Preclinical Pharmacokinetics and Bioavailability of Oxypeucedanin in Rats after Single Intravenous and Oral Administration.

Oxypeucedanin, a furanocoumarin extracted from many traditional Chinese herbal medicines, has a variety of pharmacological effects. However, the independent pharmacokinetic characteristics and bioavailability of this compound remains elusive. In this study, a rapid, sensitive, and selective method using ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC/MS/MS) was developed for evaluating the intravenous and oral pharmacokinetics of oxypeucedanin. After intravenous administration of oxypeucedanin (2.5, 5, and 10 mg/kg), and intragastric administration of oxypeucedanin (20 mg/kg), blood samples were collected periodically from the tail vein. The plasma concentration-time curves were plotted, and the pharmacokinetic parameters were calculated using a non-compartmental model analysis. After intravenous administration of oxypeucedanin (single dosing at 2.5, 5, and 10 mg/kg) to rats, the pharmacokinetics fit the linear kinetics characteristics, which showed that some parameters including average elimination half-life (T1/2Z of 0.61~0.66 h), mean residence time (MRT of 0.62~0.80 h), apparent volume of distribution (VZ of 4.98~7.50 L/kg), and systemic clearance (CLZ of 5.64~8.55 L/kg/h) are dose-independent and the area under concentration-time curve (AUC) increased in a dose-proportional manner. Single oral administration of oxypeucedanin (20 mg/kg) showed poor and slow absorption with the mean time to reach the peak concentration (Tmax) of 3.38 h, MRT of 5.86 h, T1/2Z of 2.94 h, and a mean absolute bioavailability of 10.26% in rats. These results provide critical information for a better understanding of the pharmacological effect of oxypeucedanin, which will facilitate its research and development.

LncRNA CHRF promotes TGF-ß1 induced EMT in alveolar epithelial cells by inhibiting miR-146a up-regulating L1CAM expression.

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a type of progressive lung fibrosis disease. The survival time of diagnosed IPF patients is often only 2 years. Currently much evidence showed that the epithelial-mesenchymal transition (EMT) process is the main cause of the occurrence and development of IPF. LncRNA cardiac hypertrophy related factor (CHRF) was reported to be related with IPF development. Here we explored the functions and regulatory mechanisms of CHRF on EMT in IPF. MATERIALS AND METHODS: A549 cells were treated with transforming growth factor-ß1 (TGF-ß1) for 48 h to construct IPF cell model. CHRF and miR-146a expression were quantified using qPCR. The expression of L1 cell adhesion molecule (L1CAM) and EMT related indicators (E-cadherin, Vimentin, Slug and N-cadherin) were detected by qPCR and western blot. Dual luciferase reporter experiment was conducted to prove the molecular interaction of miR-146a and L1CAM, as well as CHRF and miR-146a. RESULTS: CHRF and L1CAM expression were significantly upregulated and promoted the EMT process in A549 after treatment of TGF-ß1. MiR-146a was obviously down-regulated, and knockdown of CHRF inhibited the EMT process by up-regulating miR-146a, in A549 after treatment of TGF-ß1. Meanwhile, overexpression of miR-146a inhibited EMT process via targeting L1CAM. In addition, L1CAM overexpression eliminated the inhibitory effect of sh-CHRF on the EMT process. CONCLUSIONS: These results provided evidence that CHRF promoted EMT process in A549 after treatment of TGF-ß1, which proposed a new insight for depth understanding the pathological mechanisms of IPF.

One-year results for myopia control of orthokeratology with different back optic zone diameters: a randomized trial using a novel multispectral-based topographer.

AIM: To present the 1-year results of a prospective cohort study investigating the efficacy, potential mechanism, and safety of orthokeratology (ortho-k) with different back optic zone diameters (BOZD) for myopia control in children. METHODS: This randomized clinical study was performed between Dec. 2020 and Dec. 2021. Participants were randomly assigned to three groups wearing ortho-k: 5 mm BOZD (5-MM group), 5.5 mm BOZD (5.5-MM group), and 6 mm BOZD (6-MM group). The 1-year data were recorded, including axial length, relative peripheral refraction (RPR, measured by multispectral refractive topography, MRT), and visual quality. The contrast sensitivity (CS) was evaluated by CSV-1000 instrument with spatial frequencies of 3, 6, 12, and 18 cycles/degree (c/d); the corneal higher-order aberrations (HOAs) were measured by iTrace aberration analyzer. The one-way ANOVA was performed to assess the differences between the three groups. The correlation between the change in AL and RPR was calculated by Pearson's correlation coefficient. RESULTS: The 1-year results of 20, 21, and 21 subjects in the 5-MM, 5.5-MM, and 6-MM groups, respectively, were presented. There were no statistical differences in baseline age, sex, or ocular parameters between the three groups (all P>0.05). At the 1-year visit, the 5-MM group had lower axial elongation than the 6-MM group (0.07±0.09 vs 0.18±0.11 mm, P=0.001). The 5-MM group had more myopic total RPR (TRPR, P=0.014), with RPR in the 15°-30° (RPR 15-30, P=0.015), 30°-45° (RPR 30-45, P=0.011), temporal (RPR-T, P=0.008), and nasal area (RPR-N, P<0.001) than the 6-MM group. RPR 15-30 in the 5.5-MM group was more myopic than that in the 6-MM group (P=0.002), and RPR-N in the 5-MM group was more myopic than that in the 5.5-MM group (P<0.001). There were positive correlations between the axial elongation and the change in TRPR (r=0.756, P<0.001), RPR 15-30 (r=0.364, P=0.004), RPR 30-45 (r=0.306, P=0.016), and RPR-N (r=0.253, P=0.047). The CS decreased at 3 c/d (P<0.001), and the corneal HOAs increased in the 5-MM group (P=0.030). CONCLUSION: Ortho-k with 5 mm BOZD can control myopia progression more effectively. The mechanism may be associated with greater myopic shifts in RPR.

Orthokeratology with increased compression factor in adolescent myopia control: a 2-year prospective randomized clinical trial.

AIM: To explore the long-term efficacy, safety, and optical mechanism of orthokeratology with increased compression factor in adolescent myopia control. METHODS: A prospective, double-masked, and randomized clinical trial was performed from May 2016 to June 2020. Subjects aged between 8 and 16y, with myopia (-5.00 to -1.00 D), low astigmatism (≥-1.50 D) and anisometropia (≤1.00 D), were stratified into low (-2.75 to -1.00 D) and moderate (-5.00 to -3.00 D) myopia groups. Then they were randomly assigned to wear either increased compression factor (ICF; 1.75 D) orthokeratology or conventional compression factor (CCF; 0.75 D) orthokeratology. The data were recorded including axial length (AL), spherical equivalent (SE), best corrected visual acuity (BCVA), near visual acuity (NVA), corneal staining (using Efron grading scales), corneal hysteresis (CH), corneal resistance factor (CRF), higher-order aberrations (HOAs, expressed as root mean square, RMSh), and subfoveal choroidal thickness (SFChT) in the 2-year follow-up period. Pearson's correlation coefficient was conducted to analyze the association between the changes in AL and RMSh, SFChT. RESULTS: At the 2-year visit, there were no statistical differences in all the parameters between the ICF group and the CCF group in low myopia subjects (P>0.05). For the moderate myopia subjects, the ICF group had shorter AL elongation (0.23±0.08 vs 0.30±0.11 mm, P=0.015), higher RMSh (1.94±0.50 vs 1.65±0.51 µm, P=0.041), and higher SFChT (279.04±35.72 vs 254.08±29.60 µm, P=0.008) than those in CCF group. The change in AL was negatively correlated with RMSh (r=-0.687, P<0.001) and SFChT (r=-0.464, P=0.013). CONCLUSION: ICF orthokeratology can control the progression of moderate myopia more effectively, which might be related to greater RMSh and SFChT.

A Model Based on Artificial Intelligence Algorithm for Monitoring Recurrence of HCC after Hepatectomy.

BACKGROUND: There is no satisfactory indicator for monitoring recurrence after resection of hepatocellular carcinoma (HCC). This retrospective study aimed to design and validate an HCC monitor recurrence (HMR) model for patients without metastasis after hepatectomy. METHODS: A training cohort was recruited from 1179 patients with HCC without metastasis after hepatectomy between February 2012 and December 2015. An HMR model was developed using an AdaBoost classifier algorithm. The factors included patient age, TNM staging, tumor size, and pre/postoperative dynamic variations of alpha-fetoprotein (AFP). The diagnostic efficacy of the model was evaluated based on the area under the receiver operating characteristic curves (AUCs). The model was validated using a cohort of 695 patients. RESULTS: In preoperative patients with positive or negative AFP, the AUC of the validation cohort in the HMR model was .8877, which indicated better diagnostic efficacy than that of serum AFP (AUC, .7348). The HMR model predicted recurrence earlier than computed tomography/magnetic resonance imaging did by 191.58 ± 165 days. In addition, the HMR model can predict the prognosis of patients with HCC after resection. CONCLUSIONS: The HMR model established in this study is more accurate than serum AFP for monitoring recurrence after hepatectomy for HCC and can be used for real-time monitoring of the postoperative status in patients with HCC without metastasis.

Alpha-Fetoprotein Ratio Predicts Alpha-Fetoprotein Positive Hepatocellular Cancer Patient Prognosis after Hepatectomy.

BACKGROUND: This study was conducted to investigate the effect of alpha-fetoprotein (AFP) ratio on the prognosis of AFP-positive hepatocellular carcinoma (HCC) patients after hepatectomy. METHODS: We retrospectively included 879 HCC patients with AFP-positive who underwent hepatectomy from February 2012 to October 2017 and randomly divided into training cohort and validation cohort. AFP ratio was equal to the AFP level within one week before hepatectomy to AFP level within 20-40 days after surgery. The end point of follow-up was disease-free survival (DFS) and overall survival (OS). RESULTS: AFP ratio was not associated with clinical characteristics in training cohort and validation cohort. According to the X-tile software, the optimum cut-off point was 17.8 for AFP ratio. Significant differences between AFP ratio high and AFP ratio low were observed in DFS and OS in both cohort (p < 0.05). Kaplan-Meier curves and receiver-operating curves were showed that AFP ratio was better than AFP level preoperation in predicting the prognosis of AFP-positive HCC patients after hepatectomy. The multivariate analysis demonstrated that AFP ratio was a significant independent risk factor for both OS and DFS in HCC patients with AFP-positive. CONCLUSIONS: AFP ratio might be a prognosis predictor for HCC patients with AFP-positive after hepatectomy.

[FTIR analysis of the effects of enhanced ultraviolet-B (UV-B) radiation on chemical composition of different parts of Scutellaria baicalensis Georgi].

The effects of enhanced ultraviolet-B (UV-B) radiation on chemical compositions of radix, stem and leaf of Scutellaria baicalensis Georgi were studied via FTIR Results showed that alcohols and phenolic substances in the radix and leaf of S. baicalensis Georgi were increased by UV-B radiation as well as the content of flavonoids and flavonoids glycosides. The terpenoids content in radix and protein content in leaf were increased by supplementary UV-B radiation. Contrary to the circumstance in radix and leaf, contents of alcohols and phenolic, flavonoids, unsaturated fat and lactone in stem were decreased by UV-B radiation. These results indicated that there is a trade-off in distribution of the metabolites in radix, stem and leaf of different parts. More information could be revealed for the result of FTIR spectral analysis via FTIR second derivative spectrum, especially the information of the combination between flavonoids and glycosides. The effects of UV-B radiation on chemical composition in radix, stem and leaf of S. baicalensis Georgi could be examined simply and rapidly via the method of FTIR. Thus, it can be used as a prior method before the further analysis of chemical composition.

Identification of novel CSNK2A1 variants and the genotype-phenotype relationship in patients with Okur-Chung neurodevelopmental syndrome: a case report and systematic literature review.

De novo germline variants of the casein kinase 2α subunit (CK2α) gene (CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur-Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype-phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1 variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype-phenotype relationship in OCNS.

Smoking status combined with tumor mutational burden as a prognosis predictor for combination immune checkpoint inhibitor therapy in non-small cell lung cancer.

BACKGROUND: This study aimed to explore the prognostic value of tumor mutational burden (TMB) combined with smoking status in advanced non-small cell lung cancer (NSCLC) patients who received immune checkpoint inhibitor therapy (anti PD-1/PD-L1 therapy) combined with chemotherapy or anti-angiogenesis therapy. METHODS: We conducted a retrospective analysis of NSCLC patients who underwent next-generation sequencing test (either 295-gene panel NGS or 1021-gene panel NGS) from September 2017 to November 2020. The relationship between TMB and smoking status was investigated. Kaplan-Meier survival analysis was used to compare progression-free survival (PFS) of the NSCLC patients who received combination immunotherapy grouped by TMB value and smoking status. RESULTS: We enrolled 323 cases and 388 cases of NSCLC patients in the 295-gene panel cohort and 1021-gene panel cohort, respectively. Positive correlation between TMB and smoking status was found in lung adenocarcinoma, but not in lung squamous cell carcinoma. Participants with both high TMB and smoking status who received immune checkpoint therapy combined with chemotherapy or anti-angiogenesis therapy had longer PFS than other participants (p < 0.05). CONCLUSIONS: The combination of TMB with smoking status might be a potential predictor for the efficacy of combination immunotherapy in advanced NSCLC.

Photodecomposition of ibuprofen over g-C3N4/Bi2WO6/rGO heterostructured composites under visible/solar light.

A microwave-assisted hydrothermal preparation of heterostructured graphitic carbon nitride/bismuth tungsten oxide/reduced graphene oxide nanocomposites (denoted as GBR-T, T = microwave irradiation time) is performed. The prepared GBR-T photocatalysts are identified by employing X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), time-resolved photoluminescence (TRPL) and nitrogen adsorption-desorption isotherms. The photocatalytic performance of these GBR-T is evaluated by the photocatalytic degradation of ibuprofen (IBP) under the visible light (λ > 420 nm) and solar light irradiation. Among all prepared photocatalysts, ca. 93% of IBP photodegradation can be achieved with a degradation rate constant (k) of 0.011 min-1 under visible-light irradiation upon the optimal microwave-assisted reaction time of 60 min. The improvement is primarily attributable to the higher crystallization degree, specific surface area and increased charge transfer efficiency as verified by XRD, nitrogen adsorption-desorption isotherms and TRPL, respectively. The photocatalytic performance of this catalyst is further enhanced in the photodecomposition of IBP (ca. 98.6%) under sun light irradiation. The electron spin resonance (ESR) and liquid chromatography-mass/mass spectrometry (LC-MS/MS) studies show that the superoxide radicals and hydroxyl radicals are the dominant active species in the photocomposition of IBP and degradation intermediates are formed through three probable photodegradation pathways. This investigation provides a simple way to prepare triple 2D heterojuction photocatalysts which could be effectively used in the advanced oxidation process for removal of emerging contaminants in wastewater by using renewable energy.

Adsorption of nicotine in aqueous solution by a defective graphene oxide.

Extensive concerns have been focused on the emerging contaminants including nicotine in the aquatic system recently. Graphene oxide (GO) and modified graphene oxides (GO-COOH and defective GO-COOH) are used as effective adsorbents to remove nicotine from aqueous solution. The adsorption isotherms and kinetics of the adsorbents all fit well with Langmuir model and pseudo-second-order model, respectively. The thermodynamic studies show that the adsorption is an exothermic and spontaneous process. The influence of pH and ionic solution strength on the adsorbents is also investigated. The maximum adsorption capacity can be observed at pH value of ca. 8. The adsorption capacities of nicotine are decreased upon the increase of sodium ion concentration. Among all the adsorbents, the defective GO-COOH adsorbents possess the maximum adsorption capacity of nicotine of 196.5 mg g-1 obtained from Langmuir isotherm. In regeneration experiments, the defective GO-COOH adsorbents can maintain 95.1% of adsorption capacity after five times of cyclic adsorption-desorption processes. The adsorbents are identified by Fourier transform infrared, 13C solid-state magic-angle spinning nuclear magnetic resonance, X-ray photoelectron and Raman spectroscopies to determine the adsorption mechanisms and structure on the adsorbents. It can be deduced that the surpassing performance of defective GO-COOH may be ascribed to the unique adsorption mechanism of defects, the enhanced π-π interaction and cation-π bonding. The highly-efficient and stable features enable the defective GO-COOH a promising adsorbent to eliminate nicotine from water.

Comparative study of the quality characteristics of fresh noodles with regular salt and alkali and the underlying mechanisms.

The quality properties of fresh noodles with NaCl and alkali were characterized by rheological, cooking, and texture properties. Microstructure, starch viscosity, protein conformation, gelatinization and protein polymerization during cooking, and water status were determined to investigate the mechanisms underlying their quality differences. The results showed that alkali induced more significantly increased (P < .05) gluten strength and noodle hardness, while NaCl resulted in superior dough extensibility. Pasting viscosity of alkali-flour increased and protein conformation changes were detected in alkaline noodles with increased ß-sheet and decreased α-helix structures. Both NaCl and alkali increased cooking loss. NaCl induced a fibrous gluten structure while alkali caused a membrane-like structure. Furthermore, remarkable protein aggregates were observed in alkaline noodles immediately after 2 min of cooking in non-reduced HPLC patterns, while 4 min in reduced patterns. Water-solids interaction in alkaline noodles was enhanced with decreased water mobility. NaCl induced no significant changes in protein aggregation and water status.

Atrial septal defect in a patient with congenital disorder of glycosylation type 1a: a case report.

BACKGROUND: Atrial septal defect often become more severe when encountered in genetic syndromes. Congenital disorder of glycosylation type 1a is an inherited metabolic disorder associated with mutations in PMM2 gene and can affect almost all organs. Cardiac abnormalities vary greatly in congenital disorder of glycosylation type 1a and congenital heart defects have already been reported, but there is little knowledge about the effect of this inherited disorder on an existing congenital heart defect. Herein we report for the first time on a baby with congenital disorder of glycosylation type 1a with atrial septal defect and make a comparison of changes in atrial septal defect by follow-ups to the age of 3. CASE PRESENTATION: Our patient was an 8-month-old Han Chinese boy. At the initial visit, he presented with recurrent lower respiratory infection, heart murmur, psychomotor retardation, inverted nipples, and cerebellar atrophy. Echocardiography revealed a 8 mm secundum atrial septal defect with left-to-right shunt (Qp/Qs ratio 1.6). Enzyme testing of phosphomannomutase 2 demonstrated decreased levels of phosphomannomutase 2 activities in fibroblasts. Whole exon sequencing showed he was heterozygous for a frameshift mutation (p.I153X) and a missense mutation (p.I132T) in PMM2 gene. The diagnosis of congenital disorder of glycosylation type 1a with atrial septal defect was issued. Now, he is 3-years old at the time of this writing, with the development of congenital disorder of glycosylation type 1a (cerebellar atrophy become more severe and the symptom of nystagmus emerged), the size of atrial septal defect increased to 10 mm and the Qp/Qs ratio increased to 1.9, which suggested exacerbation of the atrial septal defect. Congenital heart defect-associated gene sequencing is then performed and shows there are no pathogenic mutations, which suggested intrinsic cardiac factors are not the cause of exacerbation of the atrial septal defect in our patient and it is reasonable to assume congenital disorder of glycosylation type 1a can worsen the situation of the existing atrial septal defect. CONCLUSIONS: This report highlights the view that congenital disorders of glycosylation type 1a should be excluded when faced with congenital heart defect with cerebellar atrophy or neurodevelopmental delay, especially when the situation of congenital heart defect becomes more and more severe.

Simultaneous Quantitative and Qualitative Analysis of Flavonoids from Ultraviolet-B Radiation in Leaves and Roots of Scutellaria baicalensis Georgi Using LC-UV-ESI-Q/TOF/MS.

Scutellaria baicalensis Georgi is one of the most widely used traditional Chinese herbal medicines. It has been used for anti-inflammatory, anticancer, antibacterial activities, and so forth. Long-term enhanced ultraviolet-B (UV-B) radiation caused more effect on leaves than on roots of the plant. Liquid chromatography-ultraviolet detection coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (LC-UV-ESI-Q/TOF/MS) method was applied for simultaneous quantitative and qualitative analysis of flavonoids in leaves and roots of S. baicalensis by enhanced UV-B radiation. Both low-intensity radiation and high-intensity radiation were not significantly increaseing the contents of baicalin, wogonoside, and wogonin in roots. However different intensity of radiation has different effects on several flavonoids in leaves. Both low-intensity radiation and high-intensity radiation had no significant effect on contents of baicalin and tectoridin in leaves; the content of scutellarin was significantly decreased by low-intensity radiation; chrysin was detected in low-intensity radiation and high-intensity radiation, and chrysin content is the highest in low-intensity radiation, but chrysin was not detected in control group. Different changes of different flavonoids under enhanced UV-B radiation indicate that induction on flavonoids is selective by enhanced UV-B radiation.