[Urinary protein and renal pathological features in children with immunoglobulin A vasculitis with nephritis and hypercoagulability]. / 儿童IgAè¡€ç®¡ç‚Žè‚¾ç‚Žä¼´é«˜å‡çŠ¶æ€çš„å°¿è›‹ç™½å’Œè‚¾è„ç— ç†ç‰¹å¾åˆ†æž.

OBJECTIVES: To study the association of hypercoagulability with urinary protein and renal pathological damage in children with immunoglobulin A vasculitis with nephritis (IgAVN). METHODS: Based on the results of coagulation function, 349 children with IgAVN were divided into a hypercoagulability group consisting of 52 children and a non-hypercoagulability group consisting of 297 children. Urinary protein and renal pathological features were compared between the two groups, and the factors influencing the formation of hypercoagulability in children with IgAVN were analyzed. RESULTS: Compared with the non-hypercoagulability group, the hypercoagulability group had significantly higher levels of urinary erythrocyte count, 24-hour urinary protein, urinary protein/creatinine, urinary immunoglobulin G/creatinine, and urinary N-acetyl-ß-D-glucosaminidase (P<0.05). The hypercoagulability group also had a significantly higher proportion of children with a renal pathological grade of III-IV, diffuse mesangial proliferation, capillary endothelial cell proliferation, or >25% crescent formation (P<0.05). The multivariate logistic regression analysis showed that capillary endothelial cell proliferation and glomerular crescent formation >25% were associated with the formation of hypercoagulability in children with IgAVN (P<0.05). CONCLUSIONS: The renal injury in IgAVN children with hypercoagulability is more severe, with greater than 25% crescent formation and increased proliferation of glomerular endothelial cells being important contributing factors that exacerbate the hypercoagulable state in IgAVN.

Low-sodium diet with adequate water intake improved the clinical efficacy in Ménière's disease.

BACKGROUND: Ménière's disease (MD) is a common idiopathic inner ear disorder in otorhinolaryngology characterized by recurrent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus and ear fullness. OBJECTIVE: To study the effects of low-sodium diet with adequate water intake on the clinical efficacy in MD. METHODS: Fifty patients diagnosed with stage-3 unilateral MD were randomly divided into control group(n = 25) and experimental group(n = 25). The control group was given routine medication therapy, and the experimental group was restricted to an sodium intake of 1500 mg/d and a water intake of 35 ml/kg/d based in addition to the routine medication therapy. The two groups were assessed using pure tone audiometry, electrocochleography, Tinnitus Handicap Inventory (THI), and Dizziness Handicap Inventory (DHI). RESULTS: The pure tone audiometry and electrocochleography showed better improvements after treatment in the experimental group than the control group (p < 0.05). The THI improved values in the experimental group were significantly higher than the control group (p < 0.001). The DHI improved values in the experimental group were significantly higher than the control group (p = 0.004). CONCLUSIONS AND SIGNIFICANCE: Low-sodium diet with adequate water intake improved the hearing and alleviated vertigo and tinnitus in MD patients.

Urinary matrix metalloproteinase-7 is a sensitive biomarker to evaluate renal tubular injury in patients with minimal change disease and focal segmental glomerulosclerosis.

Objective: To explore the advantages of urinary matrix metalloproteinase-7 (MMP-7) in evaluating renal tubular injury in minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) patients compared with urinary cystatin C (CysC) and retinol-binding protein (RBP). Methods: Serum and urine samples were collected from 20 healthy volunteers, and 40 MCD and 20 FSGS patients. Serum and urinary MMP-7 levels were measured by enzyme-linked immunosorbent assay. Urinary total protein, CysC and RBP levels were measured by automatic specific protein analyzer and compared with urinary creatinine level for calibration. The renal tissue serial sections were stained by MMP-7 immunohistochemistry and periodic acid-Schiff. Results: Under light microscopy, MMP-7 granular weak positive expression was showed sporadically in the cytoplasm of a few renal tubular epithelial cells without obvious morphological changes in MCD patients, and MMP-7-positive expression was observed in the cytoplasm of some renal tubular epithelial cells in FSGS patients. There was no significant difference in serum MMP-7 level among the three groups. Compared with the control group, the urinary MMP-7 level in MCD patients was higher, but urinary CysC and RBP levels were not increased significantly. Compared with the control group and MCD patients, urinary MMP-7, CysC and RBP levels in FSGS patients were upregulated significantly. Conclusions: Urinary MMP-7 could not only evaluate the mild renal tubular epithelial cells injury in MCD patients with massive proteinuria, but also evaluate the continuous renal tubular epithelial cells injury in FSGS patients.

Characteristics of innate and adaptive immune disorder in IgA nephropathy based on integrated bioinformatics.

BACKGROUND: Our study aims to investigate the immunological pathogenesis underlying immunoglobulin A nephropathy (IgAN) and explore potential biomarkers for IgAN diagnosis. MATERIALS AND METHODS: Differentially expressed genes (DEGs) of formalin-fixed and paraffin-embedded (FFPE) samples were screened between IgAN patients and healthy people based on GSE115857. Gene oncology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) enrichment was performed to identify related biological processes and pathways. CIBERSORT was utilized to seek the relationship of immune cell infiltration with IgAN. Finally, the expression of paraoxonase 2 (PON2) related to innate immune response was verified in FFPE samples of minimal change disease and IgAN patients by immunohistochemistry and PAS staining. RESULTS: 25 down-regulated genes and 12 up-regulated genes were identified in IgAN patients, which mainly responded to endothelial cell proliferation, inflammatory response, and angiogenesis. Toll-like receptor signaling pathway and Epstein-Barr virus (EBV) infection might be involved in IgAN pathogenesis. In addition, the infiltration of macrophages M0, naïve B cells, and follicular helper T (Tfh) cells was positively correlated in IgAN patients. Macrophages M1 and M2 infiltration were up-regulated in IgAN patients, which indicated that innate immune response was closely associated with IgAN. Besides, the results of immunohistochemistry showed that PON2 was obviously positively expressed in acute and chronic lesions of IgAN patients. CONCLUSION: In addition to abnormalities in the adaptive immune response, macrophages M1/M2 and innate immune disorder may participate in IgAN pathogenesis. PON2 may become the feasible targets for further investigation of IgAN.

Comparative study of cigarette smoke, Klebsiella pneumoniae, and their combination on airway epithelial barrier function in mice.

BACKGROUND: The airway epithelium acts as a physical barrier to protect pulmonary airways against pathogenic microorganisms and toxic substances, such as cigarette smoke (CS), bacteria, and viruses. The disruption of the structural integrity and dysfunction of the airway epithelium is related to the occurrence and progression of chronic obstructive pulmonary disease. PURPOSE: The aim of this study is to compare the effects of CS, Klebsiella pneumoniae (KP), and their combination on airway epithelial barrier function. METHODS: The mice were exposed to CS, KP, and their combination from 1 to 8 weeks. After the cessation of CS and KP at Week 8, we observed the recovery of epithelial barrier function in mice for an additional 16 weeks. To compare the epithelial barrier function among different groups over time, the mice were sacrificed at Weeks 4, 8, 16, and 24 and then the lungs were harvested to detect the pulmonary pathology, inflammatory cytokines, and tight junction proteins. To determine the underlying mechanisms, the BEAS-2B cells were treated with an epidermal growth factor receptor (EGFR) inhibitor (AG1478). RESULTS: The results of this study suggested that the decreased lung function, increased bronchial wall thickness (BWT), elevated inflammatory factors, and reduced tight junction protein levels were observed at Week 8 in CS-induced mice and these changes persisted until Week 16. In the KP group, increased BWT and elevated inflammatory factors were observed only at Week 8, whereas in the CS + KP group, decreased lung function, lung tissue injury, inflammatory cell infiltration, and epithelial barrier impairment were observed at Week 4 and persisted until Week 24. To further determine the mechanisms of CS, bacteria, and their combination on epithelial barrier injury, we investigated the changes of EGFR and its downstream protein in the lung tissues of mice and BEAS-2B cells. Our research indicated that CS, KP, or their combination could activate EGFR, which can phosphorylate and activate ERK1/2, and this effect was more pronounced in the CS + KP group. Furthermore, the EGFR inhibitor AG1478 suppressed the phosphorylation of ERK1/2 and subsequently upregulated the expression of ZO-1 and occludin. In general, these results indicated that the combination of CS and KP caused more severe and enduring damage to epithelial barrier function than CS or KP alone, which might be associated with EGFR/ERK1/2 signaling. CONCLUSION: Epithelial barrier injury occurred earlier, was more severe, and had a longer duration when induced by the combination of CS and KP compared with the exposure to CS or KP alone, which might be associated with EGFR/ERK signaling.

Poly I:C Exacerbates Airway Inflammation and Remodeling in Cigarette Smoke-Exposed Mice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory disorder characterized by chronic inflammation and airway remodeling. Cigarette smoke (CS) and respiratory viruses are major causes of COPD development and exacerbation, but the mechanisms of these compounding factors on inflammation and pathological changes in airway structure still need further investigation. PURPOSE: This work aimed to investigate the effects and mechanisms of Poly I:C on pathological changes in CS-induced COPD mice, such as airway inflammation and remodeling. METHODS: From 1 to 8 weeks, the mice were exposed to CS, Poly I:C, or a combination of both. To compare the pathological changes among different groups over time, the mice were sacrificed at week 4, 8, 16, and 24, then the lungs were harvested to measure pulmonary pathology, inflammatory cytokines, and airway remodeling. RESULTS: Our data revealed that the fundamental characteristics of COPD, such as pulmonary pathological damage, the release of inflammatory mediators, and the remodeling of airway walls, were observed at week 8 in CS-exposed mice and these pathological changes persisted to week 16. Compared with the CS group, the pathological changes, including decreased lung function, inflammatory cell infiltration, alveolar destruction, and airway wall thickening, were weaker in the Poly I:C group. These pathological changes were observed at week 8 and persisted to week 16 in Poly I:C-induced mice. Furthermore, Poly I:C exacerbated lung tissue damage in CS-induced COPD mice. The decreased lung function, airway inflammation and remodeling were observed in the combined group at week 4, and these pathological changes persisted to week 24. Our research indicated that Poly I:C enhanced the expression of p-P38, p-JNK and p-NF-κB in CS-exposed mice. CONCLUSION: Poly I:C could promote airway inflammation and remodeling in CS-induced COPD mice probably by NF-κB and MAPK signaling.

[Bufei Yishen formula attenuates cigarette smoke extract-induced airway mucus hypersecretion by regulating Notch signaling pathway].

OBJECTIVE: To explore the mechanism of Bufei Yishen formula (BYF) on attenuating cigarette smoke extract (CSE)-induced airway mucus hypersecretion by regulating Notch signaling pathway. METHODS: The human airway epithelial cell 16HBE was cultured in vitro, and the cells in logarithmic growth phase were used for the experiments. (1) Intervention condition screening experiment: the 16HBE cells were grouped, methylthiazolyldiphenyl-tetrazolium (MTT) method and enzyme-linked immunosorbent assay (ELISA) were used to detect the effects of different concentrations of CSE (2.5%, 5%, 10%, 20%, 40%), different concentrations of BYF drug-containing serum (5%, 10%, 20%, 40%), and different concentrations of Notch signal pathway blocker DAPT (5, 10, 20, 40 µmol/L) on cell activity and secretion of mucin 5AC (MUC5AC) levels. In addition, a blank control group was set up to screen out the best conditions for preparing CSE-induced cell mucus hypersecretion model and BYF and DAPT intervention. (2) Intervention experiment: the 16HBE cells were divided into four groups. The blank control group was not given any treatment; the 16HBE cells were induced by 10% CSE for 24 hours to prepare mucus hypersecretion model in the CSE model group; the cells in the CSE+BYF group and CSE+DAPT group were given 10% BYF or 20 µmol/L DAPT, respectively, for intervention at the same time for 24 hours. Real-time fluorescent quantitative polymerase chain reaction (qPCR) was used to detect the mRNA expressions of MUC5AC, Notch3 and hairy and enhancer of split 1 (HES1) in the cells. Western blotting was used to detect the protein expressions of Notch3 and HES1 in the cells. RESULTS: (1) Results of the screening experiment of intervention conditions: compared with the blank control group, 10% CSE induction for 24 hours was the best condition for establishing cell mucus hypersecretion model that neither affected cell viability nor increased the secretion of MUC5AC; while 10% BYF and 20 µmol/L DAPT was the optimal intervention condition. (2) Intervention experiment results: compared with the blank control group, the mRNA expressions of MUC5AC, Notch3, and HES1 and the protein expressions of Notch3 and HES1 in the CSE model group were significantly increased, indicating that CSE activated Notch3 and HES1 signal activation and induced 16HBE cells to secrete mucus protein. Compared with the CSE model group, BYF and DAPT could significantly down-regulate the mRNA and protein expressions of MUC5AC, Notch3, and HES1 in cells [MUC5AC mRNA (2-ΔΔCT): 1.03±0.13, 0.96±0.05 vs. 1.35±0.07, Notch3 mRNA (2-ΔΔCT): 1.10±0.14, 1.10±0.02 vs. 1.31±0.15, HES1 mRNA (2-ΔΔCT): 1.26±0.10, 1.14±0.15 vs. 1.45±0.08, Notch3 protein (Notch3/GAPDH): 0.10±0.03, 0.16±0.03 vs. 0.31±0.09, HES1 protein (HES1/GAPDH): 0.37±0.06, 0.34±0.08 vs. 0.50±0.05, all P < 0.05]. CONCLUSIONS: The mechanism of BYF attenuating mucus hypersecretion of 16HBE cells induced by CSE was associated with the inhibition of Notch signaling pathway activation.

Preclinical characterization of the novel anti-SIRPα antibody BR105 that targets the myeloid immune checkpoint.

BACKGROUND: The CD47-SIRPα pathway acts as an important myeloid cell immune checkpoint and targeting the CD47/SIRPα axis represents a promising strategy to promote antitumor immunity. Several CD47-targeting agents show encouraging early activity in clinical trials. However, due to ubiquitous expression of CD47, the antigen sink and hematologic toxicity, such as anemia and thrombocytopenia, are main problems for developing CD47-targeting therapies. Considering the limited expression of SIRPα, targeting SIRPα is an alternative approach to block the CD47-SIRPα pathway, which may result in differential efficacy and safety profiles. METHODS: SIRPα-targeting antibody BR105 was generated by hybridoma fusion and following humanization. BR105 was characterized for binding to human SIRPα alleles and blockade of the interaction with CD47. The functional activity was determined in in vitro phagocytosis assays by using human macrophages. The effect of BR105 on human T cell activation was studied using an OKT3-induced T-cell proliferation assay and an allogeneic mixed lymphocyte reaction. Human SIRPα-humanized immunodeficient mice were used in cancer models for evaluating the in vivo antitumor efficacy of BR105. Safety was addressed in a repeat-dose toxicity study in cynomolgus monkeys, and toxicokinetic analysis was further evaluated. RESULTS: BR105 shows broad binding activity across various SIRPα variants, and potently blocks the interaction of SIRPα and CD47. In vitro functional assays demonstrated that BR105 synergizes with therapeutic antibodies to promote phagocytosis of tumor cells. Moreover, the combination of BR105 and therapeutic antibody significantly inhibits tumor growth in a xenograft tumor model. Although BR105 may slightly bind to SIRPγ, it does not inhibit T cell activation, unlike other non-selective SIRPα-targeting antibody and CD47-targeting agents. Toxicity studies in non-human primates show that BR105 is well tolerated with no treatment-related adverse effects noted. CONCLUSIONS: The novel and differentiated SIRPα-targeting antibody, BR105, was discovered and displays promising antitumor efficacy in vitro and in vivo. BR105 has a favorable safety profile and shows no adverse effects on T cell functionality. These data support further clinical development of BR105, especially as a therapeutic agent to enhance efficacy when used in combination with tumor-targeting antibodies or antibodies that target other immune checkpoints.

Diagnostic efficacy and influence factors of urinary protein/creatinine ratio replacing 24-h urine protein as an evaluator of proteinuria in children.

PURPOSE: The aim was to investigate the diagnostic efficacy of urinary protein/creatinine ratio (UPCR) and factors influencing its substitutability of 24-h urine protein (24hUP) in children with proteinuria. METHODS: A total of 356 children were recruited, including 149 with non-nephrotic-range proteinuria and 207 with nephrotic-range proteinuria which were further divided into Henoch-Schönlein purpura nephritis (HSPN), lupus nephritis (LN), and primary nephrotic syndrome (PNS). The urine protein and creatinine were measured by routine methods. Bland-Altman analysis was used to test the agreement. Spearman correlation was performed to evaluate the relevance. The receiver operating characteristic curve was used to analyze the diagnostic efficacy of UPCR. RESULTS: Bland-Altman analysis showed there was an excellent agreement between UPCR and 24hUP in each group. Correlations between UPCR and 24hUP were strong in 356 children (r = 0.869) and in the non-nephrotic-range proteinuria group (r = 0.806), but moderate in nephrotic-range proteinuria group (r = 0.586). With the increase of nephrotic-range proteinuria, the correlations between UPCR and 24hUP were decreased further, however, after UPCR was adjusted by 24-h urine creatinine (24hUCr), the correlation coefficient was improved (r = 0.682). In three subgroups with nephrotic-range proteinuria, high correlation coefficient (r = 0.731) was observed in HSPN, but not in LN (r = 0.552) and PNS (r = 0.563). The sensitivity and specificity of UPCR for diagnosing nephrotic-range proteinuria were 89.9 % and 92.2%. CONCLUSIONS: UPCR is competent in evaluating proteinuria. The degree of proteinuria, 24hUCr and the underlying pathological types of renal disease may be the important influencing factors in the correlation between UPCR and 24hUP in children with nephrotic-range proteinuria.

The Anti-Inflammatory Effect of a Combination of Five Compounds From Five Chinese Herbal Medicines Used in the Treatment of COPD.

Effective compound combination (ECC; i.e, 20-S-ginsenoside Rh1, astragaloside, icariin, nobiletin, and paeonol), derived from Chinese herbal medicine, significantly ameliorates chronic obstructive pulmonary disease (COPD) in rats; however, the underlying mechanisms of ECC remain largely unclear. In this study, network pharmacology analysis integrated with experimental validation was used to explore the therapeutic mechanisms of ECC against COPD. ECC targets and COPD genes and targets were identified from multiple databases, and then used for an analysis of protein-protein interaction (PPI) networks, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and biological functioning. BisoGenet was used to comprehensively analyze the hub-network. We validated the therapeutic effect and mechanisms of ECC both in vivo and in vitro. We identified 45 ECC targets, which were mainly related to inflammatory processes, such as the NOD-like and NF-kappa B signaling pathways, hematopoietic cell lineage, Th17 cell differentiation, cellular response to lipopolysaccharide, and interleukin-8 secretion. In addition, 1180 COPD genes and 70 COPD targets were identified as being involved in the biological functions associated with COPD development, such as cytokine-cytokine receptor interaction, the TNF signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, regulation of lymphocyte proliferation, and positive regulation of leukocyte migration. Integrative analysis of COPD genes and targets and ECC target networks revealed that 54 genes were mainly involved in the inflammatory process, such as IL-17 signaling, NF-kappa B signaling, innate immune response-activating signal transduction, and macrophage cell differentiation. Six targets (AR, ESR1, HNRNPA1, PAPR1, TP53, and VCAM1) contained in the hub-network and their four related compounds were obtained and recognized as the key molecules associated with the effects of ECC. Molecular docking validation demonstrated that four compounds could bind to six targets that interact with COPD genes. Finally, in vivo and in vitro experiments verified that ECC treatment ameliorated the symptoms of COPD in rats by improving their lung function, reducing pathological changes, and suppressing oxidative responses and pro-inflammatory cytokine secretion, while inhibiting inflammation in LPS-induced macrophages, which may be associated with NF-kappa B and MAPK signaling regulation. This study demonstrates the therapeutic mechanisms and effects of ECC on COPD via regulation of the underlying inflammatory process.

Therapeutic sildenafil inhibits pulmonary damage induced by cigarette smoke exposure and bacterial inhalation in rats.

Context: Clinical reports showed sildenafil beneficial therapy on severe chronic obstructive pulmonary disease (COPD) with pulmonary hypertension (PH) patients.Objective: The study investigated therapeutic effects of silenafil on pulmonary damage induced by cigarette smoke exposure and bacterial inhalation in rats.Materials and methods: Female Sprague-Dawley rats (200-250 g) were divided into control group (no exposure, n = 10) and exposure group (n = 50) suffered from cigarette smoke exposure and Klebsiella pneumonia inhalation for 8 weeks. Then rats were orally given normal saline (control group or model group), 2.0, 3.0, or 4.5 mg/kg sildenafil for 4 weeks, respectively. Pulmonary pressure, RVHI and morphological analysis of pulmonary vascular remodeling, respiratory functions assay, morphological analysis of pulmonary alveoli, and expression of PCNA and caspase-3 of epithelial cells in bronchioles wall were examined.Results: Compared to model rats, 2.0, 3.0, and 4.5 mg/kg sildenafil increased VT by -0.6 to 9.58%, PEF by 3.12 to 6.49%, EF50 by 0.81 to 6.50%, decreased mPAP by 4.43 to 25.58%, RVHI by 6.54 to 26.41%, showing a dose-dependent improvement. Furthermore, 4.5 mg/kg sildenafil significantly increased MAN by 39.70%, LA/CSA by 37.07%, decreased muscular pulmonary arteries by 48.00%, WT by 12.83%, MT by 22.89%, caspase-3 expression by 17.71%, and showed improvement on abnormality in lung interstitial and bronchioles by microscopy.Discussion and conclusion: Our results demonstrated that sildenafil decreased pathological changes in alveoli, bronchioles, interstitial tissue, and arterioles of rats with COPD and PH.

Correlation of urine protein/creatinine ratios to 24-h urinary protein for quantitating proteinuria in children.

BACKGROUND: The purpose of this study was to evaluate the correlation and consistency between urine protein/creatinine ratio (UPCR) and 24-h urine protein (24HUPr) in children, and to determine cutoff values of UPCR relative to 24HUPr at 100 mg/m2/d (≥ 100 mg/m2/d as pathological proteinuria) and 1000 mg/m2/d (≥ 1000 mg/m2/d as nephrotic-range proteinuria). METHODS: Three hundred sixty-six children were enrolled, including 81 controls, 109 with Henoch-Schönlein purpura nephritis, 167 with nephrotic syndrome, 5 with IgA nephropathy, and 4 with lupus nephritis. Patients were divided into three groups: normal group; non-nephrotic-range proteinuria group; nephrotic-range proteinuria group. The cutoff values of UPCR in predicting the different levels of proteinuria were determined using ROC curve analysis. RESULTS: UPCR was positively correlated with 24HUPr (r = 0.915, p < 0.01). Bland-Altman diagrams showed that UPCR and 24HUPr had good consistency, and > 95% spots of UPCR and 24HUPr were within 95% confidence intervals. Relative to 24HUPr at 100 mg/m2/d, the cutoff value of UPCR (0.18 g/g Cr) had the highest sensitivity (94%) and specificity (98.8%) which is close to 0.2 g/g Cr as proposed by the American College of Rheumatology. Relative to 24HUPr at 1000 mg/m2/d, the cutoff value of UPCR (2.09 g/g Cr) had the highest sensitivity (92.1%) and specificity (92.1%) which is close to the 2.0 g/g Cr proposed in KDIGO guidelines. CONCLUSIONS: UPCR showed strong correlation and consistency with 24HUPr for evaluating levels of proteinuria in children. UPCR < 0.2 g/g Cr can be considered a criterion for normal-range proteinuria. Instead of 24HUPr ≥ 1000 mg/m2/d, UPCR ≥ 2.0 g/g Cr can be considered a criterion for nephrotic-range proteinuria or nephrotic syndrome in children.

Hesperidin inhibits the epithelial to mesenchymal transition induced by transforming growth factor-ß1 in A549 cells through Smad signaling in the cytoplasm

Hesperidin, a natural compound, suppresses the epithelial-to-mesenchymal transition through the TGF-ß1/Smad signaling pathway. However, studies on the detailed effects and mechanisms of hesperidin are rare. The present study showed that, for A549 alveolar epithelial cells, the anti-proliferative effects of hesperidin occurred in a dose-dependent manner, with an IC50= 216.8 µM at 48 h. TGF-ß1 was used to activate the Smad signaling pathway and induce the epithelial to mesenchymal transition in cells. Treatment with hesperidin or SB431542 was used for antagonism of Smad pathway activation. Hesperidin inhibited the increase in ɑ-SMA and Col1ɑ-1 and the decrease in E-cadherin in a dose-dependent manner from concentration of 20 µM to 60 µM, as assessed by both ELISA and Western blotting assays; however, there was no significant effect on cellular morphological alterations. Moreover, the Western blotting assay showed that, in the cytoplasm, hesperidin and SB431542 had no significant effect on the protein expression of Smad 2, 3, 4, or 7 as well as 2/3. However, 60 µM hesperidin and SB431542 significantly decreased p-Smad2/3 protein expression. From the above results, it is concluded that hesperidin can partly inhibit the epithelial to mesenchymal transition in human alveolar epithelial cells; the effect accounts for the blockage of the phosphorylation of Smad2/3 in the cytoplasm rather than a change in Smad protein production in the cytoplasm

Shock synthesis and characterization of titanium dioxide with α-PbO2 structure.

The phase transformation behavior of anatase and rutile titanium dioxide with particle sizes of 60 nm and 150 nm under shock compression have been investigated. To increase the shock pressure and reduce the shock temperature, copper powder and a small amount of paraffin were mixed with the TiO2 powder. The shock recovered samples were characterized by x-ray diffraction, Raman spectroscopy, and transmission electron microscope. The results indicate that both anatase and rutile TiO2 can transform to α-PbO2 phase TiO2 through shock-induced phase transition. The transformation rate of α-PbO2 phase TiO2 for anatase TiO2 under shock compression is 100% and pure α-PbO2 phase TiO2 can be obtained, while the transformation rate for rutile TiO2 is over 90%. The influence of the particle size on the yield of α-PbO2 phase TiO2 is not noticeable. The thermal stability of the recovered pure α-PbO2 phase TiO2 was characterized by high temperature x-ray diffraction, thermogravimetric analysis and differential scanning calorimetry. The results show that α-PbO2 phase TiO2 transforms to rutile TiO2 when heated to temperature higher than 560 °C. The mechanisms of the phase transition of TiO2 under shock compression are discussed.

Screening of Skin Lesion-Associated Genes in Patients with Psoriasis by Meta-Integration Analysis.

AIM: Psoriasis is an inflammatory skin disease, and approximately one quarter of individuals with psoriasis develop painful and debilitating arthritis. As a complex and polygenetic hereditary disease, it is significant to investigate skin lesion-associated genes of psoriasis. METHOD: In the present study, a total of 3,047 differentially expressed genes between lesional and nonlesional skin of psoriasis patients were screened based on 4 data sets in GEO DataSets. In the following, network module analyses were performed. RESULT: After calculating the correlation coefficients between eigenvalues of each module and disease status (psoriatic lesion and nonlesion), it was observed that the genes in black and green modules showed a significant correlation in each data set. Consequently, 58 significant characteristic genes of black modules and 74 of green modules were chosen for further analysis. The interaction network of the candidate feature genes was constructed based on the BioGRID, HPRD, and BIND databases, which contained 310 nodes. The mutual relationships of 70 genes, including 28 genes in the black module and 42 genes in the green module, were summarized, and 5 drug molecules related to these 70 factors were detected. Mepacrine and camptothecin were indicated as 2 drugs negatively related to psoriasis. CONCLUSION: The results suggested a pathogenesis mechanism of psoriasis and indicated novel therapeutic targets for psoriasis.

A Randomized Controlled Trial of Intralesional Glucocorticoid for Treating Pretibial Myxedema.

BACKGROUND: Pretibial myxedema (PTM) is an uncommon dermopathy associated with autoimmune thyroid diseases. Now it is thought to be autoimmune and its treatment with glucocorticoid is helpful. However, it has not been evaluated. METHODS: A prospective randomized controlled trial was performed in 110 patients with PTM to evaluate the efficacy and safety of triamcinolone acetonide with intralesional injection once every 3 days and once every 7 days. Randomization was performed with drawing lots and it was also stratified according to variants of PTM lesions. In the follow-up, recurrent rates were observed. The SPSS Statistics 17.0 Software was used in the statistical analysis. RESULTS: The complete response rates were 78.2%, 83.6%, and 87.3% in regimen 1 and 50.9%, 89.1%, and 90.9% in regimen 2 at 3 weeks, 7 weeks and the end of therapy, respectively. Regimen 1 had an earlier efficacy than regimen 2, but at 7 weeks and end of therapy, there were no differences between two regimens. The majority of non-severe variants got complete response but severe variants did not. The adverse reaction rates in regimen 1 were higher and earlier than those in regimen 2. Adverse reaction occurring time in regimen 1 was shorter than that in regimen 2. Recurrent rates were 31.25% and 32% in regimens 1 and 2 at 3.5-year follow-up. CONCLUSIONS: For its autoimmune, hyperplasia and disabled features, early treatment of PTM with glucocorticoid is necessary to get complete response. Dosage and frequency of intralesional steroid injection and lesional variants influence the efficacy of PTM. Once every 7 days is a better regimen.

[The effect of the fluticasone propionate to the dynamic process of the nasal mucosal remodeling in allergic rhinitis of the rats model].

OBJECTIVE: To investigate the dynamic process of the nasal mucosal remodeling, and the effect of the fluticasone propionate (FP) to remodeling, by establish animal model of allergic rhinitis (AR). METHOD: One hundred and twenty Sprague-Dawley (SD) rats were randomly divided into three groups: the normal Group A used as controls and experimental groups: Group B and C, each group had 40 rats. After the animal model were established successfully by OVA+ Al (OH)3 and disposed, then, the dynamic process of the nasal mucosal remodeling was observed, through HE staining and transmission electron microscopic section in special times. RESULT: The Group B, C nasal epithelium and cilia were not complete, eosinophil-based inflammatory cell infiltration, basement membrane thickening, collagen deposition, and a small amount of fibrosis could be found, but the structure of cells were not damaged. While those changes could not be observed in the Group A. The morphological changes of the nasal mucosa of Group B aggravated gradually under persistent allergen exposure, even stripped to the basement membrane in whole epithelial layers, cell and tissue structure were destroyed seriously. The morphological changes of nasal mucosa of Group C did not further increase, but still showed varying degrees of cilia arranged in uneven fashion, basement membrane thickening, collagen deposition and fibrous hyperplasia after treatment by FP. CONCLUSION: Remodeling happens in the nasal mucosa, which would be aggravated, and even becomes irreversible if the allergen exposure continues persistently. The FP can relieve the clinical symptoms, slow down and even reverse the remodeling of AR. And it is ineffective when the changes become irreversible.

[The dynamic expression of the TGF-beta1 and FGF-2 in the nasal mucosa in the allergic rhinitis rat models].

OBJECTIVE: To investigate the dynamic expression of the TGF-beta1 and FGF-2 in the nasal mucosa of rat models of allergic rhinitis, at different stages of the process during pathogenesis. METHOD: One hundred and eighty Sprague-Dawley (SD) rats were randomly divided into three groups, the normal Group A used for contrast and experimental groups: Group B and C, each group were 60 rats. Then, observed the expression of the TGF-beta1 and FGF-2 in the nasal mucosa at different stages of the process by immunohistochemical staining. RESULT: The expression of the TGF-beta1 and FGF-2 in the nasal mucosa of the normal Group A was negative, while the Group B and Group C were varying degrees of positive both, and Group B, the level of the TGF-beta1 and FGF-2 were both decline after allergen avoidance, but still more not ability than the expression of the Group B (P < 0.05). CONCLUSION: The expression of the TGF-beta1 and FGF-2 in the nasal mucosa of rats models were varying degrees of positive , and it is decline while the allergen avoidance.

Localization of Kv1.3 channels in presynaptic terminals of brainstem auditory neurons.

Elimination of the Kv1.3 voltage-dependent potassium channel gene produces striking changes in the function of the olfactory bulb, raising the possibility that this channel also influences other sensory systems. We have examined the cellular and subcellular localization of Kv1.3 in the medial nucleus of the trapezoid body (MNTB) in the auditory brainstem, a nucleus in which neurons fire at high rates with high temporal precision. A clear gradient of Kv1.3 immunostaining along the lateral to medial tonotopic axis of the MNTB was detected. Highest levels were found in the lateral region of the MNTB, which corresponds to neurons that respond selectively to low-frequency auditory stimuli. Previous studies have demonstrated that MNTB neurons and their afferent inputs from the cochlear nucleus express three other members of the Kv1 family, Kv1.1, Kv1.2, and Kv1.6. Nevertheless, confocal microscopy of MNTB sections coimmunostained for Kv1.3 with these subunits revealed that the distribution of Kv1.3 differed significantly from other Kv1 family subunits. In particular, no axonal staining of Kv1.3 was detected, and most prominent labeling was in structures surrounding the somata of the principal neurons, suggesting specific localization to the large calyx of Held presynaptic endings that envelop the principal cells. The presence of Kv1.3 in presynaptic terminals was confirmed by coimmunolocalization with the synaptic markers synaptophysin, syntaxin, and synaptotagmin and by immunogold electron microscopy. Kv1.3 immunogold particles in the terminals were arrayed along the plasma membrane and on internal vesicular structures. To confirm these patterns of staining, we carried out immunolabeling on sections from Kv1.3(-/-) mice. No immunoreactivity could be detected in Kv1.3(-/-) mice either at the light level or in immunogold experiments. The finding of a tonotopic gradient in presynaptic terminals suggests that Kv1.3 may regulate neurotransmitter release differentially in neurons that respond to different frequencies of sound.

Altered functional properties of satellite glial cells in compressed spinal ganglia.

The cell bodies of sensory neurons in the dorsal root ganglion (DRG) are enveloped by satellite glial cells (SGCs). In an animal model of intervertebral foraminal stenosis and low-back pain, a chronic compression of the DRG (CCD) increases the excitability of neuronal cell bodies in the compressed ganglion. The morphological and electrophysiological properties of SGCs were investigated in both CCD and uninjured, control lumbar DRGs. SGCs responded within 12 h of the onset of CCD as indicated by an increased expression of glial fibrillary acidic protein (GFAP) in the compressed DRG but to lesser extent in neighboring or contralateral DRGs. Within 1 week, coupling through gap junctions between SGCs was significantly enhanced in the compressed ganglion. Under whole-cell patch clamp recordings, inward and outward potassium currents, but not sodium currents, were detected in individual SGCs. SGCs enveloping differently sized neurons had similar electrophysiological properties. SGCs in the compressed vs. control DRG exhibited significantly reduced inwardly rectifying potassium currents (Kir), increased input resistances and positively shifted resting membrane potentials. The reduction in Kir was greater for nociceptive medium-sized neurons compared to non-nociceptive neurons. Kir currents of SGCs around spontaneously active neurons were significantly reduced 1 day after compression but recovered by 7 days. These data demonstrate rapid alterations in glial membrane currents and GFAP expression in close temporal association with the development of neuronal hyperexcitability in the CCD model of neuropathic pain. However, these alterations are not fully sustained and suggest other mechanisms for the maintenance of the hyperexcitable state.