Calcitonin gene­related peptide alleviates hyperoxia­induced human alveolar cell injury via the CGRPR/TRPV1/Ca2+ axis.

Although exogenous calcitonin gene­related peptide (CGRP) protects against hyperoxia­induced lung injury (HILI), the underlying mechanisms remain unclear. The present study attempted to elucidate the molecular mechanism by which CGRP protects against hyperoxia­induced alveolar cell injury. Human alveolar A549 cells were treated with 95% hyperoxia to establish a hyperoxic cell injury model. ELISA was performed to detect the CGRP secretion. Immunofluorescence, quantitative (q)PCR, and western blotting were used to detect the expression and localization of CGRP receptor (CGRPR) and transient receptor potential vanilloid 1 (TRPV1). Cell counting kit­8 and flow cytometry were used to examine the proliferation and apoptosis of treated cells. Digital calcium imaging and patch clamp were used to analyze the changes in intracellular Ca2+ signaling and membrane currents induced by CGRP in A549 cells. The mRNA and protein expression levels of Cyclin D1, proliferating cell nuclear antigen (PCNA), Bcl­2 and Bax were detected by qPCR and western blotting. The expression levels of CGRPR and TRPV1 in A549 cells were significantly downregulated by hyperoxic treatment, but there was no significant difference in CGRP release between cells cultured under normal air and hyperoxic conditions. CGRP promoted cell proliferation and inhibited apoptosis in hyperoxia, but selective inhibitors of CGRPR and TRPV1 channels could effectively attenuate these effects; TRPV1 knockdown also attenuated this effect. CGRP induced Ca2+ entry via the TRPV1 channels and enhanced the membrane non­selective currents through TRPV1 channels. The CGRP­induced increase in intracellular Ca2+ was reduced by inhibiting the phospholipase C (PLC)/protein kinase C (PKC) pathway. Moreover, PLC and PKC inhibitors attenuated the effects of CGRP in promoting cell proliferation and inhibiting apoptosis. In conclusion, exogenous CGRP acted by inversely regulating the function of TRPV1 channels in alveolar cells. Importantly, CGRP protected alveolar cells from hyperoxia­induced injury via the CGRPR/TRPV1/Ca2+ axis, which may be a potential target for the prevention and treatment of the HILI.

Structures, Biosynthesis, and Bioactivity of Oligomycins from the Marine-Derived Streptomyces sp. FXY-T5.

Oligomycins are potent antifungal and antitumor agents. Mass spectrometry (MS)- and nuclear magnetic resonance (NMR)-based metabolomic fingerprinting analysis of marine-derived actinomycetes in our in-house library provided an oligomycin-producing strain, Streptomyces sp. FXY-T5. Chemical investigation led to the discovery of five new oligomycins, 24-lumooligomycin B (1), 4-lumooligomycin B (2), 6-lumooligomycin B (3), 40-homooligomycin B (4), and 15-hydroxy-oligomycin B (5), together with seven biosynthetically related known derivatives. Their structures were assigned by MS, NMR, electronic circular dichroism (ECD), and single-crystal X-ray diffraction analyses. The biosynthesis pathway of oligomycins was first proposed based on the analysis of a type I modular polyketide synthase (PKS) system and targeted gene disruption. As expected, the isolated oligomycins showed significant antiagricultural fungal pathogen activity and antiproliferative properties from which the possible structure-activity relationships were first suggested. More importantly, oligomycins induced significant G1-phase cell cycle arrest on cancer cells and significantly attenuated their Cyclin D1 and PCNA expression through a ß-catenin signaling pathway.

Efficient isolation of immunostimulatory polysaccharides from Lentinula edodes by autoclaving-ultrasonication extraction and fractional precipitation.

A hyphenated process, autoclaving followed by ultrasonication (AU), was evaluated for efficient extraction of polysaccharides (PS) from Lentinula edodes (Shiitake) mushroom. The PS yield (w/w) was 8.44 % from hot-water extraction (HWE), 11.01 % by autoclaving extraction (AE), and 16.3 % by AUE. The AUE water extract was subject to fractional precipitation in four-steps with increasing ethanol concentration of 40 %, 50 %, 70 % and 80 % (v/v), yielding four PS fractions in descending molecular weight (MW), PS40 > PS50 > PS70 > PS80. All the four PS fractions were composed of four monosaccharide residues, mannose (Man), glucose (Glc) and galactose (Gal) but in different mole ratios. The PS40 fraction with the highest average MW (4.98 × 106) was the most abundant fraction, accounting for 64.4 % of the total PS mass and also had the highest glucose molar ratio (~80 %). PS40 also most significantly enhanced the NO, and ROS generation and phagocytic activity in RAW 264.7 cells. The results proved that AUE followed by fractional ethanol precipitation is an efficient strategy with reduced solvent expenditure for isolation of the major immunostimulatory PS from L. edodes mushroom.

NIR C-Myc Pu22 G-quadruplex probe as a photosensitizer for bioimaging and antitumor study.

Despite the fact that C-Myc G-quadruplex in the oncogene promoter regions is one of the crucial targets of antitumor drugs, the selectivities and proliferation inhibitions of its probes towards tumor cells remain a big challenge. Until now, no effective C-Myc G-quadruplex probes have been reported as a photosensitizer to increase their antitumor activities. Here, the first NIR C-Myc G-quadruplex probe PDS-SQ has been designed, comprising a G-quadruplex binder PDS and a squaraine dye SQ as a photosensitizer. Conjugate PDS-SQ could selectively NIR image C-Myc Pu22 G-quadruplex in tumor cells, and show stronger antitumor activity in the irradiation by a chemo-photodynamic method than in the dark. The study provides a new way to develop the novel NIR C-Myc G-quadruplex probes with more potent antitumor activities.

Single aromatics sulfonamide substituted dibenzothiazole squaraines for tumor NIR imaging and efficient photodynamic therapy at low drug dose.

On the base of the zwiterionic dibenzothiazole squaraine SQ, five cationic aromatics sulfonamide substituted dibenzothiazole squaraines SQ-D1 âˆ¼ 5 have been designed and synthesized. Through the formation of the cationic compound, a higher rigid structure and the addition of the strong electron-withdrawing group (-CN), an ideal photosensitizer SQ-D2 has been gotten. In all the sulfonaminosquaraines, compound SQ-D2 exhibited the highest ROS generation efficacy and photostability. It also showed the highest photo-cytotoxicity (IC50 = 0.25 ± 0.08 µM), very low dark-cytotoxicity and the excellent cell uptake. In animal study, it not only showed the effective tumor retention and the easy removal from the body, but also exhibited the effective PDT efficacy at low drug dose (0.15 mg/kg) and the good biocompatibility. Furthermore, photosensitizer SQ-D2 as a single component exhibited greater potential than clinically approved photosensitizer m-THPC and some nanomaterials with photosensitizers in PDT therapy towards human breast cancer. This work provides a new perspective to develop the ideal photosensitizer of the squaraine dyes.

ZNF384-ZEB1 feedback loop regulates breast cancer metastasis.

BACKGROUND: Breast cancer has become the most frequently diagnosed cancer worldwide. Increasing evidence indicated that zinc finger proteins (ZNFs), the largest family of transcription factors, contribute to cancer development and progression. Although ZNF384 is overexpressed in several types of human cancer, the role of ZNF384 in breast cancer remains unknown. Therefore, our research focused on ZNF384 regulation of the malignant phenotype of breast cancer and the underlying molecular mechanisms. METHODS: CCK-8 and colony formation assays were used to evaluate cell proliferation. Transwell and scratch assays were used to evaluate the cell migration and invasion. Chromatin immunoprecipitation (ChIP)-qPCR and luciferase reporter assays were used to confirm the target relationship between ZNF384 and zinc finger E-box binding homeobox 1 (ZEB1). Xenografts were used to monitor the targets in vivo effects. RESULTS: We noted that ZNF384 was significantly overexpressed in breast cancer and highlighted the oncogenic mechanism of ZNF384. ZNF384 transactivated ZEB1 expression and induced an epithelial and mesenchymal-like phenotype, resulting in breast cancer metastasis. Furthermore, ZNF384 may be a target of miR-485-5p, and ZEB1 can up-regulate ZNF384 expression by repressing miR-485-5p expression. Together, we unveiled a feedback loop of ZNF384-ZEB1 in breast cancer metastasis. CONCLUSIONS: The findings suggest that ZNF384 can serve as a prognostic factor and a therapeutic target for breast cancer patients.

High value of early secretory antigenic target-6 and culture filtrate protein-10 in diagnosis of IgA nephropathy with renal tuberculosis: a retrospective study.

BACKGROUND: This retrospective study aimed to evaluate the diagnostic value of early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10) in immunoglobulin A nephropathy (IgAN) associated with renal tuberculosis (RT). METHODS: Forty patients with IgAN (IgAN group), 32 patients with RT (RT group), and 52 patients with IgAN associated with RT (IgAN + RT group) were retrospectively selected for this study. A tuberculin skin test (TST) was conducted, and Mycobacterium tuberculosis (MTB) antibody levels were measured. Immunohistochemistry and western blotting were used to determine the expression of ESAT-6 and CFP-10 proteins in renal tissues. RESULTS: The positive results of TST and levels of serum and urinary MTB antibodies were higher in the RT group than in the IgAN + RT group. The expression levels of ESAT-6 and CFP-10 proteins were the highest in the IgAN + RT group and lowest in the IgAN group. The receiver operating characteristic curves indicated that the area under curve (AUC) value of the ESAT-6 protein for the diagnosis of IgAN associated with RT was 0.907 and the cut-off value of the integral optical density (IOD) was 26.72. Diagnosis based on ESAT-6 protein levels showed 75% sensitivity and 94.2% specificity. The AUC value of the CFP-10 protein for the diagnosis of IgAN associated with RT was 0.8 and the cut-off value of IOD was 25.67. Detection based on CFP-10 protein levels showed 63.9% sensitivity and 84.6% specificity. CONCLUSIONS: Our study provides evidence for the potential of ESAT-6 and CFP-10 proteins as candidate markers in the diagnosis of IgAN associated with RT.

[Clinical Efficacy of Haplo-HSCT of ATG Combined with PTCy for Children with Myelodysplastic Syndrome].

OBJECTIVE: To investigate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (haplo-HSCT) in combination of ATG and post-transplant cyclophosphamide (PTCy) -induced immune tolerance after transplantation in treatment of childhood myelodysplastic syndromes(MDS）. METHODS: From July 2016 to November 2020, a total of 8 children with MDS receiving the haploidentical allo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation in our hospital were enrolled, whose clinical data were retrospected and analyzed. RESULTS: Median age at diagnosis of the 8 children (1 male and 7 females) was 6.4 (range, 10 months to 15 years) years old. The median medical history of MDS was 2.7 years (range, 3 months to 8 years). Among the 8 patients, 7 cases were diagnosed with refractory cytopenia of childhood and one with refractory anemia with excess of blasts. The HSC donors were father, mother or brother of patients and HLA matching in 6-9/12 loci were identical. All the donors were healthy and didn't carry the same pathogenic genes as the recipients. The median age of donors was 36.4 (range, 25 to 49) years old. The median mononuclear cell (MNC) number of the graft was 19.8, ranging in (13.2-47.3)×108/kg, and the median CD34+ cell number was 11.8×106/kg, ranging in (5.0-18.3)×106/kg. Graft-versus-host disease prophylactic regimen was started on day 3 and 4 after transplantation, in which cyclophosphamide (50 mg/kg·d) was administered by intravenous infusion. From day 5 after transplantation, low-dose tacrolimus was administered by intravenous infusion and mycophenolate mofetil was administered orally. The median time of neutrophil and platelet engraftment was 12.6 (rang, 11 to 15) days and 13.3 (rang, 11 to 18) days, respectively. All the patients achieved full donor chimerism on neutrophil engraftment after transplantation. The median follow-up time was 1 032 (rang, 747 to 1 536) days. Both overall survival rate and disease-free survival rate were 100%. CONCLUSION: Haplo-HSCT combined with ATG and PTCy-induced immune tolerance after transplantation is a safe and effective treatment for children with MDS.

Study on the single-mode condition for x-cut LNOI rib waveguides based on leakage losses.

Lithium niobate-on-insulator (LNOI) has recently emerged as a promising material platform for high-density and advanced photonics integrated circuits (PICs). And single-mode waveguides (SMW) are the most basic building blocks for structuring various PICs. In this paper, single-mode conditions (SMCs) for shallowly etched LNOI rib waveguides in x-cut LNOI wafer are investigated with the finite element method (FEM) in consideration of the lateral leakage and the magic width for the first time, to our best knowledge. Our results indicate that due to the lateral leakage and the magic width these shallowly etched x-cut LNOI rib waveguides have unique and complex SMCs. Our method and results provide a guidance in designing low-loss LNOI SMW and high-performance PICs.

Restraint of FAM60A has a cancer-inhibiting role in pancreatic carcinoma via the effects on the Akt/GSK-3ß/ß-catenin signaling pathway.

Family with sequence similarity 60A (FAM60A) has been reported as a new cancer-related protein that affects the malignant progression of some cancers. However, whether FAM60A plays a part in pancreatic carcinoma is undetermined. This work was designed to examine the impact of FAM60A in pancreatic carcinoma. Abundant expression of FAM60A was observed in the primary tumor tissue of pancreatic carcinoma. Moreover, a high FAM60A level was related to a poor overall survival in pancreatic carcinoma patients. Malignant behaviors of pancreatic carcinoma cells, such as proliferation and invasiveness, were markedly affected by FAM60A depletion. In addition, FAM60A depletion enhanced the drug sensitivity of pancreatic carcinoma cells to gemcitabine. Further study revealed that FAM60A depletion impaired the activities of Akt and ß-catenin. Inhibiting the activity of Akt abolished FAM60A-mediated ß-catenin activation. Re-expression of ß-catenin partially diminished the FAM60A-depletion-mediated cancer suppressive effect in pancreatic carcinoma cells. In vivo experiments demonstrated that FAM60A depletion prohibited the xenograft formation of pancreatic carcinoma cells, with concurrent reductions of Akt and ß-catenin activities. Collectively, our findings indicate that FAM60A exerts a cancer-promoting role in pancreatic carcinoma through affection of the Akt/ß-catenin pathway. This work indicates that FAM60A acts as a tumor promoter in pancreatic carcinoma and can be utilized as a potential target for anti-pancreatic carcinoma therapy development.

Clinical outcomes of individualized busulfan-dosing in hematopoietic stem cell transplantation in Chinese children undergoing with therapeutic drug monitoring.

To identify relationships between busulfan (Bu) exposure and outcomes of a cohort pediatric patients receiving hematopoietic stem cell transplantation (HSCT), along with a targeted busulfan-based conditioning regimen. We retrospectively evaluated targeted busulfan concentrations in 53 pediatric patients (age 0.4-16 years) who received busulfan 4 times daily according to recommended weight-based doses in a single-center analysis between 2018 and 2020. In this trial, individual busulfan pharmacokinetics were performed following dose 5 of the conditioning regimen. Twenty four of 53 patients (45.3%) studies did not require dose adjustments. Equal number of patients (24/53) required one dose adjustments while two-dose adjustment applied for 5 of 53 (9.4%). Twenty-one percent of the patients exhibited ll-lV aGVHD. The incidence of veno-occlusive disease (VOD) was in 3.8% of the 53 patients, while incidence of hemorrhagic cystitis (II-III) reached to 9.7%. Engraftment was successful in 98% of the 53 patients with relapse in 2% of cases. The probability of overall survival and disease-free survival at day 100 was 96% and 94%, respectively. In conclusion, therapeutic drug monitoring (TDM) and individualization of Bu dosage are essential to improve the efficacy and safety of busulfan-based regimen in Chinese pediatric HSCT recipients.

HS3ST3A1 and CAPN8 Serve as Immune-Related Biomarkers for Predicting the Prognosis in Thyroid Cancer.

Background: Thyroid cancer (TC) tends to be a common malignancy worldwide and results in various outcomes due to its different subtypes. The tumor microenvironment (TME) was demonstrated to play crucial roles in various malignancies, including thyroid cancer. This study combined the ESTIMATE and CIBERSORT algorithms, identified four TME-related genes, and evaluated their correlation with clinical characteristics. These findings revealed the malignant performance of TME in TC, and the TME-related DEGs might serve as prognostic biomarkers, which can be utilized for the prediction of immunotherapy effects in patients with TC. Methods: The clinical and gene expression profiles of TC patients were collected from the TCGA dataset. The ESTIMATE algorithm was utilized to estimate stromal and immune scores and predict the level of stromal and immune cell infiltration. The differential expressed genes related to TME were filtered by the "limma" package in R, and the PPI network was constructed by a string website. KEGG pathway and GO analyses were performed to investigate the biological progression and molecular functions of TME-related DEGs. Then, univariate Cox regression analysis was employed to screen four genes correlated with clinical characteristics. GSEA was conducted to assess their roles in the TME of TC. To further investigate the association between TME-related genes and tumor-infiltrating immune cells (TIICs), the CIBERSORT algorithm was performed. Finally, the malignancy behaviors of the two genes were verified by RT-qPCR, IHC, MTT, colony formation, and transwell assays. Results: Four TME-related DEGs, LRRN4CL, HS3ST3A1, PCOLCE2, and CAPN8, were identified and were significantly predictive of poor overall survival. KEGG and GO pathway analysis established that the TME-related DEGs were involved in immune responses and pathways in cancer. Furthermore, the malignancy behaviors of HS3ST3A1 and CAPN8 were verified by cellular functional experiments. These results revealed that the TME-related genes HS3ST3A1 and CAPN8 were able to serve as predictors of prognosis in patients with TC. Conclusion: HS3ST3A1 and CAPN8 may serve as valuable prognostic biomarkers and TME indicators, which can be utilized for the prediction of immunotherapy effects and provide novel treatment strategies for patients with TC.

Inhibition of Liver Cancer HepG2 Cell Proliferation by Enzymatically Prepared Low-molecular Citrus Pectin.

BACKGROUND: Low-molecular citrus pectin (LCP) is a pectin polysaccharide with low molec-ular weight, low degree of crux, and no branching. It is obtained by degrading natural citrus pectin (CP) through physical, chemical and enzymatic methods. LCP has received considerable attention in recent years due to its potential applications in the medical and biological fields. METHODS: In our previous study, LCP was prepared from CP by using recombinant Bacillus subtilis pectate lyase B. Monosaccharide comparative analysis revealed that the galacturonic acid content of LCP was higher than that of CP. The cell viability effect of LCP was elucidated by using HepG2 cells and the Cell Counting Kit-8 (CCK-8) assay. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining, Annexin V-FITC/PI staining, and flow cytometer propidium iodide stain-ing were performed to detect the effects of LCP on apoptosis and cell cycle arrest in HepG2 cells. Mi-tochondrial membrane potential (MMP) was observed through 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethyl-imidacarbocyanine assay. RESULTS & DISCUSSION: The Mw of the prepared LCP was 7.6 kDa, which was significantly lower than that of CP (140 kDa). Cell viability decreased with the increase in the concentration of LCP. The half-inhibitory concentration of 1.46 ± 0.02 mg/mL was determined. Treatment with 1.6 mg/mL LCP in-duced the apoptosis of HepG2 cells with the inhibition rate of 83.10% ± 4.72%, and the cell cycle was arrested in the S phase. Furthermore, the MMP of HepG2 cells decreased with the increase in LCP concentration. CONCLUSION: The enzymatically prepared LCP could inhibit the proliferation of HepG2 cells. This study provided a partial experimental basis and reference for LCP to become a potential functional food for anti-liver cancer.

Water and nitrogen in-situ imaging detection in live corn leaves using near-infrared camera and interference filter.

BACKGROUND: Realizing imaging detection of water and nitrogen content in different regions of plant leaves in-site and real-time can provide an efficient new technology for determining crop drought resistance and nutrient regulation mechanisms, or for use in precision agriculture. Near-infrared imaging is the preferred technology for in-situ real-time detection owing to its non-destructive nature; moreover, it provides rich information. However, the use of hyperspectral imaging technology is limited as it is difficult to use it in field because of its high weight and power. RESULTS: We developed a smart imaging device using a near-infrared camera and an interference filter; it has a low weight, requires low power, and has a multi-wavelength resolution. The characteristic wavelengths of the filter that realize leaf moisture measurement are 1150 and 1400 nm, respectively, the characteristic wavelength of the filter that realizes nitrogen measurement is 1500 nm, and all filter bandwidths are 25 nm. The prediction result of the average leaf water content model obtained with the device was R2 = 0.930, RMSE = 1.030%; the prediction result of the average nitrogen content model was R2 = 0.750, RMSE = 0.263 g. CONCLUSIONS: Using the average water and nitrogen content model, an image of distribution of water and nitrogen in different areas of corn leaf was obtained, and its distribution characteristics were consistent with the actual leaf conditions. The experimental materials used in this research were fresh leaves in the field, and the test was completed indoors. Further verification of applying the device and model to the field is underway.

[Lingnan fire needling combined with 0.1% sodium hyaluronate eye drops in the treatment of xerophthalmia: a randomized controlled trial].

OBJECTIVE: To observe the effect of Lingnan fire needling combined with artificial tears in the treatment of xerophthalmia. METHODS: A total of 86 xerophthalmia patients were equally and randomly divided into treatment group and control group. The patients of both groups were received treatment with 0.1% sodium hyaluronate eye drops in their eyes 3 times a day, one drop in each eye. In addition, the patients of treatment group also treated by Lingnan fire needling on bilateral Shaoze (SI1), Neichengqi and beside lacrimal puncta once a week. The treatment was conducted for 4 consecutive weeks. Before and after 4 weeks of treatment, the clinical efficacy, visual acuity, intraocular pressure, ocular symptom score, OSDI score, fluorescence staining （FL） score, schemer I, tear menisci height, tear film break-up time (BUT) and eye redness index were recorded and evaluated. RESULTS: After the treatment, self-comparison showed that the symptom score, OSDI score, FL score and eye redness index were significantly decreased (P<0.05), and BUT was notably increased in both groups (P<0.05) in comparison with their own pre-treatment. The tear menisci height in the treatment group was higher than that before the treatment (P<0.05). Comparison between the two groups showed that the symptom score, OSDI score and eye redness index were obviously lower in the treatment group than in the control group (P<0.05), whereas the BUT and tear menisci height were evidently higher (P<0.05). The total effective rate of the treatment group was 84.88% (73/86), better than 76.74% (66/86) of the control group (P<0.05). CONCLUSION: Lingnan fire needling combined with 0.1% sodium hyaluronate eye drops is more effective than simple sodium hyaluronate eye drops for xerophthalmia patients, with significant curative effect and no adverse reactions.

G-quadruplex binder pyridostatin as an effective multi-target ZIKV inhibitor.

At present, there are still no anti-Zika virus (ZIKV) drugs or vaccines approved by FDA with accurate targets and antiviral mechanisms. Considering the RNA G-quadruplex sequences in ZIKV genome, it is very meaningful to develop G-quadruplex binders as potential anti-ZIKV drugs with novel and accurate targets. In this paper, five classical G-quadruplex binders including Ber, Braco 19, NiL, 360A and PDS have been chosen to discuss their interaction with ZIKV RNA G-quadruplexes. PDS shows higher binding affinity and thermal stability than the other G-quadruplex binders. This property is further evidenced in cells by immunofluorescence microscopy. And PDS shows higher anti-ZIKV activity (EC50 = 4.2 ± 0.4 µM) than the other G-quadruplex binders as well as the positive control ribavirin, with a low cytotoxicity. By time-of-addition assay, PDS exerts antiviral activity at the post-entry process of ZIKV replication cycle, thus inhibiting ZIKV mRNA replication and protein expression. Furthermore, PDS combines with ZIKV NS2B-NS3 protease and reduces its catalytic activity. This study suggests that G-quadruplex binder PDS is an effective multi-target ZIKV inhibitor, which provides more guidance to design some novel anti-ZIKV drugs targeting ZIKV RNA G-quadruplexes.

[Effect of invisalign on anterior and posterior upper airway and maxillary bone changes in the treatment of high-angle skeletal Class â ¡ malocclusion].

PURPOSE: To investigate the effect of invisalign on anterior and posterior upper airway and maxillary bone changes in the treatment of high-angle skeletal Class II malocclusion. METHODS: Thirty-seven patients with malocclusion undergoing invisible orthodontic treatment in Hospital of Stomatology of Xi'an Jiaotong University from June 2016 to June 2018 were enrolled. Before and 18 months after correction, the correction effect was evaluated. Cone-beam CT (CBCT) was performed to measure the upper airway volume and tongue position. Cephalometric examination was performed to determine the anteroposterious diameter of the upper airway and the position of hyoid bone. The pre-therapy and post-treatment facial profile images of patients and stars were graded by 0-10 numerical rating scale. SPSS 20.0 software package was used to analyze the data. RESULTS: After correction, oropharyngeal volume, glossopharyngeal volume and minimum cross-sectional area of upper airway significantly increased(P<0.05). Sagittal diameter of the upper airway at mandibular plane significantly increased after correction (P<0.05). After correction, ANB angle, GoGn-SN angle, OPP-SN angle, Y-axis angle, UI-SN angle, UI-PP angle, UI-AP angle, and UI-AP distance significantly decreased, SNB angle and UI- LI angle significantly increased(P<0.05). The aesthetics scores of facial profile images significantly increased after correlation(P<0.05), which was significantly lower than that of the stars(P<0.05). CONCLUSIONS: Invisalign can effectively correct open upper airway and malocclusion, achieving better treatment results and satisfactory facial aesthetics effect.

Lipophilic ferulic acid derivatives protect PC12 cells against oxidative damage via modulating ß-amyloid aggregation and activating Nrf2 enzymes.

Ferulic acid (FA) has been shown to have a neuroprotective effect on Alzheimer's disease induced by amyloid-beta (Aß) neurotoxicity. This work aims to ascertain the structure-activity relationship of FA and its alkyl esters (FAEs) for evaluating the antioxidant activities in PC12 cells and Aß1-42 aggregation inhibitory activities in vitro, as well as the signaling mechanisms against oxidative stress elicited by Aß1-42 in PC12 cells. Our data showed that alterations in the subcellular localization and cytotoxicity of FAEs caused by the lipophilicity of FA were crucial when evaluating their antioxidant capacities. Pre-treating cells with butyl ferulate (FAC4) significantly attenuated Aß1-42-evoked intracellular ROS formation. Besides, FAC4 exhibited the highest Aß1-42 aggregation inhibitory effectiveness. The molecular docking results showed that FAC4 binds to amide NH in Gln15 and Lys16 via a hydrogen bond. Notably, FAC4 could upregulate antioxidant defense systems by modulating the Keap1-Nrf2-ARE signaling pathway. Identification of the functions of FAEs could be useful in developing food supplements or drugs for treating AD.

Human telomere double G-quadruplex recognition by berberine-bisquinolinium imaging conjugates in vitro and cells.

Molecular tools of double or multimeric G-quadruplexes have been given higher requirements on detection sensitivity, thermal stabilization and cell imaging to establish functions of these G-quadruplex aggregates and biological mechanisms as anticancer reagents. Here, two smart berberine-bisquinolinium conjugates (Ber-360A and Ber-PDS) by linking the berberine fluorophore ligand and an established G-quadruplex binder (i.e. bisquinolinium scaffold), have been designed and evaluated their activities and mechanisms for G-quadruplex aggregation. Two conjugates, especially Ber-PDS, are two highly selective, sensitive and fluorescent sensors which can distinguish human telomere double G-quadruplexes from other type G-quadruplexes and ds DNA. These two ligands could be the first example to stack two adjacent G-quadruplex units and fluorescently recognize human telomere double G-quadruplexes. Furthermore, conjugate Ber-PDS could enter the nucleoli and target G-quadruplex DNA through microscopy experiments, and also display strong telomerase inhibition and antitumor activities.

Dimers formed with the mixed-type G-quadruplex binder pyridostatin specifically recognize human telomere G-quadruplex dimers.

By choosing pyridostatin (PDS) with high thermal stabilization towards mixed-type G-quadruplexes as the monomer in dimers, three novel polyether-tethered PDS dimers (1a-c) were first synthesized and their interaction with human telomere G-quadruplex dimers (G2T1) was studied. Through the regulation of the linker length in PDS dimers, the dimer with a medium-length polyether linker (1b) showed higher binding selectivity and thermal stabilization (ΔTm = 29.5 °C) towards antiparallel G2T1 over G-quadruplex monomers (G1). Furthermore, the dimer with the longest-length polyether linker (1c) showed higher binding selectivity and thermal stabilization towards mixed-type G2T1 over mixed-type G1, c-kit 1, c-kit 2, c-myc and ds DNA. This work provides new insights into the development of G2T1 binders, especially mixed-type G2T1 binders, which could be promoted by a polymer formed with a mixed-type G-quadruplex binder. In addition, dimer 1c exhibited stronger telomerase inhibition than dimers 1a and 1b.