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BACKGROUND: Oral squamous cell carcinoma (OSCC) usually originates from oral potentially malignant disorders (OPMD), such as oral leukoplakia (OLK) and oral lichen planus (OLP). Identifying biomarkers for the early diagnosis and evaluation of malignant transformation in OPMD could improve the survival rate of OSCC patients. OBJECTIVE: The present study aimed to screen for potential salivary biomarkers for evaluating the malignant transformation of OPMD. METHODS: Salivary proteases from OLK and OSCC patients or healthy donors and proteases in cultural medium from DOK and Cal-27 cells were detected with a human protease array kit. The concentrations of the salivary Kallikrein 5 (KLK5) and urokinase-type plasminogen activator (uPA) proteases were measured by ELISA. Receiver operating characteristics (ROC) to determine the potential value of these proteases in clinical diagnosis were calculated using SPSS software. Immunohistochemistry was used to detect the KLK5 and uPA expression in the oral organizations. RESULTS: The salivary protease spectrum was different among patients with OLK and OSCC and healthy donors. KLK5 and uPA levels in saliva tended to increase as the disease progressed (healthy < OPMD [OLK and OLP] < OSCC). ROC curves showed the optimum diagnostic cutoffs for KLK5 as a biomarker for OLK, OLP, and OSCC were 5.97, 6.03, and 9.45 pg/mL, respectively, while the cutoffs for uPA were 17.19, 17.26, and 20.96 pg/mL. Their combined analysis showed a higher sensitivity for the differential diagnosis of disease. Furthermore, higher levels of KLK5 and uPA were observed in OSCC tissues than in OLK and OLP. CONCLUSIONS: Salivary KLK5 and uPA are potential biomarkers for evaluating OLK and OLP malignant transformation and early diagnosis of OSCC.

Background Polycystic ovary syndrome is a common cause of infertility and shows a high incidence in women of reproductive age. Acupuncture is an appropriate adjunctive treatment for PCOS. However, the add-on effect of acupuncture as an adjunctive treatment for obese women with PCOS has not been studied, and previous studies indicate that there are individual differences in the curative effect of acupuncture, while deeper research on the mechanism of differences in the individual curative effect of acupuncture for obese women with PCOS is still lacking. This trial aims to assess the add-on treatment efficacy of acupuncture for obese women with PCOS and to explore the role of the gut microbiome on the differences in the individual curative effect of acupuncture based on metagenomic analysis. Methods/design This is an open-label, randomized, controlled trial. A total of 86 obese women with PCOS will be recruited. Subjects will be randomly assigned to a study group and a control group in a 1:1 ratio, with 43 subjects in each group (10 patients from each group who meet the study criteria will participate in the metagenomic analysis). An additional 10 subjects who meet the study criteria will be recruited to a healthy control group. The study group will receive acupuncture and clomiphene citrate treatment; the control group will only receive clomiphene citrate. Acupuncture treatment will be conducted three times a week from the fifth day of menstruation or withdrawal bleeding until the start of the next menstruation, for up to three menstrual cycles. The primary outcome will be LH/FSH. The secondary outcomes will comprise biometric features, hormone biomarkers, metabolic biomarkers, inflammatory biomarkers, Self-Rating Anxiety Scale, Self-Rating Depression Scale, and metagenomic analysis. The outcomes will be measured at baseline and post-intervention. Data will be analyzed using SPSS 19.0, and the gut microbiome will be analyzed using metagenomic analysis. Discussion In this study, we are evaluating the add-on effects of acupuncture and exploring the mechanism of the differences in the individual curative effect of acupuncture based on the gut microbiome, which may provide evidence to explain the different outcomes of different trials on acupuncture for PCOS and hopefully to provide a new aspect to study the mechanism of acupuncture’s treatment effect. Trial registration Chinese Clinical Trial Registry ChiCTR2000029882. Registered on 16 February 2020

AIM: To compare clinical outcomes and refractive stability of implantable collamer lens (ICL) implantation and femtosecond laser assisted laser in situ keratomileusis (FS-LASIK) for high myopia correction. METHODS: The Optical Quality Analysis System (OQAS) was used to evaluate clinical outcomes objectively after operation for high myopia correction. We compared the two procedures in terms of 1-year changes in uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), safety index, efficacy index, spherical equivalent, modulation transfer function (MTF) cutoff frequency, strehl ratio (SR) and objective scatter index (OSI). RESULTS: At 1y postoperatively, the safety indices were 1.33±0.27 in ICL group, and 1.17±0.24 in FS-LASIK group. 39.58% in the ICL group and 27.59% in the FS-LASIK group gained CDVA in 2 lines or better than that in preoperative CDVA. The efficacy indices were 1.28±0.22 in ICL group, and 1.13±0.26 in FS-LASIK group. The changes of spherical equivalent from 1wk to 1y postoperatively was -0.12±0.37 D in ICL group, and -0.79±0.58 D in FS-LASIK group (P0.05) in postoperative 3mo later. CONCLUSION: ICL implantation and FS-LASIK procedures both provide good safety and predictability in high myopia correction. ICL implantation provides better clinical outcomes and refractive stability than FS-LASIK.

Cai-Tao Chen,1 Chun-Xiao Shan,2 Jun Ran,3 Lei-Miao Yin,1 Hai-Yan Li,4 Yu Wang,1 Yu-Dong Xu,1 Jing-Lei Guo,5 Yang-Lin Shi,1 Yan-Jiao Chen,1 Yong-Qing Yang1 1Shanghai Research Institute of Acupuncture and Meridian, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Changchun University of Chinese Medicine, Changchun, Jilin, People’s Republic of China; 3Chongqing Hospital of Traditional Chinese Medicine, Chongqing, People’s Republic of China; 4Shanghai First Rehabilitation Hospital, Shanghai, People’s Republic of China; 5School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of ChinaCorrespondence: Yong-Qing Yang; Yan-Jiao ChenLaboratory of Molecular Biology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, 650 South Wanping Road, Shanghai, 200030, People’s Republic of ChinaTel +86-21-54592134; +86-21-64395975Fax +86-21-64395975Email yyq@shutcm.edu.cn; cyjb1018@163.comPurpose: Cyclophilin A (CypA) inhibits CD4+ T cell signal transduction via interleukin-2-inducible T-cell kinase (Itk), a tyrosine kinase required for T helper (Th) 2 cells function. Furthermore, mice with CypA silencing developed allergic diseases associated with increased Th2 cytokines production. CD4+ T cells with a Th2-cytokine pattern have been demonstrated to have a pivotal role in the pathogenesis of asthma. However, the effects of CypA in regulating immunity in asthma and in relieving asthmatic symptoms in vivo are entirely unknown.Methods: Recombinant CypA protein (rCypA) was generated and purified. Ovalbumin (OVA)-challenged asthmatic rats model and acetylcholine chloride (ACh)-induced contraction of tracheal spirals were established. The pulmonary resistance (RL) value of asthmatic rats in vivo and the isometric tension of tracheal spirals ex vivo were recorded by MFLab 3.01 software. The levels of Th1 and Th2 cytokines and the quantities of immunoglobulin (IgA, IgG, IgM and IgE) in the supernatants of rat spleen lymphocytes were detected and analysed by bio-plex Suspension Array System and ELISA, respectively. CD4+ T cells were separated by MicroBeads, and the levels of interleukin (IL)-4 and interferon-γ (IFN-γ) were detected by ELISA.Results: rCypA (10 ng/kg) significantly reduced RL within 2– 7 min in OVA-challenged asthmatic rats in vivo, and there were no significant differences compared with terbutaline (TB) and hydrocortisone (HC). Furthermore, rCypA (10 ng/mL) significantly reduced the isometric tension in the ACh-induced contraction of the tracheal spiral ex vivo, and the effect of rCypA was better than that of TB. Additionally, rCypA suppressed the secretion of both Th1 and Th2 cytokines, and the suppressive effects of rCypA were stronger than those of HC, especially on Th2 cytokines.Conclusion: These findings indicate that CypA may serve as a potential novel therapeutic strategy for asthma.Keywords: cyclophilin A, asthma, Th2 cytokines, immunoregulation

The incidence of pediatric liposarcoma is rare and most published cases lack systematic genetic analyses. We present clinicopathologic and genetic features of 23 liposarcomas aged

Background LXYL-P1-2 is the first reported glycoside hydrolase that can catalyze the transformation of 7-β-xylosyl-10-deacetyltaxol (XDT) to 10-deacetyltaxol (DT) by removing the d -xylosyl group at the C-7 position. Successful synthesis of paclitaxel by one-pot method combining the LXYL-P1-2 and 10-deacetylbaccatin III-10-β-O-acetyltransferase (DBAT) using XDT as a precursor, making LXYL-P1-2 a highly promising enzyme for the industrial production of paclitaxel. The aim of this study was to investigate the catalytic potential of LXYL-P1-2 stabilized on magnetic nanoparticles, the surface of which was modified by Ni2+-immobilized cross-linked Fe3O4@Histidine. Results The diameter of matrix was 20–40 nm. The Km value of the immobilized LXYL-P1-2 catalyzing XDT (0.145 mM) was lower than that of the free enzyme (0.452 mM), and the kcat/Km value of immobilized enzyme (12.952 mM s−1) was higher than the free form (8.622 mM s−1). The immobilized form maintained 50% of its original activity after 15 cycles of reuse. In addition, the stability of immobilized LXYL-P1-2, maintained 84.67% of its initial activity, improved in comparison with free form after 30 d storage at 4°C. Conclusions This investigation not only provides an effective procedure for biocatalytic production of DT, but also gives an insight into the application of magnetic material immobilization technology. How to cite Zou S, Chen TJ, Li DY, et al. LXYL-P1-2 immobilized on magnetic nanoparticles and its potential application in paclitaxel production. Electron J Biotechnol 2021;50. https://doi.org/10.1016/j.ejbt.2020.12.005

Background: Oral squamous cell carcinoma (OSCC) has a high incidence of metastasis. Tumor immunotherapy targeting programmed death ligand 1 (PD-L1) or programmed cell death protein 1 (PD-1) is revolutionary; however, only a few patients with OSCC respond to this treatment. Therefore, it is necessary to understand the molecular mechanisms of OSCC growth and metastasis to identify new therapeutic targets. Methods: In this study, we first analyzed the expression level of protein kinase D3 (PKD3) and PD-L1, and their correlation with mesenchymal and epithelial markers through UALCAN database, UCSC Xena, western blot, and immunostaining of human OSCC tissue sections. We knocked down and overexpressed PKD3 in OSCC cell lines and analyzed cell growth, migration, and invasion using western blot, cell proliferation assays, wound healing assays, and Transwell assays. A mouse footpad xenograft model was used to study the effects of PKD3 on tumor growth and lymph node metastasis in vivo. Results: The expression of PKD3 and PD-L1 in OSCC cells and tissues was significantly increased, and correlated positively with mesenchymal markers but negatively with epithelial markers. Silencing PKD3 significantly inhibited the growth, metastasis, and invasion of OSCC cells, while its overexpression promoted these processes. PKD3 regulated PD-L1 expression through the ERK/STAT1/3 signaling pathway, forming a positive feedback regulatory loop with PD-L1 to induce epithelial-mesenchymal transition (EMT) in OSCC. Conclusions: There is a positive feedback regulation between PKD3 and PD-L1, which can drive the EMT of OSCC cells through the ERK/STAT1/3 pathway, thereby promoting tumor growth and metastasis. Our findings provide a theoretical basis for targeting PKD3 as an alternative method to block EMT for regulating PD-L1 expression and inhibiting OSCC growth and metastasis . Keywords: OSCC, PKD3, PD-L1, EMT, tumor growth, metastasis

Multiple myeloma (MM) is a malignant neoplasm featured by obvious drug resistance and poor prognosis. MicroRNAs (miRNAs) are a class of small noncoding RNAs with crucial roles in many biological processes including cancer initiation and progression. The current study aims to investigate the pathogenic role and molecular mechanism of miRNAs in MM drug resistance. In the present study, The expression profile of miRNAs in MM samples was analyzed by microarray and real-time polymerase chain reaction. Protein expressions were detected by Western blot analysis. Cell apoptosis was detected by the Annexin V staining assay. The interaction between miRNA and the targeting mRNA was assessed using Dual luciferase reporter assay. Herein, we show that expression profile of miRNAs is deregulated in MM. miR-218, one of the most aberrational miRNAs in MM, is significantly decreased in MM cells compared to peripheral blood mononuclear cell (PBMC). Genetic manipulation reveals miR-218 control the response of MM cells to anticancer drug bortezomib (BTZ). Overexpression of miR-218 causes a significant aberrant genes expression including leucine rich repeat containing 28 (LRRC28). Mechanistic study shows that miR-218 control the drug response through mediating the expression of LRRC28 in MM cells. Overexpression of LRRC28 significantly reserves miR-218-mediated cell response to BTZ. Taken together, miR-218 is decreased in MM that contributes to BTZ resistance via targeting LRRC28, which might be used as a novel therapeutic target for multiple myeloma.

Liver fibrosis, caused by multiple chronic liver injuries, is a known contributor to cirrhosis and even liver cancer. As a Traditional Chinese Medicine (TCM), Rhizoma curcumae has been extensively used in the treatment of liver fibrosis with satisfying therapeutic effects; however, its mechanism is unclear. The essential oil is the main bioactive component. The purpose of this study was to investigate the chemical profile and the pharmacological mechanisms of the essential oil of Rhizoma curcumae (EORC) against liver fibrosis by combining network pharmacology and transcriptomic technologies. A total of 37 active compounds were identified using the GC/MS system and literature mining, and the corresponding putative targets were predicted. Then, network pharmacology method was applied to identify the 168 candidate targets of EORC-alleviated liver fibrosis. String database and Cytoscape software were used to build the herb-compound-target network and protein-protein interactions (PPIs) network. Functional and pathway enrichment analysis indicated that EORC significantly influenced TGF-β1/Smads and PI3K/AKT pathways. Experimentally, we verified that EORC attenuated the severity and pathological changes during liver fibrosis progression based on the CCl4-induced liver fibrosis rat model. Transcriptomic technologies demonstrated that EORC ameliorated liver fibrosis partially by regulating the TGF-β1/Smads and PI3K/AKT pathways. In addition, the effect of vinegar-processed EORC was more significant than that of the raw one. Therefore, EORC can alleviate the severity of liver fibrosis through mechanisms predicted by network pharmacology and provide a basis for the further understanding of the application of EORC in the treatment of liver fibrosis.

Context Processing with vinegar could enhance the efficacy and reduce the toxicity of Curcuma phaeocaulis Valeton. (Zingiberaceae), a Chinese herbal medicine with anti-inflammatory and antitumor activities. Objective This study investigated the vinegar processing effects by evaluating anti-angiogenic effect and toxicity of C. phaeocaulis through zebrafish and rat models. Materials and methods Zebrafish embryos (AB and FLk-GFP strain) were applied to evaluate toxicity, cardiotoxicity and anti-angiogenic activity of volatile oil, and water decoction of the raw and vinegar-processed C. phaeocaulis. Meanwhile, a blood stasis syndrome rat model was applied to study the toxicity by measuring the ovarian and uterine coefficient. Results Curcuma phaeocaulis volatile oil and its vinegar-processed products in zebrafish had an LC50 of 67.315 and 95.755 μg/mL, respectively. Curcuma phaeocaulis water decoction and its vinegar-processed products had an LC50 of 161.440 and 206.239 μg/mL, respectively. The toxicity of vinegar-processed products was significantly lower than the raw, and the development characteristic of zebrafish embryos at different times confirmed these results. The volatile oil of vinegar-processed products could inhibit the growth of intersegmental blood vessels at the dose of 20 μg/mL, while the raw materials did not exhibit such effect at the same concentration. The rat experiment also confirmed that the volatile oil could reduce toxicity of ovarian and uterine. Discussion and conclusions The study indicated that processing using vinegar could decrease toxicity and increase anti-angiogenic activity of C. phaeocaulis, which could be applied for clinical treatment. Further in-depth study on the synergism and detoxification mechanism of vinegar processing technology is needed.

The aim of this study was to discover potent angiotensin-converting enzyme (ACE) inhibitory (ACEI) peptides from Pinctada fucata (P. fucata) for treating hypertension and to characterize them using in silico analysis. The P. fucata proteins were hydrolyzed by Alcalase®, a serine endopeptidase with broad selectivity, at various times (0, 2, 4, 6, 8, 10 h). The degree of hydrolysis (DH) and ACEI activity of the different hydrolysates were measured. Considering the molecular weight and ACEI activity, the 10 h hydrolysate was purified by a series of traditional separation methods, including ultrafiltration, gel G-25 chromatography, and reversed-phase high-performance liquid chromatography (RP-HPLC), with ACEI activity as a guide. The results showed two fractions, C17 and C18, eluted by means of semi-preparative RP-HPLC, and showed the highest ACEI activities of 80.33 ± 2.70% and 81.66 ± 0.29%, respectively, at 1 mg mL−1. The two fractions were then identified using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) and their MS/MS spectra data were subjected to de novo sequencing. Subsequently, the potential ACEI peptides were screened by in silico methods, namely, to analyze the average local confidence (ALC) value obtained from the sequencing software and the P-value from the Pepsite 2. In total, 13 potential ACEI peptide sequences were obtained and identified from the two fractions by LC-ESI-MS/MS, and two novel tetrapeptides, FRVW (607.3314 Da) and LPYY (555.2881 Da), were screened for synthesis according to the in silico analysis. The in vitro ACEI tests indicated that FRVW and LPYY had IC50 values of 18.34 and 116.26 μM, respectively. The Lineweaver–Burk plot showed that FRVW was a noncompetitive inhibitor, and LPYY was shown to be a mixed-mode type inhibitor. A stability study against ACE indicated that both peptides were hydrolyzed by ACE to some extent, the higher ACEI activity following incubation with ACE indicating that they should be classified as pro-drug substrates. Molecular docking results showed that hydrophobic amino acids (HAAs) within peptides formed vital interactions including hydrogen bonds, electrostatic forces, van der Waals forces and Pi–Pi interactions with ACE residues, which stabilized the enzyme–peptide complex. Furthermore, the docking results accorded with the inhibition kinetic mode. Our study demonstrated that FRVW and LPYY isolated from P. fucata have potential applications as antihypertensive agents.

Brain iron disequilibrium and dopaminergic dysfunction are key pathophysiological features of Restless Legs Syndrome (RLS). Rep1 polymorphism in the promotor region of SNCA is associated with risk of Parkinson's disease, however its association with RLS and iron status is unclear.To investigate SNCA-Rep1 polymorphism in RLS and its phenotypes.We recruited RLS patients as well as age and gender matched healthy controls. Demographic information and clinical features of RLS were recorded. Laboratory examinations were performed to exclude possible secondary causes.215 RLS patients and 369 healthy controls were included. We found that the Rep1 allele 0 homozygosity significantly decreased RLS risk (OR: 0.345; P 0.0001, and remained significant after the Bonferroni correction). Phenotypic analysis demonstrated that longer Rep1 alleles were associated with increased susceptibility to iron deficiency (53.0% vs 36.1%, P = 0.017), however had no phenotypic significant effects on age, gender, onset age, duration, RLS family history, severity, laterality, extra body involvement and seasonal fluctuation. Multivariate logistic regression analyses confirmed long Rep1 allele was associated with higher risk of iron deficiency in RLS after adjusting for potential confounding factors. In detail, Rep1 allele 2 homozygosity was prone to a higher risk of peripheral iron deficiency in RLS (OR: 4.550, P = 0.006, remained significant after the Bonferroni correction).The SNCA-Rep1 variability modified RLS risk and influenced peripheral iron deficiency in this group of Chinese RLS patients. Rep1 allele 0 homozygosity decreased the risk of RLS, while homozygous allele 2 increased the risk of nonanemic iron deficiency in RLS.

Nodular fasciitis (NF) rarely occurs in infants aged < 2 years although cranial fasciitis develops predominantly in this age group. Histologically, NF may present high cellularity and brisk mitoses, but atypical forms are generally absent. Here, we report a NF in a 22-month-old Chinese boy. Microscopically, the lesion was manifested as cellular variant of NF. Notably, atypical mitotic figures including multipolar form were identified. Immunohistochemically, the neoplastic cells showed strong positivity for smooth muscle actin. Fluorescence in situ hybridization analysis revealed an unbalanced rearrangement of USP6, along with the USP6 increased copies. Subsequent next-generation sequencing-based technology revealed a novel PAFAH1B1-USP6 fusion gene as well as unusual fusion point on USP6 (exon 9). To the best of our knowledge, this is the only reported case with overt atypical mitosis. This case is also the first published example of genetically confirmed infant NF. Additionally, PAFAH1B1-USP6 fusion has never been described in NF.

Epidemiological studies on the association of sulfur dioxide (SO2) with neural tube defects (NTDs) are lacking. The purpose of this study was to assess the aforementioned association through a population-based case–control study. This study involved 1457 NTDs cases and 7950 randomly selected healthy infants born in 14 cities in Liaoning province between 2010 and 2015. Ambient SO2 levels were acquired from 75 monitoring stations. The exposure assessment was based on the mean concentration of all stations in mother’s residential city. We used logistic regression models to assess the associations. In multivariable models adjusted for the confounding variables selected based on the 10 percent change-in-estimate method, we found that maternal SO2 exposure was positively associated with an increased risk of NTDs during the first month after conception (per 10 μg/m3 increase: adjusted odds ratio [aOR] = 1.02, 95% confidence interval [CI]: 1.00–1.04; highest versus lowest quartile: aOR = 2.55, 95% CI: 1.97–3.31) and the second month after conception (per 10 μg/m3 increase: aOR = 1.02, 95% CI: 1.00–1.04; highest versus lowest quartile: aOR=2.31, 95% CI: 1.77–3.00). For other exposure windows, positive associations also emerged in high- versus low-exposure analyses, except for the third month before conception; however, we could not further confirm significant findings from the continuous exposure analyses. Our study provides a new evidence that SO2 exposure may increase the risk of NTDs.

The pathophysiological differences between menstrually-related migraine (MRM) and pure menstrual migraine (PMM) are largely unclear. The aim of this study was to investigate the potential differences in brain structure and function between PMM and MRM. Forty-eight menstrual migraine patients (32 MRM; 16 PMM) were recruited for this study. Voxel-based morphometry (VBM) was applied on structural magnetic resonance imaging (sMRI), and the amplitude of low-frequency fluctuations (ALFF) and regional homogeneity (ReHo) in resting state functional MRI (rsfMRI) were calculated. No significant between-group difference was observed in the grey matter volume (GMV). MRM patients exhibited lower ALFF values at the dorsolateral prefrontal cortex (DLPFC) and medial prefrontal cortex (mPFC) than PMM patients. Moreover, the MRM group showed significantly higher ReHo values in the DLPFC. Higher values in the mPFC were related to higher expression of calcitonin gene-associated peptide (CGRP) in the PMM group (r = 0.5, P = 0.048). Combined ALFF and ReHo analyses revealed significantly different spontaneous neural activity in the DLPFC and mPFC, between MRM and PMM patients, and ALFF values in the mPFC were positively correlated with CGRP expression, in the PMM group. This study enhances our understanding of the relationship between neural abnormalities and CGRP expression in individuals with PMM.

The proline-rich coiled-coil 2A (PRRC2A) gene has been reported to underlie risk of various autoimmune diseases. However, no data reveal the risk susceptibility of PRRC2A to neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) so far. To explore the association between PRRC2A variants and NMOSD and MS susceptibility in Han Chinese population. Totally, 207 NMOSD (98 AQP4+ and 109 AQP4−) patients, 141 MS and 196 healthy controls (HC) were enrolled. Candidate tagging single nucleotide polymorphisms (tag-SNPs) were selected from the 1000G database based on the Chinese data. SNP genotyping was performed using MassArray and Sanger sequencing. PRRC2A variants rs2736171, rs2736157, rs2844470 alter susceptibility to AQP4+ NMOSD, while rs2242659 to MS. Genotype AT of rs2844470 and AG of rs2242659 increased risk susceptibility for AQP4+ NMOSD and MS, respectively. AQP4+ NMOSD exhibited a higher frequency of genotype AG of rs2736157 compared with AQP4− NMOSD. Haplotype TCAAGGTAG was conferred risk susceptibility to AQP4+ NMOSD and haplotype TTAGAGTAG had a protective effect on both AQP4+ and AQP4− NMOSD. Further, we identified various gene expression levels in disease-related regions that are significantly modulated by three cis-eQTL SNPs rs2736157, rs2736171 and rs2242659 (p

Purpose The aim of this study was to explore the use of self-assembling nanoparticles loaded with two chemotherapy drugs for the treatment of multiple myeloma. Materials and methods Nanoparticle systems were developed based on amine polyethylene glycol-polycaprolactone (NH2-PEG-PCL) to encapsulate 5-Aza-2'-deoxycytidine and Bortezomib using the self-assemble method. Morphological changes were observed by transmission electron microscopy (TEM), and the size, drug release, long-term stability, and release of reactive oxygen species (ROS) were analyzed. The MTT assay was used to evaluate the effects of drug-loaded nanoparticles (PEG-PCL-DAC-BTZ) in inhibiting the proliferation of multiple myeloma cells (U266 and LP-1), and the TUNEL assay and Western blotting were used to measure the induction of cell apoptosis. Results Based on the diameter of NH2-PEG-PCL and PEG-PCL-DAC-BTZ, the drug-loaded nanoparticles were successfully prepared. TEM revealed that PEG-PCL-DAC-BTZ was spherically shaped. More than 90% of the drugs were released after 72 h, and PEG-PCL-DAC-BTZ maintained a good stability. U266 and LP-1 cells treated with PEG-PCL-DAC-BTZ showed the highest growth inhibition, release of ROS, and cell apoptosis compared to those treated with unloaded nanoparticles and chemotherapy drugs alone. Conclusion The drug-loaded nanoparticles are a good foundation for the treatment of multiple myeloma as they showed a slow release profile, good stability, and superior anti-cancer effects in vitro.

Despite dramatic advances in drug discovery over the decades, effective therapeutic strategies for cancers treatment are still in urgent demands. PROteolysis TArgeting Chimera (PROTAC), a novel therapeutic modality, has been vigorously promoted in preclinical and clinical applications. Unlike small molecule PROTAC, peptide PROTAC (p-PROTAC) with advantages of high specificity and low toxicity, while avoiding the limitations of shallow binding pockets through large interacting surfaces, provides promising substitutions for E3 ubiquitin ligase complex-mediated ubiquitination of "undruggable proteins". It is worth noting that successful applications of p-PROTAC still have some obstacles, including low stability and poor membrane permeability. Hence, we highlight that p-PROTAC combined with cell-penetrating peptides, constrained conformation technique, and targeted delivery systems could be the future efforts for potential translational research.

BackgroundCurrent literature describes limited and controversial evidence on the associations between maternal preconception and first trimester exposure to particulate matter with a diameter ≤10 µm (PM10) and the risk of oral cleft (OC).MethodsWe conducted a case–control study involving 3086 OC cases and 7950 controls, registered in the Maternal and Child Health Certificate Registry in Liaoning Province between 2010 and 2015. PM10 concentrations were obtained from the Environment Protection Bureau. The exposure windows included the 3 months before pregnancy, the first trimester and the individual months. Unconditional logistic regression model was performed to estimate the OR and 95% CI for the association between PM10 exposure and the risk of OC, cleft lip only (CLO), cleft palate only (CPO), and cleft lip and palate (CLP).ResultsMaternal PM10 exposure was positively associated with an increased risk for OC during the 3 months preconception (per 10 µg/m3 increment: OR=1.04, 95% CI 1.01 to 1.07; highest vs lowest quartile: OR=1.23, 95% CI 1.04 to 1.45) and the first trimester (per 10 µg/m3 increment: OR=1.05, 95% CI 1.02 to 1.08; highest vs lowest quartile: OR=1.37, 95% CI 1.15 to 1.64). Analyses based on individual months presented similar positive associations, particularly in the second month of pregnancy (OR=1.77, 95% CI 1.51 to 2.09) for highest versus lowest quartile. In the subtype analysis, stronger associations were observed for CLO, whereas there was negligible evidence for CPO and CLP. Sensitivity analyses using propensity score matching generated similar findings.ConclusionsOur study provides evidence that PM10 exposure during the 3 months preconception and the first trimester increases the risk of OC.

Non-coding RNAs (ncRNAs) are key players in variety of biogenesis and biological functions. Their aberrant expression has been implicated in disease progression. NcRNAs can be divided into short ncRNAs whose subtypes are mainly microRNA (miRNA), long non-coding RNA (lncRNA) and circular RNA (circRNA). They are involved in cellular processes, including gene regulation, development and disease. The retina is a remarkably sophisticated instrument with interconnected cell types and is the primary target of many genetic diseases. In addition, in terms of retinal dyshomeostasis and inflammation, ncRNAs seems to play critical roles in many retinal diseases. Here, we provide an overview of ncRNAs in developing retina. We also review how does these ncRNAs function in various retinal diseases including animal and human models. These data indicate that ncRNAs regulate cellular processes including cell proliferation, differentiation, apoptosis and contribute to initiation and progression of retinal diseases.

Purpose Pediatric acute promyelocytic leukemia (APL) accounts for 10% of pediatric acute myelogenous leukemia (AML) case and is accompanied by a tendency to hemorrhage. miR-188-5p plays an important role in adult AML. Therefore, the purpose of this study was to explore the effects of miR-188-5p on cell proliferation and apoptosis and tumor growth, and its mechanism in pediatric APL patients. Materials and methods Survival-associated miRNAs or mRNAs from TCGA database associated with AML were identified via using the "survival R" package in R language. CCK8, clone formation, flow cytometry, RT-PCR, immunohistochemistry and Western blot assays were used to detect the viability, proliferation, apoptosis, cell cycle, and related gene expression in APL cell lines. The prognostic value of miR-188-5p was evaluated using a ROC curve. The tumorigenic ability of APL cell lines was determined using a nude mouse transplantation tumor experiment. Tumor cell apoptosis was determined by TUNEL assay in vivo. The target genes of miR-188-5p were predicted using the miRDB, miRTarBase, and TargetScan databases. A PPI network was constructed using STRING database and the hub gene was identified using the MCODE plug-in of the Cytoscape software. The DAVID database was used to perform GO and KEGG pathway enrichment analyses. A luciferase reporter assay was used to demonstrate the binding of miR-188-5p to CD2AP. Results miR-188-5p overexpression or CD2 associated protein (CD2AP) inhibition was significantly associated with poor survival in pediatric APL patients. Upregulation of miR-188-5p was identified in the blood of pediatric APL patients and cell lines. Increased expression of miR-188-5p also promoted the viability, proliferation, and cell cycle progression, and reduced the apoptosis of APL cells. Additionally, upregulation of miR-188-5p regulated the expressions of cyclinD1, p53, Bax, Bcl-2 and cleaved caspase-3. The area under the ROC curve (AUC) of miR-188-5p was 0.661. miR-188-5p overexpression increased the tumorigenic ability of APL and Ki67 expression, and reduced cell apoptosis in vivo. CD2AP was identified as the only overlapping gene from the list of miR-188-5p target genes and survival-related mRNAs of the TCGA database. It was mainly enriched in the "biological process (BP)" and "cellular component (CC)" terms, and was downregulated in the blood of pediatric APL patients and cell lines. The luciferase reporter, RT-PCR, and Western blot assays demonstrated that the binding of miR-188-5p to CD2AP. CD2AP inhibition promoted the proliferation and inhibited the apoptosis of APL cells. Rescue experiments showed that inhibition of miR-188-5p inhibited cell proliferation, activated the PI3K/AKT/mTOR signaling pathway, induced G0/G1 phase arrest, regulated gene expression, and promoted cell apoptosis, which were reversed by CD2AP inhibition. Conclusion miR-188-5p, an oncogene, promoted tumor growth and progression of pediatric APL in vitro and in vivo via targeting CD2AP and activating the PI3K/AKT/mTOR signaling pathway.

Background Osteonecrosis of the femoral head (ONFH) causes severe hip dysfunction. Left untreated, 80% of patients experience femoral head collapse, and 65–70% of patients require total hip arthroplasty (THA). Therefore, effective treatment is very important for ONFH. Objective To examine the effectiveness of fibula allografting for the treatment of early-stage ONFH Methods A systematic review was conducted by searching PubMed, EMBASE, and Web of Science databases using “avascular necrosis” or “ischemic necrosis” or “osteonecrosis” and “femoral head” and “fibula*,” and checking the references of primary articles and reviews. Two independent authors completed the study selection separately. We extracted the following details from each article: characteristics of the patients, clinical efficacy evaluation (Harris hip score [HSS], radiographic outcomes, the rate of conversation to total hip arthroplasty [THA], and adverse effects). Results A total of 213 articles were selected from PubMed (n = 45), EMBASE (n = 77), Web of Science (n = 203), and other sources (n = 10). After checking the articles, five articles were included in the final analysis. The average age of patients involved in this review was 34.48 years. The studies investigated fibula allografts to treat ONFH in 394 hips with a mean follow-up of 49.06 months. HHS was improved from 62.73 to 86.94. Radiographic progression was found in 33.66% of hips. The failure rate of head-saving surgery by THA was 14.5%. No patients had serious postoperative complications. Limitations The number of articles included in the study was small, and all studies were single-center studies. Most studies were retrospective with a low level of evidence. Surgical procedures were not identical with different follow-up times. Conclusion Although there are some limitations to our approach, this systematic review supports fibula allografting as a simple, effective treatment for early-stage ONFH, which presents less postoperative complications, and has a satisfactory clinical effect. We consider it to be worthy of promotion as a therapy for ONFH.

Lowe syndrome is an X-linked multisystem disorder affecting eyes, nervous system, and kidney. The main causes are mutations in the OCRL gene that encodes a member of the inositol polyphosphate-5-phosphatase protein family. In this study, we aimed to gain new insights into the consequences of a novel OCRL intronic variant on pre-mRNA splicing as a main cause of Lowe syndrome in a boy. After clinical diagnosis of the patient with Lowe syndrome, genetic testing was used to detect the presence of the OCRL variants. In silico analysis, human splicing finder and PyMol were used to predict this variant effect. Then, we analyzed the variant transcript by using a minigene construct in addition to in silico analysis. A hemizygous novel splicing variant in the intron 10 splice donor site of OCRL (c.939 + 3A > C) was identified in a boy with Lowe syndrome. We detected that the splice junction variant leads to aberrant OCRL mRNA splicing which results in the formation of an alternative transcript in which 29 nucleotides of exon 10 were skipped. The findings obtained from the exon-trapping assay were identical to those of in silico analysis. Hence, the truncated OCRL protein may lacked the last 597 native amino acids. The minigene assays detected the same transcript abnormality to in silico assay and were reliable in revealing the pathogenicity of the intronic variant we have used previously. Overall, this study provides new insights about Lowe syndrome and further reveals the molecular pathogenicity mechanism of the intronic variant disease.

To evaluate the quality of the existing studies and summarize evidence of important outcomes of meta-analyses/systematic reviews (MAs/SRs) of CFS. Potentially eligible studies were searched in the following electronic databases from inception to 1 September, 2019: Chinese Biomedical Literature Database (CBM), China Science and Technology Journal Database (VIP), China National Knowledge Infrastructure (CNKI), WanFang Database (WF), Web of Science, Embase, PubMed and Cochrane Library. Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) was used to evaluate the quality of evidence. The methodological quality of the literature was evaluated by A Measure Tool to Assess Systematic Reviews-2 (AMSTAR-2) and the quality of the report was assessed by Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The intra-class correlation coefficient was used to assess the consistency of the reviewers, with an overall intraclass correlation coefficient score of 0.967. Ten MAs/SRs were included. The overall conclusions were that acupuncture had good safety and efficacy in the treatment of CFS, but some of these results were contradictory. The GRADE indicated that out of the 17 outcomes, high-quality evidence was provided in 0 (0%), moderate in 3 (17.65%), low in 10 (58.82%), and very low in 4 (23.53%). The results of AMSTAR-2 showed that the methodological quality of all included studies was critically low. The PRISMA statement revealed that 8 articles (80%) were in line with 20 of the 27-item checklist, and 2 articles (20%) matched with 10–19 of the 27 items. We found that acupuncture on treating CFS has the advantage for efficacy and safety, but the quality of SRs/MAs of acupuncture for CFS need to be improved.

Background IDH2/R140Q mutation is frequently detected in acute myeloid leukemia (AML). It contributes to leukemia via accumulation of oncometabolite D-2-HG. Therefore, mutant IDH2 is a promising target for AML. Discovery of IDH2 mutant inhibitors is in urgent need for AML therapy. Methods Structure-based in silico screening and enzymatic assays were used to identify IDH2/R140Q inhibitors. Molecular docking, mutant structure building and molecular dynamics simulations were applied to investigate the inhibitory mechanism and selectivity of CP-17 on IDH2/R140Q. TF-1 cells overexpressed IDH2/R140Q mutant were used to study the effects of CP-17 on cellular proliferation and differentiation, the wild-type TF-1 cells were used as control. The intracellular D-2-HG production was measured by LC-MS. The histone methylation was evaluated with specific antibodies by western blot. Results CP-17, a heterocyclic urea amide compound, was identified as a potent inhibitor of IDH2/R140Q mutant by in silico screening and enzymatic assay. It exhibits excellent inhibitory activity with IC50 of 40.75 nM against IDH2/R140Q. More importantly, it shows poor activity against the wild-type IDH1/2, resulting in a high selectivity of over 55 folds, a dramatic improvement over previously developed inhibitors such as AGI-6780 and Enasidenib. Molecular simulations suggested that CP-17 binds to IDH2/R140Q at the allosteric site within the dimer interface through extensive polar and hydrophobic interactions, locking the enzyme active sites in open conformations with abolished activity to produce D-2-HG. Cellular assay results demonstrated that CP-17 inhibits intracellular D-2-HG production and suppresses the proliferation of TF-1 erythroleukemia cells carrying IDH2/R140Q mutant. Further, CP-17 also restores the EPO-induced differentiation that is blocked by the mutation and decreases hypermethylation of histone in the TF-1(IDH2/R140Q) cells. Conclusions These results indicate that CP-17 can serve as a lead compound for the development of inhibitory drugs against AML with IDH2/R140Q mutant.

Circular RNAs (circRNAs) represent a class of noncoding RNAs with a wide expression pattern, and they constitute an important layer of the genome regulatory network. To date, the expression pattern and regulatory potency of circRNAs in the retina, a key part of the central nervous system, are not yet well understood. In this study, RNAs from five stages (E18.5, P1, P7, P14, and P30) of mouse retinal development were sequenced. A total of 9,029 circRNAs were identified. Most circRNAs were expressed in different stages with a specific signature, and their expression patterns were different from those of their host linear transcripts. Some circRNAs could act as sponges for several retinal microRNAs (miRNAs). Furthermore, circTulp4 could function as a competitive endogenous RNA (ceRNA) to regulate target genes. Remarkably, silencing circTulp4 in vivo led to mice having a thin outer nuclear layer (ONL) and defective retinal function. In addition, we found that circRNAs were dysregulated at a much earlier time point than that of disease onset in a retinal degeneration model (rd8 mice). In summary, we provide the first circRNA expression atlas during retinal development and highlight a key biological role for circRNAs in retinal development and degeneration.

Aims Diseases caused by pathogenic fungi was a major constrain in increasing productivity and improving quality of Panax notoginseng. The aim of this research was to evaluate the inhibitory activity of essential oils (EOs) from Asteraceae family, Chrysanthemum indicum and Laggera pterodonta, against pathogenic fungi of P. notoginseng. Methods and results The antifungal activity was investigated using multiple methods, disclosing that the EOs from C. indicum and L. pterodonta are active against hypha growth of different fungi but with different degrees of potency. Checkerboard testing indicated that the combination of EOs with hymexazol had synergistic effect against Pythium aphanidermatum, and exhibited additive effects against bulk of targeted pathogenic fungi. Besides, we found that the baseline sensitivity of Fusarium oxysporum to L. pterodonta EOs was higher than those of C. indicum by means of mycelium growth rate method. Finally, the practicability of those EOs as plant pesticide was confirmed by in vivo model showing that EOs can significantly inhibit the occurrence of root rot of P. notoginseng caused by F. oxysporum. Conclusion Those studies suggest that the EOs from C. indicum and L. pterodonta had the potential to develop into new pollution-free pesticides for the protection of precious Chinese herbal medicines. Significance and impact of the study This study provided a new way of biological control for overcoming the frequent diseases occurrence of P. notoginseng.

It has been reported that abnormal epigenetic modification is associated with the occurrence of Parkinson’s disease (PD). Here, we found that a ten-eleven translocation 2 (TET2), a staff of the DNA hydroxylases family, was increased in dopaminergic neurons in vitro and in vivo. Genome-wide mapping of DNA 5-hydroxymethylcytosine (5-hmC)-sequencing has revealed an aberrant epigenome 5-hmC landscape in 1-methyl-4-phenylpyridinium iodide (MPP+)-induced SH-SY5Y cells. The TET family of DNA hydroxylases could reverse DNA methylation by oxidization of 5-methylcytosine (5-mC) to 5-hmC. However, the relationship between modification of DNA hydroxymethylation and the pathogenesis of PD is not clear. According to the results of 5-hmC-sequencing studies, 5-hmC was associated with gene-rich regions in the genomes related to cell cycle, especially gene-cyclin-dependent kinase inhibitor 2A (Cdkn2A). Downregulation of TET2 expression could significantly rescue MPP+-stimulated SH-SY5Y cell damage and cell cycle arrest. Meanwhile, knockdown of Tet2 expression in the substantia nigra pars compacta of MPTP-induced PD mice resulted in attenuated MPTP-induced motor deficits and dopaminergic neuronal injury via p16 suppression. In this study, we demonstrated a critical function of TET2 in PD development via the CDKN2A activity-dependent epigenetic pathway, suggesting a potential new strategy for epigenetic therapy.

Healing of the chronic diabetic ulceration and large burns remains a clinical challenge. Therapeutic fasting has been shown to improve health. Our study tested whether fasting facilitates diabetic and burn wound healing and explored the underlying mechanism. Methods: The effects of fasting on diabetic and burn wound healing were evaluated by analyzing the rates of wound closure, re-epithelialization, scar formation, collagen deposition, skin cell proliferation and neovascularization using histological analyses and immunostaining. In vitro functional assays were conducted to assess fasting and refeeding on the angiogenic activities of endothelial cells. Transcriptome sequencing was employed to identify the differentially expressed genes in endothelial cells after fasting treatment and the role of the candidate genes in the fasting-induced promotion of angiogenesis was demonstrated. Results: Two times of 24-h fasting in a week after but especially before wound injury efficiently induced faster wound closure, better epidermal and dermal regeneration, less scar formation and higher level of angiogenesis in mice with diabetic or burn wounds. In vitro, fasting alone by serum deprivation did not increase, but rather reduced the abilities of endothelial cell to proliferate, migrate and form vessel-like tubes. However, subsequent refeeding did not merely rescue, but further augmented the angiogenic activities of endothelial cells. Transcriptome sequencing revealed that fasting itself, but not the following refeeding, induced a prominent upregulation of a variety of pro-angiogenic genes, including SMOC1 (SPARC related modular calcium binding 1) and SCG2 (secretogranin II). Immunofluorescent staining confirmed the increase of SMOC1 and SCG2 expression in both diabetic and burn wounds after fasting treatment. When the expression of SMOC1 or SCG2 was down-regulated, the fasting/refeeding-induced pro-angiogenic effects were markedly attenuated. Conclusion: This study suggests that fasting combined with refeeding, but not fasting solely, enhance endothelial angiogenesis through the activation of SMOC1 and SCG2, thus facilitating neovascularization and rapid wound healing.

Oral cancer has emerged as a global health problem due to its relatively high incidence and mortality. Human saliva as a diagnostic fluid can offer an easy, inexpensive, safe and non-invasive approach for disease detection. Direct contact between saliva and oral cancer lesions make detection of salivary biomarkers for oral cancer especially attractive. Proteins are important molecules involved in pathological processes of oral cancer growth, apoptosis and metastasis. Proteins such as hormones, antibodies, enzymes and cytokines in saliva secreted by oral cancer cells or by host cells not only provide comprehensive pathological information of oral cancer but also are considered potential targets for non-invasive screening of oral cancer. This article provides a review of potential salivary proteomic biomarkers in oral cancer screening.

Adverse cardiac remodeling after myocardial infarction (MI) is associated with extremely high mortality rates worldwide. Although optimized medical therapy, Preservation of lusitropic and inotropic function and protection against adverse remodeling in ventricular structure remain relatively frequent. This study demonstrated that Andrographolide (Andr) significantly ameliorated adverse cardiac remodeling induced by myocardial infarction and improves contractile function in mice with LAD ligation compared with the control group. Briefly, Andr markedly attenuated cardiac fibrosis and relieved inflammation after myocardial infarction. Specifically, Andr significantly blocked oxidative stress and the nuclear translocation of p-P65 following myocardial infarction. At the mechanistic level, antioxidant effect of Andr was achieved through strengthening antioxidative stress capacity and attributed to the activation of Nrf2/HO-1 Signaling. Consistently, H9C2 administrated with Andr showed a decreased oxidative stress caused by hypoxia precondition, but treatment with specific Nrf2 inhibitor (ML385) or the silence of Nrf2 blunted the activation of Nrf2/HO-1 Signaling and removed the protective effects of Andr in vitro. Thus, we suggest that Andr alleviates adverse cardiac remodeling following myocardial infarction through enhancing Nrf2 signaling pathway.

Increases in atmospheric greenhouse gases will not only raise Earth’s temperature but may also change its variability and seasonal cycle. Here CMIP5 model data are analyzed to quantify these changes in surface air temperature (Tas) and investigate the underlying processes. The models capture well the mean Tas seasonal cycle and variability and their changes in reanalysis, which shows decreasing Tas seasonal amplitudes and variability over the Arctic and Southern Ocean from 1979 to 2017. Daily Tas variability and seasonal amplitude are projected to decrease in the twenty-first century at high latitudes (except for boreal summer when Tas variability increases) but increase at low latitudes. The day of the maximum or minimum Tas shows large delays over high-latitude oceans, while it changes little at low latitudes. These Tas changes at high latitudes are linked to the polar amplification of warming and sea ice loss, which cause larger warming in winter than summer due to extra heating from the ocean during the cold season. Reduced sea ice cover also decreases its ability to cause Tas variations, contributing to the decreased Tas variability at high latitudes. Over low–midlatitude oceans, larger increases in surface evaporation in winter than summer (due to strong winter winds, strengthened winter winds in the Southern Hemisphere, and increased winter surface humidity gradients over the Northern Hemisphere low latitudes), coupled with strong ocean mixing in winter, lead to smaller surface warming in winter than summer and thus increased seasonal amplitudes there. These changes result in narrower (wider) Tas distributions over the high (low) latitudes, which may have important implications for other related fields.

Objective: Evaluating the serum level of IL-35, IL-36γ and CCL27 cytokines expression in patients with psoriasis and to explore their correlation with disease severity. To explore the role of these cytokines in the pathogenesis of psoriasis vulgaris and to guide clinical practice.Methods: Thirty patients with psoriasis vulgaris (PV) were treated with routine drug treatment for7 weeks, and 30 healthy controls were used as control group. Peripheral blood of the PV group before and after treatment and control group were detected by double-antibody sandwich ELISA. The expression levels of IL-35, IL-36γ and CCL27 in peripheral blood were analyzed statistically.Results: The expression of IL-35 in the peripheral blood of the pre-PV group (187.54 ± 172.41) was significantly lower than that of the control group (310.52 ± 174.22) and the PV treatment group (417.75 ± 47.07). The level of IL-36γ in peripheral blood of pre-PV group (295.11 ± 27.91) was higher than that of control group (155.40 ± 45.66) and PV treatment group (209.86 ± 27.91). The level of CCL27 in peripheral blood of patients pre-PV treatment (479.06 ± 285.80) was significantly higher than that of the control group (341.53 ± 98.72) and the group after PV treatment (316.56 ± 245.53). There was a negative correlation between IL-35 and IL-36γ levels in serum (r= -0.826, p < .001); IL-36γ was positively correlated with CCL27 level (r = 0.906, p < .001); IL-35 and CCL27 levels were negative correlation (r= -0.810, p < .001).Conclusion: IL-36γ and CCL27 may be involved in the pathogenesis of psoriasis as a pro-inflammatory factor. IL-35 may be involved in the pathogenesis of psoriasis as an anti-inflammatory factor.

Polycystic ovary syndrome (PCOS) is a chronic metabolic disease that is associated with obesity and adipose tissue dysfunction. This study aimed to explore the roles of Dicer (an enzyme that processes primary microRNAs) and microRNAs in PCOS. Protein levels were detected by western blotting, and mRNA and microRNA levels were detected by RT-PCR. Dicer-deficient pre-adipocytes were established by lentiviral transfection, and an miR-223 mimic and miR-223 inhibitor were used to overexpress and inhibit miR-223, respectively. 3T3-L1 cells were induced to differentiate into mature adipocytes by IBMX, insulin, and dexamethasone. The degree of differentiation was determined by oil red O staining. An insulin resistance model was established by exposing mature adipocytes to excessive glucose and insulin. The protein levels of Dicer and Ago2 in adipose tissues of PCOS patients were significantly lower than those in control females. A Dicer-deficient 3T3-L1 cell model was successfully established, whose proliferation was inhibited significantly. Insulin-resistant mature adipocytes expressed significantly less Dicer protein than control cells. The differentiation of Dicer-deficient 3T3-L1 cells and their expression of miR-223 and marker genes associated with adipose differentiation were reduced significantly. Furthermore, 3T3-L1 cells showed a weaker ability to develop into mature adipocytes when miR-223 expression was inhibited. An miR-223 mimic was used to recover the differentiation block induced by Dicer deficiency. This rescued the expression of genes associated with adipose differentiation, although the differentiation block was not efficiently rescued. It is concluded that insulin resistance may contribute to the decreased levels of Dicer protein in adipose tissue of PCOS patients. This suggests that dysfunction of Dicer plays a significant role in obesity of PCOS patients. miR-223 is a key factor in Dicer-regulated adipose differentiation, and other microRNAs may be involved in the process.

Zileuton has been demonstrated to be an anti-inflammatory agent due to its well-known ability to inhibit 5-lipoxygenase (5-LOX). However, the effects of zileuton on cardiac remodeling are unclear. In this study, the effects of zileuton on pressure overload-induced cardiac remodeling were investigated and the possible mechanisms were examined. Aortic banding was performed on mice to induce a cardiac remodeling model, and the mice were then treated with zileuton 1 week after surgery. We also stimulated neonatal rat cardiomyocytes with phenylephrine (PE) and then treated them with zileuton. Our data indicated that zileuton protected mice from pressure overload-induced cardiac hypertrophy, fibrosis, and oxidative stress. Zileuton also attenuated PE-induced cardiomyocyte hypertrophy in a time- and dose-dependent manner. Mechanistically, we found that zileuton activated PPARα, but not PPARγ or PPARθ, thus inducing Keap and NRF2 activation. This was confirmed with the PPARα inhibitor GW7647 and NRF2 siRNA, which abolished the protective effects of zileuton on cardiomyocytes. Moreover, PPARα knockdown abolished the anticardiac remodeling effects of zileuton in vivo. Taken together, our data indicate that zileuton protects against pressure overload-induced cardiac remodeling by activating PPARα/NRF2 signaling.

Ehlers-Danlos syndrome (EDS) type IV is characterized by thin skin with visible veins, easy bruising, characteristic facial features, arterial and digestive complications, as well as rupture of the gravid uterus. It has never been previously reported that trigeminal autonomic cephalalgias (TACs) could manifest as the only initial symptom of EDS type IV. Here, we report a case of a 27-year-old man who presented atypical headache like TACs stimulated by right internal carotid artery dissection. About one month after his discharge, he suffered dissection of the right renal artery and splenic artery, in addition to partial infarction of the right kidney and spleen. Genetic testing revealed a novel splicing variant c.799-1G>A within COL3A1. He was ultimately diagnosed with Ehlers-Danlos syndrome type IV. This case expanded the genetic spectrum and clinical manifestation of EDS type IV and provided a significant implication for the diagnosis of EDS type IV when the initial symptom manifested as TACs, not the typical presentation of EDS type IV.

Limited studies have focused on the impact of ambient air pollution on spina bifida. A population-based case-control study was conducted in Liaoning Province, China to assess the associations between maternal PM10 exposures in various exposure windows and spina bifida risk. Data on spina bifida cases born between 2010 and 2015 were available from the Maternal and Child Health Certificate Registry of Liaoning Province. Controls were a random sample of healthy livebirths without any birth defects delivered in the selected five cities during 2010–2015. Ambient air monitoring data for PM10 were obtained from 75 monitoring stations in Liaoning Province. The multivariable logistic regression models were established to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI). We further performed sensitivity analyses by using three propensity score methods. A total of 749 spina bifida cases and 7,950 controls were included. After adjusting for potential confounders, spina bifida was associated with a 10 μg/m3 increment in PM10 during the first trimester of pregnancy (adjusted OR = 1.06, 95% CI: 1.00–1.12) and the 3 months before pregnancy (adjusted OR = 1.12, 95% CI: 1.06–1.19). The adjusted ORs in the final model for the highest vs. the lowest quartile were 1.51 (95% CI: 1.04–2.19) for PM10 during the first trimester of pregnancy and 2.01 (95% CI: 1.43–2.81) for PM10 during the 3 months before pregnancy. Positive associations were found between PM10 exposures during the single month exposure windows and spina bifida. Sensitivity analyses based on two propensity score methods largely reported similar positive associations. Our findings support the evidence that maternal PM10 exposure increases the risk of spina bifida in offspring. Further, validation with a prospective design and a more accurate exposure assessment is warranted.

Background: To observe the relationship between Tumor Necrosis Factor-alpha (TNF-α) and Neuropeptide Y (NPY) expression and neurological function score in epileptic children. Methods: Fifty-four epileptic children diagnosed and treated in Xuzhou Children's Hospital, China from Feb 2017 to Mar 2018 were collected and included in a research group (RG), while 30 healthy children who underwent physical examination at the same time were included in the control group (CG). ELISA was used to detect the expression of TNF-α and NPY in the serum of children in the two groups, and those before treatment were compared. The National Institute of Health stroke scale (NIHSS) and Hamilton Anxiety (HAMA) scores before and after treatment were observed, and Pearson correlation was used to analyze the relationship between the expression levels of TNF-α and NPY in the serum as well as NIHSS and HAMA scores. Results: The expression levels of TNF-α and NPY in the serum of children in the RG were significantly higher than those in the CG (P

Study Objectives: We conducted a meta-analysis to assess the effects of different regular exercise (lasting at least 2 months on a regular basis) on self-reported and physiological sleep quality in adults. Varied exercise interventions contained traditional physical exercise (e.g., walking, cycling) and mind–body exercise characterized by gentle exercise with coordination of the body (e.g., yoga).Methods: Procedures followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematical searches were conducted in three electronic databases (PubMed, Embase, and Web of Science) for relevant research that involved adult participants without pathological diseases receiving exercise intervention. The search strategy was based on the population, intervention, comparison, and outcome study design (PICOS) framework. The self-reported outcomes included varied rating scales of Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS). Subgroup meta-analyses of PSQI scores were conducted based on type of exercise, duration of intervention, and participants' age and gender. The physiological outcomes were measured by Actigraph. All meta-analyses were performed in a fixed or random statistic model using Revman software.Results: Twenty-two randomized controlled trials were included in the analysis. The overall analysis on subjective outcomes suggests that exercise interventions significantly improved sleep quality in adults compared with control interventions with lower PSQI (MD −2.19; 95% CI −2.96 to −1.41), ISI (MD −1.52; 95% CI −2.63 to −0.41), and ESS (MD −2.55; 95% CI −3.32 to −1.78) scores. Subgroup analyses of PSQI scores showed both physical and mind–body exercise interventions resulted in improvements of subjective sleep to the same extent. Interestingly, short-term interventions (≤3 months) had a significantly greater reduction in sleep disturbance vs. long-term interventions (>3 months). Regarding physiological sleep, few significant effects were found in various sleep parameters except the increased sleep efficiency in the exercise group vs. control group.Conclusions: Results of this systematic review suggest that regular physical as well as mind–body exercise primarily improved subjective sleep quality rather than physiological sleep quality in adults. Specifically, self-reported sleep quality, insomnia severity, and daytime sleepiness could be improved or ameliorated with treatment of exercise, respectively, evaluated by PSQI, ISI, and ESS sleep rating scales.

Bone erosion is the most evident pathological condition of rheumatoid arthritis (RA), which is the main cause of joint deformities and disability in RA patients. At present, the conventional RA drugs have not achieved satisfactory effect in improving bone erosion. ZhiJingSan (ZJS), which is a traditional Chinese prescription composed of scolopendra (dried body of Scolopendra subspinipes mutilans L. Koch, scolopendridae) and scorpion (dried body of Buthus martensii Karsch, Buthus), exhibits anti-rheumatism, analgesic and joint deformities improvement effects. This study aimed to assess the therapeutic effect of ZJS on RA bone erosion and to elucidate the underlying mechanism. The effect of ZJS on RA bone erosion was investigated in a murine model of bovine collagen-induced arthritis (CIA), and the underlying mechanism was investigated in vitro in an osteoclast differentiation cell model. Administration of ZJS delayed the onset of arthritis, alleviated joint inflammation, and attenuated bone erosion in the CIA mice. Meanwhile, ZJS decreased the serum levels of TNF-α, IL-6, and anti-bovine collagen II-specific antibodies. Furthermore, ZJS treatment reduced the number of osteoclasts and the expression of cathepsin K in the ankle joints of CIA mice. ZJS also inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclast differentiation and the expression of MMP9 and cathepsin K in vitro. Mechanistically, ZJS blocked RANKL-induced p65 phosphorylation, nucleation, and inhibited the expression of downstream NFATc1 and c-Fos in bone marrow-derived macrophages (BMMs). Taken together, ZJS exerts a therapeutic effect on bone erosion in CIA mice by inhibiting RANKL/NF-κB-mediated osteoclast differentiation, which suggested that ZJS is a promising prescription for treating RA bone erosion.

Faced with the challenges posed by infectious diseases and cancer, nucleic acid vaccines present excellent prospects in clinical applications. Compared with traditional vaccines, nucleic acid vaccines have the characteristics of high efficiency and low cost. Therefore, nucleic acid vaccines have potential advantages in disease prevention and treatment. However, the low immunogenicity and instability of nucleic acid vaccines have limited their development. Therefore, a large number of studies have been conducted to improve their immunogenicity and stability by improving delivery methods, thereby supporting progress and development for clinical applications. This article mainly reviews the advantages, disadvantages, mechanisms, delivery methods, and clinical applications of nucleic acid vaccines.

The present study conducted QTL (quantitative trait locus) mapping using F2 and F2:3 generations derived from a cross between an overwintering cultivated rice Nuodao89-1 and Shuhui527, to identify potential yield component related QTLs. A total of 37 QTLs were detected across all chromosome except chromosome 7, with LOD values ranging from 3.10 to 12.67. Three QTLs including qTGW3.1, qTGW6.1 and qNEG9.1 were repeatedly detected in both generations. qTGW3.1 was from Nuodao89-1, a total of 46 functional genes involved in 229 gene ontology terms were identified within its locus. Six QTL clusters were founded and corresponding agronomic traits of those QTLs showed highly significant correlation. Three types of epistatic interaction including 47 epistatic QTL pairs for eight yield component traits were detected, but the epistatic QTLs was not so important in controlling the genetic expression of the yield-related Nuodao89-1 as the additive QTLs. Overall, this research provides a theoretical basis for the mining of yield-related genes from overwintering cultivated rice.

BackgroundRheumatoid arthritis (RA) is a chronic autoimmune disease. Soufeng sanjie formula (SF), which is composed of scolopendra (dried body ofScolopendra subspinipes mutilansL. Koch), scorpion (dried body ofButhus martensiiKarsch), astragali radix (dried root ofAstragalus membranaceus(Fisch.) Bge), and black soybean seed coats (seed coats ofGlycine max(L.) Merr), is a traditional Chinese prescription for treating RA. However, the mechanism of SF in treating RA remains unclear. This study was aim to investigate the anti-arthritic effects of SF in a collagen-induced arthritis (CIA) mouse model and explore the mechanism by which SF alleviates arthritis in CIA mice.MethodsFor in vivo studies, female DBA/1J mice were used to establish the CIA model, and either SF (183 or 550 mg/kg/day) or methotrexate (MTX, 920 mg/kg, twice/week) was orally administered to the mice from the day of arthritis onset. After administration for 30 days, degree of ankle joint destruction and serum levels of IgG and inflammatory cytokines were determined. The balance of Th17/Treg cells in the spleen and lymph nodes was analyzed using flow cytometry. Moreover, the expression levels of retinoic acid receptor-related orphan nuclear receptor (ROR) γt and phosphorylated STAT3 (pSTAT3, Tyr705) in the spleen were detected by immunohistochemistry. Furthermore, the effect of SF on Th17 cells differentiation in vitro was investigated in CD4+T cells under Th17 polarization conditions.ResultsSF decreased the arthritis score, ameliorated paw swelling, and reduced cartilage loss in the joint of CIA mice. In addition, SF decreased the levels of bovine collagen-specific IgG in sera of CIA mice. SF decreased the levels of inflammatory cytokines (TNF-α, IL-6, and IL-17A) and increased the level of IL-10 both in the sera and the joint of CIA mice. Moreover, SF treatment rebalanced the Th17/Treg ratio in the spleen and lymph nodes of CIA mice. SF also reduced the expression levels of ROR γt and pSTAT3 (Tyr705) in the spleen of CIA mice. In vitro, SF treatment reduced Th17 cell generation and IL-17A production and inhibited the expression of RORγt, IRF4, IL-17A, and pSTAT3 (Tyr705) under Th17 polarization conditions.ConclusionsOur results suggest that SF exhibits anti-arthritic effects and restores Th17/Treg homeostasis in CIA mice by inhibiting Th17 cell differentiation.

Objective： Preoperative differentiation between parotid Warthin’s tumor (WT) and pleomorphic adenoma (PMA) is crucial for treatment decisions. The purpose of this study was to establish and validate an MRI-based radiomics nomogram for preoperative differentiation between WT and PMA. Methods and materials: A total of 127 patients with histological diagnosis of WT or PMA from two clinical centres were enrolled in training set (n = 75; WT = 34, PMA = 41) and external test set (n = 52; WT = 24, PMA = 28). Radiomics features were extracted from axial T1WI and fs-T2WI images. A radiomics signature was constructed, and a radiomics score (Rad-score) was calculated. A clinical factors model was built using demographics and MRI findings. A radiomics nomogram combining the independent clinical factors and Rad-score was constructed. The receiver operating characteristic analysis was used to assess the performance levels of the nomogram, radiomics signature and clinical model. Results: The radiomics nomogram incorporating the age and radiomics signature showed favourable predictive value for differentiating parotid WT from PMA, with AUCs of 0.953 and 0.918 for the training set and test set, respectively. Conclusions: The MRI-based radiomics nomogram had good performance in distinguishing parotid WT from PMA, which could optimize clinical decision-making.

Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease that includes seven heterogeneous subgroups with different prognoses. In particular, polyarticular JIA (pJIA) has a longer period of active disease and a poorer prognosis. Tumor necrosis factor (TNF)-alpha inhibitors are effective in patients with pJIA, but the therapeutic regimen remains controversial. Here, we performed a single-center study to determine the potential correlation between TNF-alpha inhibitor (infliximab) therapy and outcomes in these patients. Clinical data of 40 pJIA patients were collected at our center from January 1, 2010 to January 1, 2018, and patients were grouped according to the timing of infliximab therapy. The erythrocyte sedimentation rate (ESR), the number of joints with active disease, and the 27-point juvenile arthritis disease activity score (JADAS-27) were analyzed. The ESR, the active joint count, and the JADAS-27 decreased significantly in all groups after 3 months (P = 0.041/0.415/0.008, 0.022/0.030/

Efficacy of levetiracetam (LEV) combined with sodium valproate (SV) on pediatric epilepsy and its effect on serum miR-106b in children were investigated. One hundred and twenty children with epilepsy in Xuzhou Children's Hospital from July 2015 to July 2017 were enrolled, and divided into control group (n=60) and observation group (n=60) according to random sampling. Additionally, 100 children undergoing normal physical examination were collected as normal group. Patients in the control group were treated with SV, and patients in the observation group were treated with SV and LEV. RT-qPCR was used for detecting the relative expression of serum miR-106b in children. The clinical efficacy was evaluated. After treatment, the relative expression of serum miR-106b in the control group was significantly higher than that in the observation group (P

Accumulating experimental evidence has shown that the aberrant expression of microRNAs (miRNAs) is involved in the development and progression of human cervical cancer. Previously, we identified miR-182 as an oncomiRNA in cervical cancer. However, the mechanism by which miR-182 is regulated and the interaction between human papillomavirus (HPV) and miR-182 in cervical cancer development remains unknown. In the present study, we explored the link between HPV E7 and miR-182 and verified that high-risk HPV E7 upregulated miR-182 expression through TGF-β/Smad4 signaling pathway in cervical cancer. By contrast, low-risk HPV E7 did not affect the expression of TGF-β and miR-182. Mechanistically, as high-risk HPV E7 bound to pRb, E2F was released from the complex and bound to the TGF-β promoter region, resulting in TGF-β overexpression. Furthermore, the Smad4 signaling pathway was activated upon TGF-β overexpression, which led to an interaction between Smad4 and the miR-182 promoter region, subsequently inducing the upregulation of miR-182 in both cervical cancer cells and the surrounding normal cells. In conclusion, this newly identified high-risk HPV E7/TGF-β/miR-182 regulatory network might inform the development of specific therapeutic strategies for cervical cancer.

As an endogenous neuroprotectant agent, adenosine is extensively distributed and is particularly abundant in the central nervous system (CNS). Under physiological conditions, the concentration of adenosine is low intra‐ and extracellularly, but increases significantly in response to stress. The majority of adenosine functions are receptor‐mediated, and primarily include the A1, A2A, A2B, and A3 receptors (A1R, A2AR, A2BR, and A3R). Adenosine is currently widely used in the treatment of diseases of the CNS and the cardiovascular systems, and the mechanisms are related to the disease types, disease locations, and the adenosine receptors distribution in the CNS. For example, the main infarction sites of cerebral ischemia are cortex and striatum, which have high levels of A1 and A2A receptors. Cerebral ischemia is manifested with A1R decrease and A2AR increase, as well as reduction in the A1R‐mediated inhibitory processes and enhancement of the A2AR‐mediated excitatory process. Adenosine receptor dysfunction is also involved in the pathology of Alzheimer's disease (AD), depression, and epilepsy. Thus, the adenosine receptor balance theory is important for brain disease treatment. The concentration of adenosine can be increased by endogenous or exogenous pathways due to its short half‐life and high inactivation properties. Therefore, we will discuss the function of adenosine and its receptors, adenosine formation, and metabolism, and its role for the treatment of CNS diseases (such as cerebral ischemia, AD, depression, Parkinson's disease, epilepsy, and sleep disorders). This article will provide a scientific basis for the development of novel adenosine derivatives through adenosine structure modification, which will lead to experimental applications.

Alzheimer’s disease (AD) is a chronic neurodegenerative disease that locks into long clinical latency and low curative ratio. Therefore, early diagnosis before the clinical phase is quite essential and may be effective for therapeutic prevention. Peripheral blood or cerebrospinal fluid biomarkers symbolizing functional neuronal impairment are gradually applied to diagnose AD in research studies. Exosomes have generated immense interest in the diagnosis field of neurodegenerative disorders after confirmation of their roles as mediators, delivering important proteins and microRNAs (miRNAs) in intercellular communication. Compelling research results reveal that miRNAs released from exosomes modulate expression and function of amyloid precursor proteins and tau proteins. These findings open up possibility that dysfunctional exosomal miRNAs may influence AD progression. In this review, we summarized the existing knowledge of exosomal miRNAs and their involvement in AD, emphasizing their potential to serve as diagnostic biomarkers during the preclinical phase of AD.

Long noncoding RNAs (lncRNAs) play important roles in the development and progression of human cancers. The lncRNA prostate cancer-associated transcript 1 (PCAT1) has been reported to be involved in multiple human cancers, including oesophageal squamous cell carcinoma (ESCC). However, the detailed biological functions, underlying mechanisms and clinical relevance of PCAT1 in ESCC remain unclear. Here, we confirmed that PCAT1 was highly expressed in ESCC tissues and cell lines. Knockdown of PCAT1 inhibited the growth of ESCC cells, whereas overexpression of PCAT1 showed the opposite effect both in vitro and in vivo. Moreover, knockdown of PCAT1 arrested the cell cycle at G2/M phase, reduced the expression of cyclin B1 and CDC2, and caused cells to be more sensitive to paclitaxel. Furthermore, PCAT1 could bind to miR-326, a tumour suppressor in diverse human cancers. Rescue experiments revealed that enforced expression of miR-326 attenuated the promotive effect of PCAT1 on ESCC cell growth. In addition, we discovered that PCAT1 was present in ESCC cell-derived exosomes, was higher in the serum of ESCC patients than those of healthy volunteer donors, and promoted cell growth through exosomes. Thus, our data indicate that PCAT1 promotes ESCC cell proliferation by sponging miR-326 and may serve as a non-invasive biomarker for ESCC.