Formononetin Inhibits Mast Cell Degranulation to Ameliorate Compound 48/80-Induced Pseudoallergic Reactions.

Formononetin (FNT) is a plant-derived isoflavone natural product with anti-inflammatory, antioxidant, and anti-allergic properties. We showed previously that FNT inhibits immunoglobulin E (IgE)-dependent mast cell (MC) activation, but the effect of FNT on IgE-independent MC activation is yet unknown. Our aim was to investigate the effects and possible mechanisms of action of FNT on IgE-independent MC activation and pseudoallergic inflammation. We studied the effects of FNT on MC degranulation in vitro with a cell culture model using compound C48/80 to stimulate either mouse bone marrow-derived mast cells (BMMCs) or RBL-2H3 cells. We subsequently measured ß-hexosaminase and histamine release, the expression of inflammatory factors, cell morphological changes, and changes in NF-κB signaling. We also studied the effects of FNT in several in vivo murine models of allergic reaction: C48/80-mediated passive cutaneous anaphylaxis (PCA), active systemic anaphylaxis (ASA), and 2,4-dinitrobenzene (DNCB)-induced atopic dermatitis (AD). The results showed that FNT inhibited IgE-independent degranulation of MCs, evaluated by a decrease in the release of ß-hexosaminase and histamine and a decreased expression of inflammatory factors. Additionally, FNT reduced cytomorphological elongation and F-actin reorganization and attenuated NF-κB p65 phosphorylation and NF-κB-dependent promoter activity. Moreover, the administration of FNT alleviated pseudoallergic responses in vivo in mouse models of C48/80-stimulated PCA and ASA, and DNCB-induced AD. In conclusion, we suggest that FNT may be a novel anti-allergic drug with great potential to alleviate pseudoallergic responses via the inhibition of IgE-independent MC degranulation and NF-κB signaling.

[Clinical Outcome and Risk Factors of Treatment Failure of Peritoneal Dialysis Associated Peritonitis Caused by Klebsiella Pneumoniae:A Multicenter Study].

Objective To investigate the treatment outcomes,prognosis,and risk factors of treatment failure of peritoneal dialysis associated peritonitis (PDAP) caused by Klebsiella pneumoniae,and thus provide clinical evidence for the prevention and treatment of this disease. Methods The clinical data of PDAP patients at four peritoneal dialysis centers from January 1,2014 to December 31,2019 were collected retrospectively.The treatment outcomes and prognosis were compared between the patients with PDAP caused by Klebsiella.pneumoniae and that caused by Escherichia coli.Kaplan-Meier method was employed to establish the survival curve of technical failure,and multivariate Logistic regression to analyze the risk factors of the treatment failure of PADP caused by Klebsiella pneumoniae. Results In the 4 peritoneal dialysis centers,1034 cases of PDAP occurred in 586 patients from 2014 to 2019,including 21 cases caused by Klebsiella pneumoniae and 98 cases caused by Escherichia coli.The incidence of Klebsiella pneumoniae caused PDAP was 0.0048 times per patient per year on average,ranging from 0.0024 to 0.0124 times per patient per year during 2014-2019.According to the Kaplan-Meier survival curve,the technical failure rate of Klebsiella pneumoniae caused PDAP was higher than that of Escherichia coli caused PDAP (P=0.022).The multivariate Logistic regression model showed that long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP (OR=1.082,95%CI=1.011-1.158,P=0.023).Klebsiella pneumoniae was highly sensitive to amikacin,meropenem,imipenem,piperacillin,and cefotetan,and it was highly resistant to ampicillin (81.82%),cefazolin (53.33%),tetracycline (50.00%),cefotaxime (43.75%),and chloramphenicol (42.86%). Conclusion The PDAP caused by Klebsiella pneumoniae had worse prognosis than that caused by Escherichia coli,and long-term dialysis was an independent risk factor for the treatment failure of Klebsiella pneumoniae caused PDAP.

Natural isoflavone formononetin inhibits IgE-mediated mast cell activation and allergic inflammation by increasing IgE receptor degradation.

Immunoglobulin (Ig)E-associated mast cell (MC) activation triggers pro-inflammatory signals that underlie type I allergic diseases. Here, we examined the effects of the natural isoflavone formononetin (FNT) on IgE-mediated MC activation and associated mechanisms of high-affinity IgE receptor (FcεRI) signal inhibition. The effects of FNT on the mRNA expression of inflammatory factors, release of histamine and ß-hexosaminidase (ß-hex), and expression of signaling proteins and ubiquitin (Ub)-specific proteases (USPs) were analyzed in two sensitized/stimulated MC lines. FcεRIγ-USP interactions were detected by co-immunoprecipitation (IP). FNT dose-dependently inhibited ß-hex activity, histamine release, and inflammatory cytokine expression in FcεRI-activated MCs. FNT suppressed IgE-induced NF-κB and MAPK activity in MCs. The oral administration of FNT attenuated passive cutaneous anaphylaxis (PCA) reactions and ovalbumin (OVA)-induced active systemic anaphylaxis (ASA) reactions in mice. FNT reduced the FcεRIγ chain expression, via increased proteasome-mediated degradation, and induced FcεRIγ ubiquitination by inhibiting USP5 and/or USP13. FNT and USP inhibition may be useful for suppressing IgE-mediated allergic diseases.

Risk factors for mortality within 6 mo in patients with diabetes undergoing urgent-start peritoneal dialysis: A multicenter retrospective cohort study.

BACKGROUND: The risk of early mortality of patients who start dialysis urgently is high; however, in patients with diabetes undergoing urgent-start peritoneal dialysis (USPD), the risk of, and risk factors for, early mortality are unknown. AIM: To identify risk factors for mortality during high-risk periods in patients with diabetes undergoing USPD. METHODS: This retrospective cohort study enrolled 568 patients with diabetes, aged ≥ 18 years, who underwent USPD at one of five Chinese centers between 2013 and 2019. We divided the follow-up period into two survival phases: The first 6 mo of USPD therapy and the months thereafter. We compared demographic and baseline clinical data of living and deceased patients during each period. Kaplan-Meier survival curves were generated for all-cause mortality according to the New York Heart Association (NYHA) classification. A multivariate Cox proportional hazard regression model was used to identify risk factors for mortality within the first 6 mo and after 6 mo of USPD. RESULTS: Forty-one patients died within the first 6 mo, accounting for the highest proportion of mortalities (26.62%) during the entire follow-up period. Cardiovascular disease was the leading cause of mortality within 6 mo (26.83%) and after 6 mo (31.86%). The risk of mortality not only within the first 6 mo but also after the first 6 mo was higher for patients with obvious baseline heart failure symptoms than for those with mild or no heart failure symptoms. Independent risk factors for mortality within the first 6 mo were advanced age [hazard ratio (HR: 1.908; 95%CI: 1.400-2.600; P < 0.001), lower baseline serum creatinine level (HR: 0.727; 95%CI: 0.614-0.860; P < 0.001), higher baseline serum phosphorus level (HR: 3.162; 95%CI: 1.848-5.409; P < 0.001), and baseline NYHA class III-IV (HR: 2.148; 95%CI: 1.063-4.340; P = 0.033). Independent risk factors for mortality after 6 mo were advanced age (HR: 1.246; 95%CI: 1.033-1.504; P = 0.022) and baseline NYHA class III-IV (HR: 2.015; 95%CI: 1.298-3.130; P = 0.002). CONCLUSION: To reduce the risk of mortality within the first 6 mo of USPD in patients with diabetes, controlling the serum phosphorus level and improving cardiac function are recommended.

[Clinical Characteristics and Treatment Outcome of Pseudomonas Peritoneal Dialysis-associated Peritonitis].

Objective To explore the clinical characteristics and treatment of Pseudomonas peritoneal dialysis-associated peritonitis(PsP). Methods The data of patients receiving peritoneal dialysis in four tertiary hospitals in Jilin province from 2015 to 2019 were retrospectively analyzed.According to the etiological classification,the patients with peritoneal dialysis-associated peritonitis(PDAP)were classified into PsP group and non-PsP group.The incidence of PsP was calculated,and the clinical characteristics and treatment outcomes of the two groups were compared.Kaplan-Meier method was used to draw the survival curve,and Cox regression was performed to analyze the risk factors affecting the technical failure of PsP.The treatment options of Pseudomonas aeruginosa-caused PDAP and the drug sensitivity of PsP were summarized. Results A total of 1530 peritoneal dialysis patients with complete data were included in this study,among which 439 patients had 664 times of PDAP.The incidence of PsP was 0.007 episodes/patient-year.PsP group had higher proportion of refractory peritonitis(41.38% vs.19.69%,P=0.005),lower cure rate(55.17% vs.80.79%, P=0.001),and higher extubation rate(24.14% vs.7.09%,P=0.003)than non-PsP group.The technical survival rate of PsP group was lower than that of non-PsP group(P<0.001).Multivariate Cox regression analysis showed that Pseudomonas aeruginosa was an independent risk factor for technical failure in patients with PsP(HR=9.020,95%CI=1.141-71.279,P=0.037).Pseudomonas was highly sensitive to amikacin,meropenem,and piperacillin-tazobactam while highly resistant to compound sulfamethoxazole,cefazolin,and ampicillin. Conclusion The treatment outcome of PsP is worse than that of non-PsP,and Pseudomonas aeruginosa is an independent risk factor for technical failure of PsP.

Comparison of clinical features and outcomes in peritoneal dialysis-associated peritonitis patients with and without diabetes: A multicenter retrospective cohort study.

BACKGROUND: The number of end-stage renal disease patients with diabetes mellitus (DM) who are undergoing peritoneal dialysis is increasing. Peritoneal dialysis-associated peritonitis (PDAP) is a serious complication of peritoneal dialysis leading to technical failure and increased mortality in patients undergoing peritoneal dialysis. The profile of clinical symptoms, distribution of pathogenic organisms, and response of PDAP to medical management in the subset of end-stage renal disease patients with DM have not been reported previously. Discrepant results have been found in long-term prognostic outcomes of PDAP in patients with DM. We inferred that DM is associated with bad outcomes in PDAP patients. AIM: To compare the clinical features and outcomes of PDAP between patients with DM and those without. METHODS: In this multicenter retrospective cohort study, we enrolled patients who had at least one episode of PDAP during the study period. The patients were followed for a median of 31.1 mo. They were divided into a DM group and a non-DM group. Clinical features, therapeutic outcomes, and long-term prognostic outcomes were compared between the two groups. Risk factors associated with therapeutic outcomes of PDAP were analyzed using multivariable logistic regression. A Cox proportional hazards model was constructed to examine the influence of DM on patient survival and incidence of technical failure. RESULTS: Overall, 373 episodes occurred in the DM group (n = 214) and 692 episodes occurred in the non-DM group (n = 395). The rates of abdominal pain and fever were similar in the two groups (P > 0.05). The DM group had more infections with coagulase-negative Staphylococcus and less infections with Escherichia coli (E. coli) as compared to the non-DM group (P < 0.05). Multivariate logistic regression analysis revealed no association between the presence of diabetes and rates of complete cure, catheter removal, PDAP-related death, or relapse of PDAP (P > 0.05). Patients in the DM group were older and had a higher burden of cardiovascular disease, with lower level of serum albumin, but a higher estimated glomerular filtration rate (P < 0.05). Cox proportional hazards model confirmed that the presence of diabetes was a significant predictor of all-cause mortality (hazard ratio = 1.531, 95% confidence interval: 1.091-2.148, P < 0.05), but did not predict the occurrence of technical failure (P > 0.05). CONCLUSION: PDAP patients with diabetes have similar symptomology and are predisposed to coagulase-negative Staphylococcus but not E. coli infection compared those without. Diabetes is associated with higher all-cause mortality but not therapeutic outcomes of PDAP.

Anionic glycosylated polysulfone membranes for the affinity adsorption of low-density lipoprotein via click reactions.

An anionic glycosylated polysulfone (PSf) membrane was prepared as a high-affinity adsorbent for low-density lipoprotein (LDL). The UV-induced grafting of acrylic acid to the membrane was followed by amidation and a 'thiol-yne' click reaction to achieve glycosylation and sulfonation. Membrane modification was confirmed by attenuated total reflectance-Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy. These tests revealed that the chemical compositions of the membranes' surfaces were easily regulated by controlling the 'thiol-yne' click reaction through the feed ratio of 2,3,4,6-tetra-O-acetyl-1-thio-ß-d-glucopyranose and sodium 3-mercapto-1-propanesulfonate. LDL adsorption and desorption rates were estimated using an enzyme-linked-immunosorbent assay, which revealed that the obtained anionic glycosylated PSf membrane had a higher affinity for LDL than either glycosylated or sulfonated membranes alone. The combination of glycosyl and sulfonyl groups enhanced the membranes' affinities for LDL. The modified PSf membrane had an excellent biocompatibility and adsorbed a large amount of LDL, making it a promising material for LDL apheresis. STATEMENT OF SIGNIFICANCE: Low-density lipoprotein (LDL) adsorbents normally contain negative charged ligand to induce electrostatic interaction with the positively charged regions of LDL. Furthermore, saccharide is another common component which share in most of the LDL-adsorbents and the LDL-receptor (LDLR). Such structural similarity impels us to investigate the synergistic effect of anionic and saccharide on LDL recognition. For this purpose, an anionic glycosylated membrane of which surface composition can be controlled by click reaction with mutable glycosyl/sulfonyl ratios was prepared. The obtained membrane showed better LDL adsorption/desorption property and the adsorption amount for LDL at an optimum feed ratio. This finding highlights the role of synergistic effect of anionic and saccharide, which offer a new strategy for designing LDL adsorbent with high efficiency.

What's the Optimal Lipids Level for Dialysis Patients? A Cohort Study from a Chinese Dialysis Center in a University Hospital.

BACKGROUND: With lipid level being a major contributing factor for cardiovascular health, the high cardiovascular mortality among dialysis patients has raised substantial concerns in regard to the optimal lipid level in these patient population. OBJECTIVE: To explore the optimal lipid level for the survival of dialysis patients. METHODS: The lipid profile was measured for each patient. All participants were followed throughout the course of the study. Cox proportional hazards analysis was performed to analyze the prognostic value of lipid level on the survival of these patients. RESULTS: In our study that included 311 stable maintenance dialysis patients, 54.98% of the participants had LDL-C level ≥100 mg/dl and 82.91% of the patients with triglycerides ≥200 mg/dl had non-HDL level ≥130 mg/dl. During the follow-up period of 48.0 (18.0, 55.5) months, 149 (47.91%) participants died. Among those who died, 59 patients died of cardiovascular disease (CVD) and 33 patients died of ischemic CVD (12.0, 4.7, and 2.7 events per 100 patient-years, respectively). Patients with LDL-C 100-130 mg/dl or non-HDL 130-160 mg/dl had a lower all-cause mortality rate than those who did not meet these criteria. After adjusting for the traditional and ESRD-related risk factors, non-HDL was found to be the independent risk factor for the all-cause mortality. Compared to those patients with non-HDL 130-160 mg/dl, patients with non-HDL <100 mg/dl, 100-130 mg/dl, 160-190 mg/dl, or ≥190 mg/dl all had higher all-cause mortality: HR (95% CI) 3.207 (1.801, 5.713), 2.493 (1.485, 4.184), 2.476 (1.423, 4.307), and 1.917 (1.099, 3.345), respectively. There were no differences in nutrition, comorbidity, and inflammation indices among the patients with different non-HDL groups. However, patients with non-HDL of 130-160 mg/dl had the lowest corrected calcium and calcium phosphate product values as compared with other non-HDL groups. CONCLUSION: Our study demonstrated that non-HDL 130-160 mg/dl might be the most appropriate lipid level in our dialysis patients. Our follow-up data also showed that patients with higher lipid level had poorer prognosis, just as in the general population.

[Research on chemical constituents from stem of Gymnema sylvestre].

OBJECTIVE: To study on the chemical constituents from the stem of Gymnema sylvestre. METHODS: The constituents were extracted by percolation with ethanol. Then the extract was separated by systemic solvent separation methods. The part of n-butanol extract was isolated and purified by macroporous adsorptive resins, silica gel column chromatography, sephadex gel column chromatography and recrystallization. The isolated compounds were identified by spectrum methods. RESULTS: Eight compounds were isolated and identified as fallows: Conduritol A(I), 1-Heptadecanol(II), Stigmasterol glucoside(III), 1-Quercitol(IV), 1-Octadecanol(V), Potassium nitrate(VI), Lupeol cinnamate(VII), Stigmasterol(VIII). CONCLUSION: Chemical compounds II, III, V, VII are firstly obtained from this plant.