Exploration of material basis: Chemical composition profile, metabolic profile and pharmacokinetic characteristics in Xingbei Zhike granule.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Xingbei Zhike granule (XBZK), a widely prescribed Chinese patent medicine, is known for its efficacy in clearing lung qi, relieving cough and reducing phlegm, as well as fever, dry and bitter taste, and irritability. Despite its clinical popularity, comprehensive investigations into its chemical composition, in vivo metabolism, and pharmacokinetic characteristics are limited. AIM OF THE STUDY: This study investigates the chemical composition, in vivo metabolism, and in vivo dynamics of XBZK to clarify its material basis and pharmacokinetic characteristics. MATERIALS AND METHODS: Ultra-high performance liquid chromatography with Orbitrap tandem mass spectrometry (UPLC-Orbitrap-MS) was used to determine the chemical composition and in vivo metabolic profile of XBZK. Additionally, UPLC with triple quadrupole mass spectrometry (UPLC-TQ-MS/MS) was performed to quantify its main components and evaluate its in vivo dynamics in rat plasma. RESULTS: In total, 57 components were identified in XBZK. Furthermore, 40 prototype components and 31 metabolites were detected in various biological matrices of rats, including plasma, tissues, bile, feces, and urine. After administration, the area under the curve (AUC) for ephedrine (Eph), pseudoephedrine (Peph), neotuberostemonine (Neo), amygdalin (Amy), and enoxolone (Eno) exhibited a strong linear relationship with the administered dose (r > 0.9) in all rats. And gender-related differences in the absorption of peiminine (Pmn), peimisine (Pms), and chrysin-7-O-glucuronide (Cog) were notable among rats, with male rats showing a dose-dependent pattern of absorption, while female rats exhibited minimal absorption. CONCLUSIONS: XBZK contains 57 components, primarily composed of flavonoids, alkaloids, and coumarins. The eight main components were rapidly absorbed and eliminated, with some, such as Eph, Peph, Neo, Amy and Eno, following a linear pharmacokinetic pattern. Furthermore, Pmn, Pms and Cog were well absorbed in male rats, showing a dose-dependent behavior.

Gender-specific effects of oxidative balance score on the prevalence of diabetes in the US population from NHANES.

Background: The relationship between oxidative balance score (OBS) and diabetes remains poorly understood and may be gender-specific. We conducted a cross-sectional study to investigate the complex association between OBS and diabetes among US adults. Methods: Overall, 5,233 participants were included in this cross-sectional study. The exposure variable was OBS, composed of scores for 20 dietary and lifestyle factors. Multivariable logistic regression, subgroup analysis, and restricted cubic spline (RCS) regression were applied to examine the relationship between OBS and diabetes. Results: Compared to the lowest OBS quartile group (Q1), the multivariable-adjusted odds ratio (OR) (95% confidence interval (CI) for the highest OBS quartile group (Q4) was 0.602 (0.372-0.974) (p for trend = 0.007), and for the highest lifestyle, the OBS quartile group was 0.386 (0.223-0.667) (p for trend < 0.001). Moreover, gender effects were found between OBS and diabetes (p for interaction = 0.044). RCS showed an inverted-U relationship between OBS and diabetes in women (p for non-linear = 6e-04) and a linear relationship between OBS and diabetes in men. Conclusions: In summary, high OBS was negatively associated with diabetes risk in a gender-dependent manner.

Discovery of the material basis of Jiuwei Xifeng granules using pharmaco-chemistry and pharmacokinetics.

ETHNOPHARMACOLOGICAL RELEVANCE: Jiuwei Xifeng granules (JWXF) is primarily used for the treatment of Tourette syndrome (TS) with kidney-Yin deficiency and internal stirring of liver wind. However, few studies have focused on this issue. AIM OF THE STUDY: This study aimed to clarify chemical composition of JWXF using in vitro and in vivo pharmaco-chemistry and to provide a basis for the clinical use of JWXF using a strategy of pharmacokinetics. MATERIALS AND METHODS: In this study, the chemical constituents and in vivo metabolism of JWXF were evaluated using high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS/MS), and the time-dependent processes of the three main components in rats were detected using ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-QQQ-MS/MS). RESULTS: A total of 75 constituents were identified, including 22 alkaloids, 21 terpenes, 15 organic acids and their derivatives, and 17 other compounds. After administration, 12 compounds were identified in rat plasma, including 11 prototypes and one metabolite. Pharmacokinetic analysis showed that the effects of gentiopicroside, gastrodin, and sweroside in rats were dose-dependent when the dose of JWXF was 1-4 g/kg. They were rapidly absorbed and did not accumulate in the plasma after 7-day continuous intragastric administration. CONCLUSIONS: JWXF consists of 75 components, including alkaloids, terpenes, and organic acids. The three main compounds, gastrodin, gentiopicroside, and sweroside, undergo rapid absorption, elimination, and dose-dependent pharmacokinetics.

Thickness measurements of graphene oxide flakes using atomic force microscopy: results of an international interlaboratory comparison.

Flake thickness is one of the defining properties of graphene-related 2D materials (GR2Ms), and therefore requires reliable, accurate, and reproducible measurements with well-understood uncertainties. This is needed regardless of the production method or manufacturer because it is important for all GR2M products to be globally comparable. An international interlaboratory comparison on thickness measurements of graphene oxide flakes using atomic force microscopy has been completed in technical working area 41 of versailles project on advanced materials and standards. Twelve laboratories participated in the comparison project, led by NIM, China, to improve the equivalence of thickness measurement for two-dimensional flakes. The measurement methods, uncertainty evaluation and a comparison of the results and analysis are reported in this manuscript. The data and results of this project will be directly used to support the development of an ISO standard.

The tissue distribution of Jinzhen oral liquid in healthy and influenza mice.

Jinzhen oral liquid (JZOL) is widely used in China. However, its tissue distribution, a vital part of the efficacy substances research, has not been reported yet. This study characterized its chemical components and its prototypes and metabolites in mice, and investigated its tissue distribution in pathological and healthy mice. Several constituents were characterized, including 55 constituents in JZOL, 11 absorbed prototypes and six metabolites in plasma and tissues. The metabolic pathways were demethylation, dehydration and acetylation. A sensitive, accurate and stable quantitative method was established and applied to the tissue distribution. After administration of JZOL, these seven components were rapidly distributed to various tissues, mainly staying in the small intestine, and less distributed to lung, liver and kidney. Compared with healthy mice, the absorption of baicalin, wogonoside, rhein, glycyrrhizic acid and liquiritin apioside was reduced in influenza mice, but their elimination was slow. However, influenza infection had no obvious effect on the overall distribution of the most important components (baicalin, glycyrrhizic acid and wogonoside) in the plasma or small intestine, but obviously affected the distribution of baicalin in liver. In summary, seven components are rapidly distributed to various tissues, and influenza infection has certain influence on the tissue distribution of JZOL.

Posterior reversible encephalopathy syndrome in children with acute lymphoblastic leukemia during remission induction chemotherapy: a single-center retrospective study.

BACKGROUND: This study investigated the clinical characteristics, cranial magnetic resonance imaging (MRI) features, MRI follow-up, and prognosis of children with acute lymphoblastic leukemia (ALL) who developed posterior reversible encephalopathy syndrome (PRES) during remission induction chemotherapy. METHODS: We analyzed the age, gender, PRES symptoms and signs, cranial MRI findings, therapeutic effect, and prognosis of children with ALL who developed PRES during chemotherapy from January 2010 to December 2013 at the Hematology Oncology Center of Beijing Children's Hospital. Changes in cranial MRI findings were analyzed, and intelligence (IQ) and cognitive function were evaluated using the Wechsler Scale and the Wisconsin Card Score Test after the children completed chemotherapy. RESULTS: There were 850 children with newly diagnosed ALL in this period; 13 (1.5%), 6 boys and 7 girls, developed PRES. All were diagnosed as B-cell ALL. The median age at PRES onset was 7 years (2-11 years). The median day of PRES onset was day 28 (day 17-34) of remission induction chemotherapy. Of the 13 children with PRES onset and seizures, 4 had visual disturbances and 2 had consciousness disturbances. Cranial MRI showed hyperintensity in the subcortical white matter on T2-weighted axial and fluid-attenuated inversion recovery (FLAIR) images. The lesion locations were as follows: occipital lobe, 12 (92.3%) patients; frontal lobe, 7 (53.8%) patients; temporal lobe, 5 (38.4%) patients; parietal lobe, 3 (23.1%) patients; and cerebellum, 1 (7.7%) patient. There were 8 (61.5%) patients with vasogenic edema and 5 (38.5%) with cytotoxic edema. After treatment, all children recovered within one month, when their PRES symptoms were relieved, they continued to receive chemotherapy. However, 1 child (1.07%) died of severe central nervous system infection one year after PRES treatment, and 3 (25%) had recurrent seizures and were diagnosed with epilepsy after three months of PRES treatment. Their cranial MRIs showed cytotoxic edema, which was acute stage on day 15, with aggravated lesions on cranial MRI. The cranial MRI lesions returned to normal at one month in 3 (23.1%) patients, at three months in 6 (46.1%) patients, at one year in 8 (61.5%) patients, and at two years in 12 (92.3%) patients. The 12 surviving children all returned to school, and their full-scale, verbal, and performance IQs were normal, with no significant differences in intelligence or cognitive function compared with children with ALL without PRES during the same period. CONCLUSIONS: PRES can occur during remission induction chemotherapy treatment of children with ALL, but the incidence is low. Cranial MRI can be used for diagnosis and to characterize lesions. The children recover about a month after treatment, and cranial MRI lesions return to normal within two years. The time for complete resolution of MRI lesions differs, and children with cytotoxic edema have worse prognosis with sequelae, such as epilepsy, which requires close monitoring. PRES does not affect intelligence or cognitive development.

Mechanism of Jinzhen Oral Liquid against influenza-induced lung injury based on metabonomics and gut microbiome.

ETHNOPHARMACOLOGICAL RELEVANCE: Jinzhen Oral Liquid (JZOL) is a traditional Chinese patent medicine and widely used clinically, which consists of eight herbs including Bovis Calculus Atifactus, Fritillariae Ussuriensis Bulbus (Fritillaria ussuriensis Maxim.), Caprae Hircus Cornu, Rhei Radix et Rhizoma (Rheum palmatum L.), Scutellariae Radix (Scutellaria baicalensis Georgi), Glycyrrhizae Radix et Rhizoma (Glycyrrhiza uralensis Fisch. ex DC.), Chloriti Lapis, and Gypsum Fibrosum (Their ratio is 9.45 : 47.25: 94.5 : 31.5: 15.75 : 31.5: 15.75 : 23.62). A large number of clinical studies have proved that JZOL has a good antiviral effect and can treat lung injury, pneumonia, and bronchitis caused by a variety of viral infections. AIM OF THE STUDY: Influenza infection frequently exhibit dysregulation of gut microbiota and host metabolomes, but the mechanism of JZOL is still unclear and needs to be further explored. Here, after influenza virus infection induced lung injury, the regulation roles of JZOL in metabolic and gut microbiota balances are investigated to comprehensively elucidate its therapeutic mechanism. MATERIALS AND METHODS: A mouse model of lung injury was replicated via intranasal instillation of influenza A (H1N1). The efficacy of JZOL was evaluated by pathological sections, lung index, the levels of TNF-α and IFN-γ, and viral load in lung tissue. Its modulation of endogenous metabolites and gut microbiota was assessed using plasma metabolomic technique and 16S rRNA high-throughput sequencing technique. RESULTS: JZOL not only significantly relieved lung inflammation and edema in influenza mice, but also alleviated the disturbance of endogenous metabolites and the imbalance of gut microbiota mainly by regulating glycerophospholipid and fatty acid metabolism and Lactobacillus. The anti-influenza effects of JZOL were gut microbiota dependent, as demonstrated by antibiotic treatment. The altered metabolites were significantly correlated with Lactobacillus and pharmacodynamic indicators, further confirming the reliability of these results. CONCLUSIONS: JZOL attenuates H1N1 influenza infection induced lung injury by regulating lipid metabolism via the modulation of Lactobacillus. The results support the clinical application of JZOL, and are useful to further understand the mechanism of TCM in the treatment of influenza.

Quality evaluation of ginkgo biloba leaves based on non-targeted metabolomics and representative ingredient quantification.

Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC-Q-TOF-MS/MS) combined with multivariate statistical analysis was applied to the study of plant metabolomics to reveal the factors affecting the content of ginkgo leaf compounds. As a follow-up analysis, the terpene lactones and ginkgolic acids were quantified simultaneously using ultra-performance liquid chromatography coupled with triple quadrupole mass spectrometry (UPLC-QqQ-MS/MS), and subsequently total flavonol glycosides were quantified by high-performance liquid chromatography (HPLC). The results revealed that a total of 52 compounds were potentially identified by establishing a database, and 10 compounds were verified by reference standards; terpene lactones, ginkgolic acids, and flavonoids were the differential compounds; and ginkgolide A was identified as an important indicator compound for tree age. In addition, quantitative analysis showed that the contents of total flavonol glycosides and terpene lactones were highest during April and August in young ginkgo leaves, and differed based on origin. In summary, numerous compounds were rapidly detected by liquid chromatography coupled with MS, the ginkgo leaf samples were compared, and the differential metabolites were screened out. The content changing rules of the target compounds in ginkgo leaves from different regions with different tree ages and harvesting periods were clarified.

[Changes in physicochemical property and microbial community of Pseudostellaria heterophylla soil at diffe-rent fallow ages]. / 太子参不同休耕年限土壤理化特征和微生物群落变化.

Pseudostellaria heterophylla is authentic traditional Chinese herbal medicine in Fujian Province. P. hete-rophylla suffers from serious consecutive monoculture problems. Fallow can alleviate such problems, but the mecha-nism is still unclear. In this study, high-throughput sequencing was performed to analyze the changes in soil microbial community structure and diversity in the P. heterophylla soil at different fallow ages as well as their relationships with soil physicochemical properties and phenolic acids. The results showed that fungal community diversity decreased but bacterial community diversity increased in fallow soils compared with the control soil of P. heterophy-lla. For bacterial communities, the relative abundance of Acidobacteria increased, while that of Proteobacteria and Actinobacteria decreased in fallow soils. For fungal communities, the relative abundance of dominant phyla had no significant difference between fallow and control soils. Soil acidity and organic matter content showed a trend of weakening and decreasing, respectively, with the increases of fallow years. In addition, with the increases of fallow years, the content of phenolic acids in soil, including benzoic acid and salicylic acid, showed significant decrease, while some other phenolic acids such as p-coumaric acid were accumulated obviously. Taken together, fallow could efficiently ameliorate the structure of soil microbial community and soil properties of P. heterophylla, and thus alleviate the effects of continuous cropping.

Exogenous Arginine Treatment Maintains the Appearance and Nutraceutical Properties of Hard- and Soft-Seed Pomegranates in Cold Storage.

Arginine is a natural preservative; however, its effects on the storage of different cultivars of pomegranates have not been investigated extensively. Therefore, the fruit quality of soft-seed Tunisia and hard-seed Yudazi pomegranates was investigated after treatment with arginine at four concentrations during cold storage for 80 days. Pomegranates treated with 1.0 mM arginine exhibited a relatively lower loss of vitamin C, soluble solid, total phenol, and anthocyanin contents in arils, together with a better fruit appearance. Combined with principal component analysis (PCA), the storage life of fruits treated with 1.0 mM arginine showed a higher correlation with antioxidant enzyme activity (e.g., superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT)) during the first 40 days of cold storage, whereas after 40 days of cold storage, storage life was more dependent on the integrity of the cell membrane affected by malondialdehyde (MDA) content, electrolyte leakage (EL), and hydrogen peroxide (H2O2) accumulation. Arginine treatment contributed significantly to the appearance and inner quality of the hard-seed pomegranate cv. Yudazi fruit during cold storage compared to those of soft-seed Tunisia. Taken together, arginine application combined with cold storage enhanced the nutraceutical properties and marketability of pomegranate fruits.

Metabolic characteristics and pharmacokinetic differences of Qiwei Tongbi oral liquid in rheumatoid arthritis rats.

Qiwei Tongbi oral liquid (QWTB), a classical traditional Chinese medicine formula, is widely used to treat arthritis-related diseases in clinical practice. Currently, in vivo metabolic characteristics and pharmacokinetic studies are lacking. This study analyzed the prototype components of QWTB absorbed in the blood and their metabolic transformation process after intragastric administration and compared the differences in pharmacokinetic properties between healthy and rheumatoid arthritis model rats. In sum, 17 prototype components and 21 related metabolites were identified in the plasma and urine of the treated rats. Metabolites were derived from sinomenine and magnoflorine. Through systematic methodology verification, an accurate and stable detection method for sinomenine and magnoflorine in plasma samples was established and applied to pharmacokinetic research of QWTB. At the three dose levels, the AUC0-∞ (area under the curve) of the two components showed a good positive correlation with the dose (R2 > 0.9). Compared with healthy rats, the Tmax , t1/2z , and AUC of sinomenine were markedly increased, and Cmax was decreased in rheumatoid arthritis model rats, indicating that the rate of absorption and elimination rate decreased, but the body exposure increased. However, there were no significant differences in the pharmacokinetic parameters of magnoflorine under healthy and pathological conditions. In summary, the main active ingredients of QWTB are sinomenine and magnoflorine, which exhibit linear kinetic characteristics within a set dose range, and the rheumatoid arthritis pathological state is more conducive to the absorption and efficacy of sinomenine. The results of this study demonstrate the rationality of the clinical application of the QWTB.

Electroplating Deposition of Bismuth Absorbers for X-ray Superconducting Transition Edge Sensors.

An absorber with a high absorbing efficiency is crucial for X-ray transition edge sensors (TESs) to realize high quantum efficiency and the best energy resolution. Semimetal Bismuth (Bi) has shown greater superiority than gold (Au) as the absorber due to the low specific heat capacity, which is two orders of magnitude smaller. The electroplating process of Bi films is investigated. The Bi grains show a polycrystalline rhombohedral structure, and the X-ray diffraction (XRD) patterns show a typical crystal orientation of (012). The average grain size becomes larger as the electroplating current density and the thickness increase, and the orientation of Bi grains changes as the temperature increases. The residual resistance ratio (RRR) (R300 K/R4.2 K) is 1.37 for the Bi film (862 nm) deposited with 9 mA/cm2 at 40 °C for 2 min. The absorptivity of the 5 µm thick Bi films is 40.3% and 30.7% for 10 keV and 15.6 keV X-ray radiation respectively, which shows that Bi films are a good candidate as the absorber of X-ray TESs.

Metabolomics analysis of the therapeutic effects of Qiwei Tongbi oral liquid on rheumatoid arthritis in rats.

Qiwei Tongbi oral liquid (QWTB), a classical traditional Chinese medicine (TCM) formula, has a good therapeutic effect on rheumatoid arthritis (RA) and is widely used in China. To comprehensively elucidate the therapeutic mechanism of QWTB in the treatment of RA, the effects of QWTB on biomarkers and metabolic pathways in a rat model of kidney deficiency arthritis were investigated in this study. The effects of QWTB on pharmacodynamic indicators, including paw swelling, arthritis score; interleukin-1ß, interleukin-6, interleukin-17 F, tumor necrosis factor-α, tartrate-resistant acid phosphatase 5b, bone alkaline phosphatase, bone-specific alkaline phosphatase, bone glaprotein, urea, and creatinine levels; and histopathology, suggested that QWTB significantly improved renal function, inhibited the inflammatory response, and reduced bone loss. In total, 39 differential metabolites were screened by comparing the endogenous components between blank and model rat plasma, among which 16 metabolites were altered by QWTB. The metabolism pathway analysis revealed that α-linolenic acid metabolism, phenylalanine metabolism, sphingolipid metabolism, histidine metabolism and glycerophospholipid metabolism were greatly disturbed. Thus, the biomarkers investigated included (1) α-linolenic acid, (2) hippuric acid, (3) phosphatidylethanolamine (15:0/22:2(13Z,16Z)), (4) phenylpyruvic acid, (5) sphinganine, and (6) urocanic acid. QWTB affected three abnormal biomarkers: (3), (4), and (6). Phenylphruvic acid, sphinganine and urocanic acid were significantly associated with pharmacodynamic indicators, as shown by Pearson correlation analysis. These results indicated that RA-related biomarkers had certain reliability and biological significance. In summary, QWTB regulated the metabolic disorders in rats with RA. Its therapeutic mechanism may involve the regulation of phenylalanine metabolism, histidine metabolism, and glycerophospholipid metabolism. The results of this study are useful for understanding the therapeutic mechanisms of TCM.

Influence of the Interface Composition to the Superconductivity of Ti/PdAu Films.

In this work, the interface composition of the superconducting Ti/PdAu bilayer is tuned by an annealing process in N2 from 100 to 500 °C to control the superconducting transition temperature (Tc). This Ti-PdAu composition layer is characterized with a high-resolution transmission electron microscopy (HRTEM) and energy-dispersive spectrometer (EDS) to show the infiltration process. The surface topography, electrical, and cryogenic properties are also shown. The inter-infiltration of Ti and PdAu induced by the thermal treatments generates an intermixed layer at the interface of the bilayer film. Due to the enforced proximity effect by the annealing process, the Tc of Ti (55 nm)/PdAu (60 nm) bilayer thin films is tuned from an initial value of 243 to 111 mK which is a temperature that is suitable for the application as the function unit of a superconducting transition edge sensor.

USP7 negatively controls global DNA methylation by attenuating ubiquitinated histone-dependent DNMT1 recruitment.

Previous studies have implicated an essential role for UHRF1-mediated histone H3 ubiquitination in recruiting DNMT1 to replication sites for DNA maintenance methylation during S phase of the cell cycle. However, the regulatory mechanism on UHRF1-mediated histone ubiquitination is not clear. Here we present evidence that UHRF1 and USP7 oppositely control ubiquitination of histones H3 and H2B in S phase of the cell cycle and that DNMT1 binds both ubiquitinated H3 and H2B. USP7 knockout markedly increased the levels of ubiquitinated H3 and H2B in S phase, the association of DNMT1 with replication sites and importantly, led to a progressive increase of global DNA methylation shown with increased cell passages. Using DNMT3A/DNMT3B/USP7 triple knockout cells and various DNA methylation analyses, we demonstrated that USP7 knockout led to an overall elevation of DNA methylation levels. Mechanistic study demonstrated that USP7 suppresses DNMT1 recruitment and DNA methylation through its deubiquitinase activity and the interaction with DNMT1. Altogether our study provides evidence that USP7 is a negative regulator of global DNA methylation and that USP7 protects the genome from excessive DNA methylation by attenuating histone ubiquitination-dependent DNMT1 recruitment.

Recruiting a Phosphite Dehydrogenase/Formamidase-Driven Antimicrobial Contamination System in Bacillus subtilis for Nonsterilized Fermentation of Acetoin.

Microbial contamination, especially in large-scale processes, is partly a life-or-death issue for industrial fermentation. Therefore, the aim of this research was to create an antimicrobial contamination system in Bacillus subtilis 168 (an ideal acetoin producer for its safety and acetoin synthesis potential). First, introduction of the formamidase (FmdA) from Helicobacter pylori and the phosphite dehydrogenase (PtxD) from Pseudomonas stutzeri enabled the engineered Bacillus subtilis to simultaneously assimilate formamide and phosphite as nitrogen (N) and phosphorus (P) sources. Thus, the engineered B. subtilis became the dominant population in a potentially contaminated system, while contaminated microbes were starved of key nutrients. Second, stepwise metabolic engineering via chromosome-based overexpression of the relevant glycolysis and acetoin biosynthesis genes led to a 1.12-fold increment in acetoin titer compared with the starting host. Finally, with our best acetoin producer, 25.56 g/L acetoin was synthesized in the fed-batch fermentation, with a productivity of 0.33 g/L/h and a yield of 0.37 g/g under a nonsterilized and antibiotic-free system. More importantly, our work fulfills many key criteria of sustainable chemistry since sterilization is abolished, contributing to the simplified fermentation operation with lower energy consumption and cost.

CYP4A11 is involved in the development of nonalcoholic fatty liver disease via ROS­induced lipid peroxidation and inflammation.

Nonalcoholic fatty liver disease (NAFLD) is a fat metabolism disorder that occurs in liver cells. The development of NAFLD is considered to be associated with hepatic oxidative stress. The present study aimed to investigate the role of cytochrome P450 4A11 (CYP4A11) in the pathogenesis of NAFLD. The levels of plasma CYP4A11 and lipid peroxidation products levels exhibited a high correlation, and were increased significantly compared with those from normal subjects. Further in vitro studies demonstrated that the expression levels of CYP4A11 and the content of reactive oxygen species (ROS) were increased in free fatty acid (FFA)­stimulated HepG2 cells. Clofibrate, a CYP4A11 inducer, aggravated cell damage. Opposite results were observed for the CYP4A11 inhibitor HET0016, which attenuated apoptosis in FFA­treated cells. Furthermore, CYP4A11 gene overexpression and silencing were used to investigate the effects on inflammatory cytokine secretion. The data demonstrated that CYP4A11 promoted an increase in the mRNA expression of tumor necrosis factor α, interleukin (IL)­1ß and IL­6 in response to FFA. In addition, western blot analysis highlighted that CYP4A11 caused an upregulation of phosphorylated p65 levels and therefore affected the NF­κB signaling pathway. The data demonstrated that CYP4A11 may metabolize fatty acids to promote the production of ROS and accelerate the progression of NAFLD.

Hypermethylation of the PTTG1IP promoter leads to low expression in early-stage non-small cell lung cancer.

Despite the clinical requirement for early diagnosis, the early events in lung cancer and their mechanisms are not fully understood. Pituitary tumor transforming gene 1 binding factor (PTTG1IP) is a tumor-associated gene; however, to the best of our knowledge, its association with lung cancer has not been reported. The present study analyzed PTTG1IP expression in early-stage non-small cell lung cancer (NSCLC) samples and investigated its epigenetic regulatory mechanisms. The results revealed that the mRNA level of PTTG1IP in NSCLC tissues was significantly downregulated by 43% compared with that in adjacent tissues. In addition, overexpression of this gene significantly inhibited cell proliferation. According to data from The Cancer Genome Atlas, a significant negative correlation was identified between the PTTG1IP gene methylation level and expression level in lung adenocarcinoma and lung squamous cell carcinoma cases. Reduced representation bisulfite sequencing (RRBS) analysis of six paired early-stage NSCLC tissue samples indicated that the CpG island shore of the PTTG1IP promoter is hypermethylated in lung cancer tissues, which was further validated in 12 paired early-stage NSCLC samples via bisulfite amplicon sequencing. Following treatment with 5-aza-2'-deoxycytidine to reduce DNA methylation in the promoter region, the PTTG1IP mRNA level increased, indicating that the PTTG1IP promoter DNA methylation level negatively regulates PTTG1IP transcription. In conclusion, in early-stage NSCLC, the PTTG1IP gene is regulated by DNA methylation in its promoter region, which may participate in the development and progression of lung cancer.

Development and Evaluation of a Water-in-oil Microemulsion Formulation for the Transdermal Drug Delivery of Teriflunomide (A771726).

Teriflunomide (TEF, A771726) is the active metabolite of leflunomide (LEF), a disease-modifying anti-rheumatic drug. The main purpose of this study was to develop and evaluate water-in-oil (W/O) microemulsion formulation of TEF. The W/O microemulsion was optimized formula is the physical and chemical stability of lecithin, ethanol, isopropyl myristate (IPM) and water (20.65/20.78/41.52/17.05 w/w) by using the pseudo-ternary phase diagram and the average droplet size is about 40 nm. The permeability of TEF microemulsion is about 6 times higher than control group in vitro penetration test. The results of anti-inflammatory effect showed that compared with the control group, the external TEF microemulsion group could significantly inhibit swelling of paw in rats, and no significant difference compared with oral LEF group. The results of hepatotoxicity test show that there were normal content of alanine aminotransferase (ALT)/aspartate aminotransferase (AST) and no obvious inflammatory infiltration of TEF microemulsion group compared with LEF group. The plasma concentration curve showed that compared with LEF group, the peak concentration of TEF microemulsion group was decreased, the half-life (t1/2) was prolonged, and the relative bioavailability of TEF microemulsion was 75.35%. These results suggest that TEF W/O microemulsion can be used as a promising preparation to play an anti-inflammatory role while significantly reducing hepatotoxicity.

Size and shape dependences of the adsorption kinetics of malachite green on nano-MgO: a theoretical and experimental study.

Compared with bulk materials, there is a considerable difference in the adsorption kinetics of nanoparticles, which mainly depend on particle size and shape. Herein, by introducing the shape factor, we have derived the relations between the kinetic parameters of adsorption and the particle size of nanoparticles of different shapes. Then, the influence of the regularities and mechanisms of particle size and shape on the kinetic parameters of adsorption were discussed. In the experiment, spherical nano-MgO and cubic nano-MgO of different particle sizes were synthesized via a sol-gel method, the kinetic parameters of the adsorption of malachite green on nano-MgO were determined, and the influence of the regularities of particle size and shape on the adsorption kinetic parameters were obtained. The experimental results show that shape and particle size may significantly influence the kinetic parameters of adsorption. For the adsorption of nano-MgO with the same equivalent particle diameter, compared to spherical shapes, the rate constant of adsorption k for cubic shapes is larger, while the apparent activation energy Ea and the pre-exponential factor A are smaller. For the adsorption of spherical or cubic nano-MgO, k increases with decreasing particle size, while Ea and A decrease, and there exist good linear relationships between ln k, Ea, ln A and the reciprocal of particle size. The experimental results are well in agreement with the theoretical relations. Furthermore, k is influenced by the shape factor, Ea by the shape factor and the specific surface enthalpy, and A by the shape factor and the temperature coefficient of surface tension. The kinetic theory of adsorption can quantitatively describe the influence of the regularities and mechanisms of particle size and shape on the adsorption kinetics of nanoparticles and provide significant guidance for the research and the application of nano-adsorptions in the related fields.