This research provides a new avenue of designing organic structures with the characteristic of bipolar AIECL for the development of luminescent devices.

The aromatic structure of three different-rank vitrinites, V-YJL (Ro =0.61%), V-AW (Ro =1.13%), and V-JC (Ro =2.22%), was investigated by X-ray diffraction (XRD), high-resolution transmission elect...

Lignin peroxidase (LiP) was obtained from Pichia methanolica through heterologous expression. LiP was extracted, purified, and immobilized on Fe3O4@SiO2@polydopamine (PDA) nanoparticles to acquire immobilized LiP. The optimal preparation conditions for immobilized LiP were investigated. Results showed that the immobilization efficiency of immobilized LiP reached 56.37% when the enzyme amount, PDA concentration, and immobilization time were 12 mg, 1.6 mg/mL, and 12 h, respectively. Compared with free LiP, the immobilized LiP showed good thermal stability and storage stability and improved pH tolerance. It also retained more than 30% of its initial activity after 8 cycles, demonstrating its improved reusability. The immobilized LiP demonstrated efficacy of reaction of 100%, 100%, 100%, 100%, 79%, 73%, and 65% for tetracycline, dibutyl phthalate, 5-chlorophenol, phenol, phenanthrene, fluoranthene, and benzo(a)pyrene, respectively, while the inactivated immobilized LiP only adsorbed

The human placenta is an important organ that forms a barrier where maternal and fetal exchange takes place. The placenta transport iodine to the fetal circulation by transfer of maternal iodine and deiodination of thyroid hormones (THs). The aim of the study was to examine the distribution of iodine and thyroid hormone transporters in the maternal and fetal sides of human-term placenta. A cross-sectional study was performed at the First Affiliated Hospital of China Medical University. Placental samples (maternal and fetal surfaces) were collected from 113 healthy-term pregnant women. The iodine content; the concentration of thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3); and the enzyme activity of placental type 2 iodothyronine deiodinase (D2) and D3 were examined. The mRNA and protein localization/expression of iodine and thyroid hormone transporters in the placenta were also studied. We also analyzed the association between expression level of Na+/I- symporter (NIS), thyroid hormone transporter protein, D3 activity in maternal and fetal surfaces of placenta with iodine content, and thyroid hormone levels. Iodine levels in placental samples from the maternal side were significantly higher than those in samples from the fetal side. T3 and T4 expression in fetal placenta was significantly lower than in maternal placenta. D3 activity in the fetal side of the placentas was significantly higher than that in the maternal side. The mRNA and protein expression of monocarboxylate transporters 8 (MCT8), L-amino acid transporters 1 (LAT1), organic anion transporting polypeptides 4A1 (OATP4A1), and TH binding protein transthyretin (TTR) were significantly increased in maternal side, while the NIS expression was higher in fetal side of human-term placenta. In conclusion, the enzymatic deiodination of thyroid hormones forms a barrier which reduces transplacental passage of the hormones and that the maternal part of the placenta is the primary factor in the mechanism regulating the hormonal transfer.

Mechanical microenvironment plays a critical role in cancer drug resistance and this study supposed that suspension state might be involved in drug resistance of breast tumor cells. The viability of cell was detected by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Cell cycle and apoptosis were detected by flow cytometry. Gene and protein were tested by RT-qPCR and Western blot, respectively. Drug resistance of MDA-MB-231 cells cultured for 72 h under suspension state was significantly increased. Suspension state was found to induce the overexpression of adenosine triphosphate-binding cassette subfamily C member 3 (ABCC3) in MDA-MB-231 cells. Silencing of ABCC3 significantly decreased drug resistance of suspension MDA-MB-231 cells. Moreover, suspension state was able to increase lamin A/C accumulation in MDA-MB-231 cells and lamin A/C regulated the expression of ABCC3. Moreover, lamin A/C knockdown also decreased drug resistance of suspension MDA-MB-231 cells, but the effect on drug resistance was less than that of ABCC3 knockdown. Suspension state plays a vital role in promoting drug resistance of MDA-MB-231 cells by inducing ABCC3 overexpression, and lamin A/C accumulation is associated with this process.

Nanozymes, nanomaterial-based artificial enzymes, have attracted researchers’ enormous interest due to their unique properties compared with natural enzymes. To mimic the catalytic function of natural enzymes, designing high-efficient, novel nanozymes is crucial yet challenging task. In this article, we described the synthesis and functions of a metalloporphyrin-based porous organic polymer, namely FePPOPs-SO3H. FePPOPs-SO3H was synthesized effortlessly via an extensive aromatic electrophilic substitution and the following sulfonation reactions. This strategy was cost-efficient without the participation of precious metal catalysts. The resultant FePPOPs-SO3H is intriguing since the framework itself is constructed by covalently linked porphyrin units, which could serve as a built-in catalyst and strengthen the stability of polymer. With sulfonic acid side groups, FePPOPs-SO3H is well water-dispersive. Owing to these unique characteristics, FePPOPs-SO3H exhibited excellent peroxidase-like activity toward a classical peroxidase substrate 3,3′,5,5′-tetramethylbenzidine (TMB) to produce a blue product only within 20 s. The peroxidase-mimicking performance of FePPOPs-SO3H outperforms the ferric porphyrin monomer and normal Fe3O4 nanoparticles. Based on the excellent catalytic activity of FePPOPs-SO3H, two visual colorimetric sensors for ultrafast detecting H2O2 and glucose, respectively, were constructed with a wide linear range of 50–1800 μM (for H2O2) and 200–1500 μM (for glucose), as well as a relative lower limit of detection (LOD) [26.70 μM (for H2O2) and 16.38 μM (for glucose)]. Our strategy highlights opportunities for the design of new metalloporphyrin-based porous organic polymers with built-in catalytic skeletons and inherently excellent peroxidase-mimicking performance.

Background Conjunctival filtering bleb scar formation is the main reason for the failure of glaucoma filtration surgery. Cytoglobin (Cygb) has been reported to play an important role in extracellular matrix (ECM) remodeling, fibrosis and tissue damage repairing. This study aimed to investigate the role of Cygb in anti-scarring during excessive conjunctival wound healing after glaucoma filtration surgery. Methods Cygb was overexpressed in human tenon fibroblasts (hTFs) by transfecting hTFs with lentiviral particles encoding pLenti6.2-FLAG-Cygb. Changes in the mRNA and protein levels of fibronectin, collagen I, collagen III, TGF-β1, and HIF1α were determined by RT-PCR and western blotting respectively. Results After Cygb overexpression, hTFs displayed no significant changes in visual appearance and cell counts compared to controls. Whereas, Cygb overexpression significantly decreased the mRNA and protein expression levels of collagen I, collagen III and fibronectin compared with control (p

Spexin/NPQ is a novel highly conserved neuropeptide. It has a widespread expression in the periphery and central nervous system. However, the effects of central spexin on acute inflammatory pain are still unknown. This study explored the mechanisms and effects of supraspinal spexin on inflammatory pain. The results from the mouse formalin test show that i.c.v. administration of spexin decreased licking/biting time during the late and early phases. The nonamidated spexin had no effect on pain response. The antinociception of spexin was blocked by galanin receptor 3 antagonist SNAP 37889. The Galr3 and Adcy4 mRNA levels in the brain were increased after injection with spexin. The antinociceptive effects of spexin were completely reversed by opioid receptor antagonist naloxone and κ-opioid receptor antagonist nor-binaltorphimine dihydrochloride. Spexin up-regulated the dynorphin and κ-opioid receptor gene and protein expression. PCR array assay and real-time PCR analysis show that spexin up-regulated the mRNA level of the FBJ osteosarcoma oncogene (Fos). T-5224, the inhibitor of c FBJ osteosarcoma oncogene (c-Fos)/activator protein 1 (AP-1), blocked the increased mRNA level of Pdyn and Oprk1 induced by spexin. I.C.V. spexin (2.43 mg/kg) increased the number of c-Fos-positive neurons in most subsections of periaqueductal gray. In addition, in the acetic acid-induced writhing test, i.c.v. spexin produced an antinociceptive effect. Our results indicate that spexin might be a novel neuropeptide with an antinociceptive effect against acute inflammatory pain.

The fresh Fe@ Zeolite Imidazolate Framework-8 (Fe@ZIF-8) was exploited as an prospective adsorbent for the removal and abruption of U(VI) ions from aqueous solutions for the first time. The material exhibited a latent adsorption capacity of 277.77 mg g−1 and an eminent selectivity to U(VI) at pH = 4.5. Moreover the adsorption property of this novel adsorbent was in accord well with the Langmuir, Freundlich isotherm and pseudo-second-order kinetic model. Given the superiorities of this sorbent including high adsorption capacity, selectivity, and environment-friendly, it may be an effective candidate for the uptake of U(VI) ions for practical application.