Factors for predicting the outcome of surgery for non-eosinophilic chronic rhinosinusitis with nasal polyps.

BACKGROUND: Despite the large patient base in Asia, the prognostic factors of patients with non-eosinophilic chronic rhinosinusitis with nasal polyps (CRSwNP) remain largely undetermined. OBJECTIVE: We aimed to systematically investigate the predictive value of clinical and biological variables for non-eosinophilic CRSwNP. METHODS: Fifty-one patients with non-eosinophilic CRSwNP who underwent functional endoscopic surgery were recruited. Clinical information and assessment were comprehensively collected before and after surgery. A broad spectrum of biomarkers was measured in tissue homogenates using multiple assays. A random forest algorithm and stepwise logistic regression were used to construct clinical, biological, and combined models. RESULTS: A total of 41.2% of non-eosinophilic CRSwNP patients were uncontrolled more than 6 months after surgery. We identified one clinical variable (22-item Sino-Nasal Outcome Test score) and four biomarkers (programmed cell death ligand 1, platelet-derived growth factor subunit B [PDGF-ß], macrophage inflammatory protein-3b, and PDGF-α) that were significantly predictive of the surgical outcome. The clinical, biological, and combined models showed predictive ability with areas under the curve of 0.78, 0.83, and 0.89, respectively. PDGF-ß and programmed cell death ligand 1 were identified as independent biomarkers for the prognosis of patients with CRSwNP without considerable eosinophilic infiltration. CONCLUSION: This study shows that clinical and biological factors, such as the 22-item Sino-Nasal Outcome Test score and PDGF-ß, are predictive of the post-functional endoscopic surgical prognosis of non-eosinophilic CRSwNP patients.

Comparing Protein and Gene Expression Signature between Nasal Polyps and Nasal Fluids in Chronic Rhinosinusitis.

INTRODUCTION: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a serious inflammatory condition. Nasal fluids (NFs) present a noninvasive alternative to nasal biopsy for studying CRSwNP pathogenesis. We aimed to compare the protein and mRNA inflammation signature between nasal polyps (NPs) and NFs. METHOD: The performance of polyvinyl alcohol (PVA) sponges and NFs absorbable device (NFAD) for collecting NFs from 20 patients with CRSwNP was compared using the Luminex assay. The other group consisted of four healthy controls and an additional 21 CRSwNP patients (including eosinophilic CRSwNP [ECRSwNP] and non-eosinophilic CRSwNP [NECRSwNP]) for protein quantification by Olink platform and gene expression evaluation by RNA-sequencing. Spearman's analysis was performed to detect correlations between protein expression levels in NFs and clinical assessment variables. RESULTS: NFAD-collected NFs contained at least a 2-fold higher concentration of cytokines than that obtained using PVA sponge, and these cytokines levels are significantly associated with NPs (ρ > 0.45, p < 0.05). Differentially expressed proteins between NFs and NPs were significantly correlated in the ECRSwNP subgroup compared with controls (ρ = 0.41, p < 0.01). Levels of Th2/IL-13, MCP4, and CCL4, characteristic of eosinophilic infiltration, were increased in ECRSwNP patients. A significant correlation between gene and protein expression was observed (ρ = 0.34, p < 0.01). PDL2 levels in NFs were positively correlated with ECRSwNP postoperative recurrence, the nasal VAS, and SNOT-22 scores (ρ > 0.68, p < 0.05 for all). CONCLUSION: Our study revealed similarities and discrepancies in inflammatory signatures between NPs and NFs in the same CRSwNP patient.

The SMYD3-dependent H3K4me3 status of IGF2 intensifies local Th2 differentiation in CRSwNP via positive feedback.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous and common upper airway disease divided into various inflammatory endotypes. Recent epidemiological findings showed a T helper 2 (Th2)-skewed dominance in CRSwNP patients. Histone modification alterations can regulate transcriptional and translational expression, resulting in abnormal pathogenic changes and the occurrence of diseases. Trimethylation of histone H3 lysine 4 (H3K4me3) is considered an activator of gene expression through modulation of accessibility for transcription, which is closely related to CRSwNP. H3K4me3 levels in the human nasal epithelium may change under Th2-biased inflammatory conditions, resulting in exaggerated local nasal Th2 responses via the regulation of naïve CD4+ T-cell differentiation. Here, we revealed that the level of SET and MYND domain-containing protein 3 (SMYD3)-mediated H3K4me3 was increased in NPs from Th2 CRSwNP patients compared with those from healthy controls. We demonstrated that SMYD3-mediated H3K4me3 is increased in human nasal epithelial cells under Th2-biased inflammatory conditions via S-adenosyl-L-methionine (SAM) production and further found that the H3K4me3high status of insulin-like growth factor 2 (IGF2) produced in primary human nasal epithelial cells could promote naïve CD4+ T-cell differentiation into Th2 cells. Moreover, we found that SAM production was dependent on the c-Myc/methionine adenosyltransferase 2A (MAT2A) axis in the nasal epithelium. Understanding histone modifications in the nasal epithelium has immense potential utility in the development of novel classes of therapeutics targeting Th2 polarization in Th2 CRSwNP. Video Abstract.

Impact of obstructive sleep apnea on cancer risk: a systematic review and meta-analysis.

PURPOSE: We aimed to study the effect of obstructive sleep apnea (OSA) on cancer risk. METHODS: We searched PubMed, Embase, and Cochrane databases for relevant studies. The qualities of included studies were assessed using Newcastle-Ottawa Scale (NOS). Unadjusted and adjusted analyses were performed. We also conducted subgroup analyses stratified by gender, severity of OSA, study design, and cancer type. RESULTS: After literatures search, 18 studies were included in the present study. In the unadjusted analysis, we discovered an increased cancer risk in patients with OSA with a pooled relative risk (RR) in the OSA group of 1.49 (95% confidence interval (CI): 1.32-1.69, I2 = 32%, P = 0.15). In adjusted analysis, OSA correlated with cancer risk (RR: 1.36, 95% CI: 1.18-1.56, I2 = 54%, P < 0.01). In subgroup stratified by gender and OSA severity, OSA statistically with cancer risk in females (RR: 1.27, 95% CI: 1.06-1.51) and moderate to severe OSA groups (RR: 2.62, 95% CI: 1.64; 4.19). In subgroup stratified by study design, a trend toward statistically significant differences was observed in prospective studies (RR: 1.21, 95% CI: 0.99-1.48) and cross-sectional studies (RR: 1.81, 95% CI: 0.96-3.41). Patients with OSA in the retrospective study group had a statistically higher chance of developing cancer (RR: 1.41, 95% CI: 1.11-1.79). When stratified by cancer group, statistically significant differences was observed in many types of cancer (breast cancer: RR: 1.32, 95% CI: 1.03-1.70; central nervous system cancer: RR: 1.71, 95% CI: 1.06-2.75; kidney cancer: RR: 1.81, 95% CI: 1.20-2.74; liver cancer: RR: 1.19, 95% CI: 1.10-1.29; and pancreatic cancer: RR: 1.23, 95% CI: 1.14-1.33). CONCLUSIONS: This systematic review and meta-analysis suggests that obstructive sleep apnea may increase risk of cancer.

Multicharge ß-cyclodextrin supramolecular assembly for ATP capture and drug release.

A hyaluronidase-responsive polysaccharide supramolecular assembly was constructed from an amphiphilic ß-cyclodextrin bearing seven hexylimidazolium units (AMCD), adamantyl-grafted hyaluronic acid, and chlorambucil, which showed specific cancer cell targeting and controlled drug release abilities. Interestingly, ternary supramolecular assembly can disassemble in the presence of hyaluronidase, and the released AMCD can assemble with ATP to form a stable 1 : 1 complex, which enhanced the efficacy of chlorambucil on cancer chemotherapy by inhibiting ATP hydrolysis.

Flavone protects HBE cells from DNA double-strand breaks caused by PM2.5.

Ambient air particulate matter 2.5 (PM2.5) contains many harmful components that can enter the circulatory system and produce reactive oxygen species (ROS) in body. Oxidative stress and DNA damage induced by ROS may affect any cellular macromolecule and lead to DNA double-strand breaks (DSBs). Flavonoids, widely distributed in some herbs and berries, have been proved having anti-oxidative or anti-cancer efficacy. In this study, we investigated whether Flavone, a kind of flavonoids, can protect human bronchial epithelial cells (HBE) from DSBs caused by PM2.5 and how this function is probably implemented. We found that cells exposed to PM2.5 obviously induced viability inhibition, DNA damage and part of apoptosis. However, Flavone treatment prior to PM2.5 apparently improved cell viability, and mitigated the formation of 8-hydroxy-2-deoxyguanosine, the expression of DNA damage-relative protein and cell apoptosis. Our studies demonstrated that PM2.5 induced oxidative DSBs while Flavone ameliorated the DNA damage and increased cell viability probably through influencing DNA repair mechanism of cells.

An in vivo study of hypoxia-inducible factor-1α signaling in ginsenoside Rg1-mediated brain repair after hypoxia/ischemia brain injury.

BACKGROUND: Hypoxia/ischemia (HI) brain injury is a common central nervous system insult in newborns. Studies have demonstrated bioactivity of ginsenoside Rg1 in increasing neural viability and promoting angiogenesis. However, there are few reports on roles of Rg1 in brain repair of neonatal HI, and the mechanisms involved are unclear. METHODS: a neonatal HI model was established by a modified Rice-Vannucci model (RVM) and pups received ginsenoside Rg1 or monosialotetrahexosyl ganglioside (GM1) treatment. Neurological function and pathologic damage of rats were evaluated. Cellular apoptosis was detected with Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Immunohistochemistry for von willebrand factor (vwf) was used to label micro vessels. Expression levels of hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and cleaved caspase 3 (CC3) were detected by western blot. RESULTS: Both Rg1 and GM1 reduced neurological impairment and pathologic damage after HI by enhancing neural survival. Rg1, but not GM1, could also facilitate angiogenesis after HI. These pharmacological effects of Rg1 may be attributed to regulation of expression level of VEGF and CC3 and HIF-1α signaling pathway was involved. CONCLUSION: Rg1 plays a neuroprotective role in brain repair following neonatal HI, and HIF-1α is a potential target for therapeutic intervention in neonates with HI brain injury.

[ROLE OF EXTRACELLULAR SIGNAL-RELATED PROTEIN KINASE 1/2 PATHWAY IN GINSENOSIDE Rg1 MEDIATED ANTI-APOPTOTIC EFFECT ON NEURON AFTER HYPOXIA ISCHEMIA BRAIN DAMAGE IN NEONATAL RATS].

OBJECTIVE: To investigate the anti-apoptotic effect of ginsenoside Rg1 in neonatal rats with hypoxia ischemia brain damage (HIBD), and to explore the possible signaling pathway involved in anti-apoptosis. METHODS: Forty-eight 10-day-old Sprague Dawley (SD) rats (weighing 17-21 g, male or female) were randomly allocated into 4 groups (12 rats in each group): sham-operation group (sham group), HIBD group (HI group), HIBD+ginsenoside Rg1 group (HI+Rg1 group), and HIBD+ginsenoside Rg1+U0126 group (HI+Rg1+U0126 group). SD rats in HI group, HI+Rg1 group, and HI+Rg1+U0126 group underwent ligation of the right common carotid artery (CCA) and hypoxic ventilation (8%O2+92%N2) for 2.5 hours to prepare the HIBD model, and rats in sham group underwent only separation of the right CCA. SD rats in HI+Rg1+U0126 group received intraventricular injection of 5 µL phosphate buffer saline (PBS) containing U0126 (25 µg/kg) at 1 hour before HIBD, and rats in the other three groups received intraventricular injection of PBS at the same time. The rats in HI+Rg1 group and HI+Rg1+U0126 group received intraperitoneal injection of 0.1 mL normal saline (NS) containing Rg1 (40 mg/kg) at immediate after HIBD, while rats in HI group and sham group received intraperitoneal injection of 0.1 mL NS at immediate after HIBD. At 4 and 24 hours after HIBD, the right hemisphere and hippocampus were collected to detect the protein expression and distribution of extracellular signal-related protein kinase 1/2 (Erk1/2), phospho-Erk1/2 (p-Erk1/2), hypoxia inducible factor 1α (HIF-1α), and cleaved Caspase-3 (CC3) by Western blot and immunohistochemistry staining. TUNEL staining was used to evaluate neural apoptosis in situ. RESULTS: Western blot results showed that there were expressions of Erk1/2, p-ERK1/2, HIF-1α, and CC3 proteins at 4 and 24 hours after HIBD in each group. The expressions of HIF-1α and CC3 protein at 4 and 24 hours, and expression of p-Erk1/2 protein at 4 hours were significantly increased in HI group when compared with sham group (P<0.05). When compared with HI group, the expressions of p-Erk1/2 and HIF-1α protein in HI+Rg1 group were significantly increased (P<0.05), while the expression of CC3 protein was significantly decreased at 4 and 24 hours (P<0.05). When compared with HI+Rg1 group, the expressions of p-Erk1/2 and HIF-1α proteins in HI+Rg1+U0126 group were significantly decreased (P<0.05), while expression of CC3 protein was significantly increased at 4 and 24 hours (P<0.05). There was no significant difference in Erk1/2 protein expression between groups at different time points (P>0.05). Immunohistochemistry staining displayed that HIF-1α and CC3 proteins mainly distributed in the nucleus and cytoplasma, while Erk1/2 and p-Erk1/2 proteins mainly distributed in the cytoplasma. The expression levels of protein by immunohistochemistry results were similar to the results by Western blot. TUNEL staining showed that the apoptotic neurons were characterized by yellow or brown particle in the nucleus. The apoptotic index (AI) of neurons at 4 and 24 hours was significantly increased in HI group when compared with sham group (P<0.05), and the AI of neurons was significantly decreased in HI+Rg1 group when compared with HI group and HI+Rg1+U0126 group at 24 hours (P<0.05). CONCLUSIONS: Rg1 could enhance HIBD induced HIF-1α expression and inhibit activation of Caspase-3 by Erk1/2 signaling pathway, and play an anti-apoptotic role in neonatal rats with HIBD.

Experimental study of super paramagnetic iron oxide labeled synovial mesenchymal stem cells.

To investigate the feasibility and changes of biological characteristics before and after synovial mesenchymal stem cells (SMSCs) labelled by super paramagnetic iron oxide (SPIO). The rabbit SMSCs were isolated, cultured, purified and identified in vitro. After adding the different concentrations of SPIO-labelled liquid, the cells were incubated 24 h in 37°C carbon dioxide incubator. The labeled-cell samples were observed by Prussian blue staining, transmission electron microscope (TEM) and the cell biology before and after the labeling was compared. The blue stained particles could be seen in the cytoplasm; the SPIO label was positive in 95% SMSC cells. With the concentration of the label liquid increasing, the blue-stained cytoplasm became darker. A large number of high electron density particles could be seen in the cytoplasm and in the pinocytosis vesicles by TEM, which suggested SPIO label positive. When the SPIO concentration was (12.5~50) µg/mL, the differences in cell proliferation and cell viability between the SMSCs after labelling and the SMSCs before labelling were not significant; when the concentration was over 100 µg/mL, the cell proliferation and cell viability were inhibited. A certain concentration range of SPIO can safely label the rabbit SMSC according to this study, which is important for solving the problem of tracing SMSCs in the joints.

Phenol acidity and ease of oxidation in isoflavonoid/ß-carotene antioxidant synergism.

Regeneration of ß-carotene from the ß-carotene radical cation by the 4'-propylpuerarin anion (second-order rate constant=1.5×10(9) L mol(-1) s(-1) in methanol/chloroform=1:9 (v/v) solution at 25 °C as determined by laser flash photolysis) was found to be marginally slower than regeneration by the 7-propylpuerarin anion (2.3×10(9) L mol(-1) s(-1)), in agreement with the 7-propylpuerarin anion being more reducing (E'=0.56 V vs NHE) than the 4'-propylpuerarin anion (E'=1.01 V vs NHE). The potentials were calculated from E°=1.12 and 1.44 V (vs NHE) as determined by cyclic voltametry in aqueous solution and pKa=9.51 and 7.23 obtained previously for 7-propylpuerarin and 4'-propylpuerarin, respectively. The less reducing but more acidic 4'-propylpuerarin showed less antioxidant activity in liposome of pH 7.4, but more significant antioxidant synergism with ß-carotene than the more reducing but less acidic 7-propylpuerarin for oxidation initiated in the liposome lipid phase. Electrostatic effects are concluded to be important in the regeneration of ß-carotene from the radical cation in the water/lipid interface because approximately 50% of 4'-propylpuerarin is present as the anion, whereas only 0.5% of 7-propylpuerarin is present as the anion. In contrast, penetration of the undissociated phenolic group into the lipid phase, more significant for 7-propylpuerarin than for 4'-propylpuerarin according to the calculated water/lipid partition coefficients, becomes important for the chain-breaking action in lipid oxidation of the puerarin derivatives as models for (iso)flavonoids and their glycosides.

Thermodynamic versus kinetic control of antioxidant synergism between ß-carotene and (iso)flavonoids and their glycosides in liposomes.

Antioxidant synergism (or antagonism) between plant (iso)flavonoids (daidzein, baicalein, and quercetin) or their glycosides (puerarin, baicalin, and rutin) and ß-carotene in phosphatidylcholine liposomes (pH 7.4) with oxidation initiated thermally by the lipophilic free radical initiator 2,2'-azobis(2,4-dimethylvaleronitrile) (AMVN) and followed by the formation of conjugated dienes did not depend simply on the bond dissociation enthalpy (BDE) of the phenol O-H bond or the HOMO/LUMO energy gap based on density functional theory (DFT) calculations. Rate of regeneration of ß-carotene from the ß-carotene radical cation as the one-electron oxidation product of the lipid phase antioxidant by the monoanion form of the (iso)flavonoids in homogeneous (1:9 v/v methanol/chloroform) solution, as studied by laser flash photolysis and occurring on a microsecond time scale with biphasic kinetics, was in better agreement with the observed nonadditive antioxidative effects. However, correcting the observed (pseudo)-first-order rate constant for ß-carotene regeneration for water/lipid distribution of the (iso)flavonoids provided an almost correct ordering of the (iso)flavonoids, according to the nonadditive effects with ß-carotene on lipid oxidation.

Comparison of flavonoids and isoflavonoids as antioxidants.

The isoflavonoid genistein was found to be a better antioxidant than the isomeric flavonoid apigenin in phosphatidyl liposomes at pH 7.4. The higher antioxidation activity of genistein compared with apigenin is in agreement with its lower oxidation potential (0.73 vs 0.86 V as determined by cyclic voltammetry in aqueous solution of pH= 7.4), lower dissociation enthalpy (87.03 vs 87.88 kcal mol(-1) as calculated for the more reducing 4'-hydroxyl group), and higher radical scavenging capacity in the TEAC assay. On the basis of quantum mechanical calculations for genistein and apigenin in comparison with the flavonoid naringenin and the isoflavonoids puerarin, daidzein, and equol, a lower dipole moment and a larger deviation for the A-to-B dihedral angle from coplanarity (39.3 degrees for genistein, 18.5 degrees for apigenin) are suggested to be important for the increased antioxidant efficiency at water/lipid interfaces among (iso) flavonoids with an equal number of phenolic groups.

[Value of serum soluble interleukin-2R, interleukin-6 and C-reactive protein in the early diagnosis of Kawasaki disease].

OBJECTIVE: Immunovasculitis is a pathologic process of Kawasaki disease (KD) in the early stage and it is more likely to result from abnormal immunoactivation. It is thus speculated that the serum levels of some cytokines have changed before immunovasculitis occurs, suggesting the cytokines may be useful markers for the early diagnosis of KD. In this study, we measured the serum levels of soluble interleukin-2 receptors (sIL-2R), interleukin-6(IL-6) and high-sensitive C-reactive protein (hs-CRP) in patients with KD to evaluate the significance of these cytokines in the early diagnosis of KD. METHODS: Serum levels of sIL-2R and IL-6 were measured by rapid one-step sandwich enzyme immunoassay and the serum hs-CRP level was measured by Dade Behring BN ProSpec in 32 KD patients before and after intravenous immunoglobulin (IVIG) therapy. Twenty healthy children were used as the controls. RESULTS: Before IVIG therapy serum levels of sIL-2R (9253.41 +/- 2568.38 pg/mL vs 2161.53 +/- 696.92 pg/mL; P < 0.05), IL-6 (57.19 +/- 45.78 ng/mL vs 7.04 +/- 1.69 ng/mL; P < 0.05) and hs-CRP (117.69 +/- 42.05 mg/L vs 1.15 +/- 0.54 mg/L; P < 0.05) in KD patients were significantly higher than those in healthy controls. After IVIG therapy in KD patients serum IL-6 levels returned to normal and sIL-2R and hs-CRP levels decreased significantly but remained significantly higher than controls (P < 0.05). There was a positive correlation between sIL-2R and hs-CRP levels (r=0.60, P < 0.01). IL-6 levels positively correlated with hs-CRP levels in KD patients before IVIG therapy (r=0.68, P < 0.01). CONCLUSIONS: IL-2R, IL-6 and hs-CRP are activated in the development of KD, and they may be of important value in the early diagnosis of KD.