OBJECTIVE To prepare a self-microemulsifying drug delivery system(SMEDDS) for the oral administration of nebivolol hydrochloride(NBH) and to conduct in vitro evaluation. METHODS The solubility of NBH was determined using various oil phases, surfactants, and co-surfactants. The composition of the blank self-microemulsifying formulation was determined using pseudo-ternary phase diagrams. A centralcomposite design-response surface method was employed to screen and optimize the formulation variables, and an excess amount of NBH raw material was incorporated to determine the drug loading capacity. RESULTS The optimized composition of the NBH-SMEDDS formulation consisted of medium-chain glycerides, capryl caproyl macrogol glycerides, and 2-(2-ethoxyethoxy) ethyl acetate at a ratio of 20∶48∶32, with a drug loading capacity of 20.05 mg. The particle size, self-emulsification time, and particle size distribution range of the formulation were in agreement with the predicted values. Dissolution testing demonstrated that the overall dissolution trend of NBH-SMEDDS in the medium was higher than that of NBH powder and NBH ordinary tablet. The stability of NBH-SMEDDS was found to be satisfactory under accelerated conditions for 1, 2, and 3 months. CONCLUSION The SMEDDS shows potential for enhancing the in vitro dissolution of NBH and demonstrates good stability.

OBJECTIVE To solve the problem of insolubility of itraconazole, improve its dissolution in vitro, and provide a reference for further industrial scale-up of the itraconazole multiparticle system. METHODS Itraconazole multiparticle system pellets were dissolved in an organic solvent and prepared in a fluidized bed by bottom spraying. Itraconazole and hydroxypropyl methylcellulose were sprayed onto the surface of the sucrose pellet core to form a uniform solid dispersion. The preparation parameters of the fluidized bed bottom spray coating were investigated by single factor method. The mass ratio of drug to carrier and core weight gain of the itraconazole multiparticle system were optimized by central composite design and response surface methodology with accumulative dissolution rate, application efficiency and adhesion rate as response values. Samples were prepared to verify the optimized prescription, the microscopic hierarchical structure of the itraconazole multiparticle system was observed by scanning electron microscope, and the solid dispersion in the itraconazole multiparticle system pellets was characterized by differential scanning calorimetry(DSC) and X-ray diffraction(XRD). The dissolution curves of itraconazole pellets and the physical mixture in 0.1 mol·L−1 HCl dissolution medium were compared to verify the solubilization effect. RESULTS Single factor method was used to determine the bottom spray coating parameters of the fluidized bed. The pumping speed was set as 3.0−5.0 mL·min−1, the atomization pressure was set as 1.5 bar, the inlet air volume was set as 110 m3·h−1, and the material temperature was set as 35 ℃. According to the central composite design and response surface methodology, the mass ratio of drug to carrier of the optimized prescription was 1∶1.5 and the core weight of the pill was 75%, and the response values reached the expected value. The result of scanning electron microscopy showed that the diameter of the itraconazole multiparticle system pellet was about 910 µm, the diameter of the sucrose pellet core was about 570 µm, the thickness of the drug loading layer was about 110 µm, and the thickness of encapsulation layer was about 11 µm. The results of DSC and XRD showed that itraconazole formed a uniform solid dispersion in the itraconazole multiparticle system pellets, which was amorphous. In the dissolution medium of 0.1 mol·L−1 HCl, the accumulative dissolution rate of the multiparticle system after 90 min was about 10 times that of the physical mixture, which showed that the solubilization effect was remarkable. CONCLUSION The dissolution of itraconazole in vitro can be significantly improved by processing itraconazole into pellets with multiparticle system and forming solid dispersion.

[This corrects the article DOI: 10.1016/j.apsb.2021.04.013.].

Diabetic neuropathic pain (DNP) is the most common disabling complication of diabetes. Emerging evidence has linked the pathogenesis of DNP to the aberrant sprouting of sensory axons into the epidermal area; however, the underlying molecular events remain poorly understood. Here we found that an axon guidance molecule, Netrin-3 (Ntn-3), was expressed in the sensory neurons of mouse dorsal root ganglia (DRGs), and downregulation of Ntn-3 expression was highly correlated with the severity of DNP in a diabetic mouse model. Genetic ablation of Ntn-3 increased the intra-epidermal sprouting of sensory axons and worsened the DNP in diabetic mice. In contrast, the elevation of Ntn-3 levels in DRGs significantly inhibited the intra-epidermal axon sprouting and alleviated DNP in diabetic mice. In conclusion, our studies identified Ntn-3 as an important regulator of DNP pathogenesis by gating the aberrant sprouting of sensory axons, indicating that Ntn-3 is a potential druggable target for DNP treatment.
Mice ; Animals ; Diabetes Mellitus, Experimental/metabolism* ; Axons/physiology* ; Diabetic Neuropathies ; Sensory Receptor Cells/metabolism* ; Neuralgia/metabolism*

OBJECTIVES: To analyze the results of neonatal screening for congenital hypothyroidism (CH) and hyperphenylalaninemia (HPA) in Zhejiang province from 1999 to 2022. METHODS: A total of 11 922 318 newborns were screened from September 1999 and December 2022 in Zhejiang province. The blood thyroid stimulating hormone (TSH) levels were measured by a fluorescence method and blood phenylalanine (Phe) levels were measured by fluorescence method or tandem mass spectrometry. TSH≥9 μIU/mL was considered positive for CH, while Phe>120 μmol/L and/or Phe/Tyr ratio>2.0 were considered positive for HPA. The positive newborns in screening were recalled, and the gene variations were detected by high-throughput sequencing and MassARRAY tests. RESULTS: The overall neonatal screening rate during 1999-2022 was 89.41% (11 922 318/13 333 929) and the screening rate was increased from 6.46% in 1999 to 100.0% in 2022. A total of 8924 cases of CH were diagnosed among screened newborns with an incidence rate of 1/1336. A total of 563 cases of HPA were diagnosed, including 508 cases of classic phenylketonuria (cPKU) and 55 cases of tetrahydrobiopterin deficiency (BH4D), with an incidence rate of 1/21 176. Ninety-seven out of 8924 cases of CH underwent genetic analysis. Gene mutations were detected in 9 CH related genes, the highest frequency mutations were found in DUOX2 gene (69.0%) with c.3329G>A (p.R1110Q) (18.2%) and c.1588A>T (p.K530X) (17.3%) as the hotspot mutations. There were 81 PAH gene variants detected in a total of 250 cases of cPKU, and c728G>A (p.R243Q) (24.4%), c.721C>T (p.R241C) (15.0%) were the hotspot mutations. Meanwhile 7 novel variants in PAH gene were detected: c.107C>A (p.S36*), c.137G>T (p.G46V), c.148A>G(p.K50E), c.285C>T (p.I95I), c.843-10delTTCC, exon4-7del and c.1066-2A>G. There were 12 PTS gene variants detected in 36 cases of BH4D, and c.259C>T (p.P87S) (31.9%) was the hotspot mutation. CONCLUSIONS The incident of CH has increased from 1999 to 2022 in Zhejiang province, and it is higher than that of national and global levels; while the incidence of HPA is similar to the national average. DUOX2 gene variation is the most common in CH patients; c.728G>A (p.R243Q) is the hotspot mutation in cPKU patients, while c.259C>T (p.P87S) is the hotspot mutation in BH4D patients.
Humans ; Infant, Newborn ; Neonatal Screening ; Dual Oxidases ; Congenital Hypothyroidism/genetics* ; Phenylketonurias/genetics* ; Thyrotropin

[This corrects the article DOI: 10.1016/j.apsb.2021.04.013.].

Objective:To evaluate the performance of machine learning (ML) based on automated breast volume scanner (ABVS) radiomics in distinguishing benign and malignant BI-RADS 4 lesions.Methods:Between May to December 2020, patients with BI-RADS 4 lesions from the Affiliated Hospital of Southwest Medical University (Center 1) and Guangdong Provincial Hospital of Traditional Chinese Medicine (Center 2) were prospectively collected and divided into training cohort (Center 1) and external validation cohort (Center 2). The radiomics features of BI-RADS 4 lesions were extracted from the axial, sagittal and coronal ABVS images by MaZda software. In the training cohort, 7 feature selection methods and thirteen ML algorithms were combined in pairs to construct different ML models, and the 6 models with the best performance were verified in the external validation cohort to determine the final ML model. Finally, the diagnostic performance and confidence (5-point scale) of radiologists (R1, R2 and R3, with 3, 6 and 10 years of experience, respectively) with or without the model were evaluated.Results:①A total of 251 BI-RADS 4 lesions were enrolled, including 178 lesions (91 benign, 87 malignant) in the training cohort and 73 lesions (44 benign, 29 malignant) in the external validation cases. ②In the training cohort, the 6 ML models (DNN-RFE, AdaBoost-RFE, LR-RFE, LDA-RFE, Bagging-RFE and SVM-RFE) had the best diagnostic performance, and their AUCs were 0.972, 0.969, 0.968, 0.968, 0.967 and 0.962, respectively. ③In the external validation cohort, the DNN-RFE still had the best performance with the AUC, accuracy, sensitivity, specificity, PPV and NPV were 0.886, 0.836, 0.934, 0.776, 86.8% and 82.5%, respectively. ④Before model assistance, R1 had the worst diagnostic performance with the accuracy, sensitivity, specificity, PPV and NPV were 0.680, 0.750, 0.640, 57% and 81%, respectively. After model assistance, the diagnostic performance of R1 was significantly improved ( P=0.039), and its diagnostic sensitivity, specificity, accuracy, PPV and NPV improved to 0.730, 0.810, 0.930, 68% and 94%; while the improvement of R2 and R3 were not significantly ( P=0.811, 0.752). Meanwhile, the overall diagnostic confidence of the 3 radiologists increased from 2.8 to 3.3 ( P<0.001). Conclusions:The performance of ML based on ABVS radiomics in distinguishing between benign and malignant BI-RADS 4 lesions is good, which may improve the diagnostic performance of inexperienced radiologists and enhance diagnostic confidence.

Alginate composite hydrogel is one of the research hotspots of tumor drug delivery system materials at present. Alginate hydrogel has good biocompatibility and regeneration properties. However, the natural alginate saline gel may not achieve the expected results in the body environment due to the slow degradation and instability of the gel. Alginate has found extensive application in cancer therapy through its combination with other materials and the utilization of ionic cross-linking, covalent cross-linking, and free radical polymerization to form hydrogels. Based on the composite system of alginate brine gel, this paper summarizes the structure and properties of alginate hydrogel, with a focus on recent research into alginate composite hydrogel in common cancer treatments application, summarizes the current research focus and discuss the existing problems of alginate composite hydrogel, so as to provide reference for further expanding the research of alginate composite hydrogel in clinical cancer treatment.

Objective : To investigate the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway molecules during the process by which kaempferol (Kae) promotes osteogenic differentiation of mouse bone marrow mesenchymal cells (BMMCs) under cyclic and uniaxial tension. Methods : BMMCs isolated and cultured in vitro were subjected to uniaxial dynamic tension with a 10% shape variable. The appropriate concentration of Kae was selected by cytotoxicity testing. The endogenous mTOR signal was inhibited by pp242. Four hours after traction, alkaline phosphatase (ALP) and osteocalcin (OCN) were detected by chemical colorimetry and ELISA, and the relative concentration of intracellular calcium was detected by flow cytometry. Phosphorylation of mTOR, 4E/BP1, and ribosomal protein S6 kinases (S6K), which are the main molecules of the endogenous mTORC1 signaling pathway, and expression of osteogenic transcription factors (Runx2 and Osterix) were detected by western blotting (WB), and mRNA expression levels of the above factors were detected by qRT-PCR. Results : The cytotoxicity test showed that 10 μmol/L Kae had little inhibitory effect on cell proliferation but had the strongest osteogenic ability. Four hours after stretching, Kae effectively promoted the osteogenic differentiation of BMMCs. The expression of ALP was （153.04 ± 18.72） U/mg, the expression of OCN was （1.64 ± 0.25） U. The mRNA and protein levels of Runx2 and Osterix were upregulated, and the intracellular calcium content was decreased. The mRNA and protein phosphorylation of mTOR and S6K was upregulated, and the opposite effect was observed with 4E/BP1. After pp242 was added to inhibit mTOR signaling, mTOR and S6K mRNA and protein phosphorylation were downregulated, but 4E/BP1 mRNA and protein phosphorylation was upregulated. The osteogenic differentiation of BMMCs was also significantly inhibited, mRNA and protein expression of Runx2 and Osterix were significantly downregulated, ALP and OCN expression were downregulated, and intracellular calcium content was increased. Conclusion Kae promotes osteogenic differentiation of mouse BMMCs under uniaxial dynamic tension through the mTORC1 signaling pathway.

Vascular smooth muscle cell (VSMC) migration plays a critical role in the pathogenesis of many cardiovascular diseases. We recently showed that TMEM16A is involved in hypertension-induced cerebrovascular remodeling. However, it is unclear whether this effect is related to the regulation of VSMC migration. Here, we investigated whether and how TMEM16A contributes to migration in basilar artery smooth muscle cells (BASMCs). We observed that AngII increased the migration of cultured BASMCs, which was markedly inhibited by overexpression of TMEM16A. TMEM16A overexpression inhibited AngII-induced RhoA/ROCK2 activation, and myosin light chain phosphatase (MLCP) and myosin light chain (MLC20) phosphorylation. But AngII-induced myosin light chain kinase (MLCK) activation was not affected by TMEM16A. Furthermore, a suppressed activation of integrin