Iguratimod ameliorates nephritis by modulating the Th17/Treg paradigm in pristane-induced lupus.

OBJECTIVE: Iguratimod, an anti-rheumatic drug, has been widely used in the treatment of rheumatoid arthritis, but is still at an investigative stage for treatment of systemic lupus erythematosus (SLE). We examined the therapeutic effects of iguratimod and the mechanism underlying the efficacy in murine lupus model. METHODS: Pristane-induced lupus model of BALB/c mice (PI mice) were treated with iguratimod and mycophenolate mofetil. Proteinuria, anti-dsDNA antibodies and immunoglobulins production were measured. Renal pathology was evaluated. The percentage of Th17 and Treg cells in spleen and the expression of cytokines and mRNAs related to Th17 and Treg cells was analyzed. RESULTS: Iguratimod attenuated the severity of nephritis in PI mice in a dose-dependent manner. Proteinuria was continuously decreased and pathology of glomerulonephritis and tubulonephritis was significantly reduced along with reduction of glomerular immune complex deposition. Also, serum anti-dsDNA and total IgG and IgM levels were reduced by iguratimod in mice. It is worth mentioning that the efficacy of the 30 mg/kg/d iguratimod dose is comparable to, or even better than, 100 mg kg/d of mycophenolate mofetil. Furthermore, the percentage of Th17 cells was found decreased and the percentage of Treg cells increased. ROR-γt mRNA and serum cytokines (IL-17A and IL-22) of Th17 cells decreased accordingly. By contrast, Foxp3 mRNA and cytokines (TGF-ß and IL-10) of Treg cells increased. CONCLUSION: Iguratimod ameliorates nephritis of SLE and modulates the Th17/Treg ratio in murine nephritis of SLE, suggesting that Iguratimod could be an effective drug in treatment of SLE.

Bioenergetic Crosstalk between Mesenchymal Stem Cells and various Ocular Cells through the intercellular trafficking of Mitochondria.

Rationale: Mitochondrial disorders preferentially affect tissues with high energy requirements, such as the retina and corneal endothelium, in human eyes. Mesenchymal stem cell (MSC)-based treatment has been demonstrated to be beneficial for ocular degeneration. However, aside from neuroprotective paracrine actions, the mechanisms underlying the beneficial effect of MSCs on retinal and corneal tissues are largely unknown. In this study, we investigated the fate and associated characteristics of mitochondria subjected to intercellular transfer from MSCs to ocular cells. Methods: MSCs were cocultured with corneal endothelial cells (CECs), 661W cells (a photoreceptor cell line) and ARPE-19 cells (a retinal pigment epithelium cell line). Immunofluorescence, fluorescence activated cell sorting and confocal microscopy imaging were employed to investigate the traits of intercellular mitochondrial transfer and the fate of transferred mitochondria. The oxygen consumption rate of recipient cells was measured to investigate the effect of intercellular mitochondrial transfer. Transcriptome analysis was performed to investigate the expression of metabolic genes in recipient cells with donated mitochondria. Results: Mitochondrial transport is a ubiquitous intercellular mechanism between MSCs and various ocular cells, including the corneal endothelium, retinal pigmented epithelium, and photoreceptors. Additionally, our results indicate that the donation process depends on F-actin-based tunneling nanotubes. Rotenone-pretreated cells that received mitochondria from MSCs displayed increased aerobic capacity and upregulation of mitochondrial genes. Furthermore, living imaging determined the ultimate fate of transferred mitochondria through either degradation by lysosomes or exocytosis as extracellular vesicles. Conclusions: For the first time, we determined the characteristics and fate of mitochondria undergoing intercellular transfer from MSCs to various ocular cells through F-actin-based tunneling nanotubes, helping to characterize MSC-based treatment for ocular tissue regeneration.

High-Dose Electron Radiation and Unexpected Room-Temperature Self-Healing of Epitaxial SiC Schottky Barrier Diodes.

Silicon carbide (SiC) has been widely used for electronic radiation detectors and atomic battery sensors. However, the physical properties of SiC exposure to high-dose irradiation as well as its related electrical responses are not yet well understood. Meanwhile, the current research in this field are generally focused on electrical properties and defects formation, which are not suitable to explain the intrinsic response of irradiation effect since defect itself is not easy to characterize, and it is complex to determine whether it comes from the raw material or exists only upon irradiation. Therefore, a more straightforward quantification of irradiation effect is needed to establish the direct correlation between irradiation-induced current and the radiation fluence. This work reports the on-line electrical properties of 4H-SiC Schottky barrier diodes (SBDs) under high-dose electron irradiation and employs in situ noise diagnostic analysis to demonstrate the correlation of irradiation-induced defects and microscopic electronic properties. It is found that the electron beam has a strong radiation destructive effect on 4H-SiC SBDs. The on-line electron-induced current and noise information reveal a self-healing like procedure, in which the internal defects of the devices are likely to be annealed at room temperature and devices' performance is restored to some extent.

Omega-3 PUFA attenuate mice myocardial infarction injury by emerging a protective eicosanoid pattern.

Omega-3 polyunsaturated fatty acid (n-3 PUFA) supplementation is a recommended preventive approach against cardiovascular diseases, but its mechanism of protection against myocardial infarction (MI) injury is not fully understood. Eicosanoid metabolomics demonstrated an abnormal eicosanoid profile was in the plasma of mice receiving MI surgery. 19,20-EDP, 17,18-EEQ, 14,15-EET and 9,10-EpOME were decreased, and PGE2 was increased by the surgery. N-3 PUFA-rich diets feeding or transgene of Fat-1 shifted the eicosanoid profile to an n-3 PUFA dominant style and attenuated the myocardial infarction injury. Multiple logistic regression analysis suggested the degree of MI injury was related with an eicosanoid pattern, composed by eicosanoids derived from both n-3 and n-6 PUFA in the three enzymatic pathways. These results suggested the benefits of n-3 PUFA on MI was achieved synergistically.

Metabolic profiling of murine plasma reveals eicosapentaenoic acid metabolites protecting against endothelial activation and atherosclerosis.

BACKGROUND AND PURPOSE: Atherosclerosis results from a maladaptive inflammatory response initiated by the intramural retention of LDL in susceptible areas of the arterial vasculature. The ω-3 polyunsaturated fatty acids (ω-3) have protective effects in atherosclerosis; however, their molecular mechanism is still largely unknown. The present study used a metabolomic approach to reveal the atheroprotective metabolites of ω-3 and investigate the underlying mechanisms. EXPERIMENTAL APPROACH: We evaluated the development of atherosclerosis in LDL receptor-deficient mice (LDLR-/- ) fed a Western-type diet (WTD) plus ω-3 and also LDLR-/- and fat-1 transgenic (LDLR-/- -fat-1tg ) mice fed a WTD. The profiles of ω-3 in the plasma were screened by LC-MS/MS using unbiased systematic metabolomics analysis. We also studied the effect of metabolites of eicosapentaenoic acid (EPA) on endothelial activation in vitro. KEY RESULTS: The ω-3 diet and fat-1 transgene decreased monocyte infiltration, inhibited the expression of pro-inflammatory genes and significantly attenuated atherosclerotic plaque formation and enhanced plaque stability in LDLR-/- mice. The content of 18-hydroxy-eicosapentaenoic acid (18-HEPE) and 17,18-epoxy-eicosatetraenoic acid (17,18-EEQ), from the cytochrome P450 pathway of EPA, was significantly higher in plasma from both ω-3-treated LDLR-/- and LDLR-/- -fat-1tg mice as compared with WTD-fed LDLR-/- mice. In vitro in endothelial cells, 18-HEPE or 17,18-EEQ decreased inflammatory gene expression induced by TNFα via NF-κB signalling and thereby inhibited monocyte adhesion to endothelial cells. CONCLUSIONS AND IMPLICATIONS: EPA protected against the development of atherosclerosis in atheroprone mice via the metabolites 18-HEPE and/or 17,18-EEQ, which reduced endothelial activation. These compounds may have therapeutic implications in atherosclerosis. LINKED ARTICLES: This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

[Effect of sintering temperature on mechanical properties of dental zirconia toughened alumina ceramics].

PURPOSE: To investigate the effect of sintering temperature on mechanical properties of dental zirconia toughened alumina (ZTA) ceramics prepared by gel-casting technique. METHODS: The samples prepared by gel-casting were sintered at 1100, 1200, 1250, 1300 and 1400degrees centigrade for each group. The flexural strength, fracture toughness, Vickers hardness and brittleness index were obtained and microscopic morphology of each group was observed under scanning electron microscope (SEM). The data were statistically analyzed using SPSS 19.0 software package. RESULTS: The flexural strength, fracture toughness and Vickers hardness increased with the increasing sintering temperature during 1100~1400degrees centigrade. The lowest brittleness index (0.74±0.16) µm-1/2 was observed in group sintered at 1200degrees centigrade and the highest (2.76±0.14) µm-1/2 was at 1400degrees centigrade (P<0.05), while the flexural strength of these two groups was (46.89±3.24) MPa and (349.64±54.72) MPa, respectively. CONCLUSIONS: The ZTA dental ceramics exhibit good machinability with proper sintering temperature (1200degrees centigrade) and the strength meets the requirement of clinical application.

Clinical and immunological consequences of total glucosides of paeony treatment in Sjögren's syndrome: A randomized controlled pilot trial.

BACKGROUND: The total glucosides of paeony (TGP) can inhibit inflammation and alleviate symptoms in autoimmune diseases. This study investigated the clinical and immunological consequences of TGP treatment in patients with primary Sjögren's syndrome (SS). METHODS: We conducted a randomized, double-blinded, placebo-controlled clinical trial in 45 patients with primary SS. Patients were randomized at 2:1 ratio to either TGP group (n=29) or placebo group (n=16) and followed up for 24weeks. The primary outocme was the European League Against Rheumatism Sjögren's Syndrome Patient Reported Index (ESSPRI). The secondary outcomes were stimulated and unstimulated salivary flow rate, Schirmer's test and erythrocyte sedimentation rate (ESR), immuneglobulin (Ig), anti-nuclear antibody (ANA), anti-SSA, and anti-SSB. The proportions of B cells in peripheral blood and the levels of serum inerleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ) and B cell activating factor belonging to the TNF family (BAFF) were measured at baseline and at the end of follow up of 24weeks. RESULTS: The average score of ESSPRI in both groups had no statistical significance at 24th week. The mean of ESSPRI in the dry-mouth part of questionnaire in patients who scored 3 to 6 points was significantly reduced in the TGP group changed from (4.81±0.60) at baseline to (4.20±1.46) (P=0.027) at week 24. Stimulated salivary flow rate increased at week 24 from (1.80±0.39) to (2.01±0.51) (P=0.031) and unstimulated salivary flow rate increased from (0.65±0.46) to (0.78±0.45) (P=0.011) in the TGP group, but the placebo group showed no significant difference. Erythrocyte sedimentation rate (ESR) was decreased significantly compared to the placebo group at 12- and 24-week from (40.9±18.0) to (29.4±12.2) (P=0.003) and (30.4±17.3) (P=0.024). The percentage of naive B cells decreased at week 24 in the TGP group from (77.34±12.20) to (64.59±15.60) (P=0.005) while memory B cells increased from (21.79±11.97) to (34.21±15.48) (P=0.006) respectively. The concentrations of TNF-α and IFN-γ decreased in the TGP group at week 24 from (32.51±26.67) to (24.22±13.56) (P=0.017) and (10.71±8.94) to (6.55±4.88) (P=0.022), respectively. No significant difference in ANA titer, anti-SSA antibodies, anti-SSB antibodies, C3 concentration or C4 concentration was observed between the two groups. CONCLUSION: TGP appears to improve the glandular secreting function and decrease the level of inflammatory cytokines.

Phenolic composition and antioxidant activity in seed coats of 60 Chinese black soybean (Glycine max L. Merr.) varieties.

Phenolics in black soybean seed coat (BSSC) are considered to be responsible for the health benefits of black soybean. BSSCs of 60 Chinese varieties were examined for phenolic contents, anthocyanin profiles, and antioxidant activity. Total phenolic and condensed tannin contents ranged from 512.2 to 6057.9 mg gallic acid equivalents/100 g and from 137.2 to 1741.1 mg (+)-catechin equivalents/100 g, respectively. Six anthocyanins (delphinidin-3-glucoside, cyanidin-3-galactoside, cyanidin-3-glucoside, petunidin-3-glucoside, peonidin-3-glucoside, and malvidin-3-glucoside) were detected by HPLC. Total anthocyanin contents (TAC) were from 98.8 to 2132.5 mg/100 g, and cyanidin-3-glucoside was the most abundant anthocyanin in all varieties, with a distribution of 48.8-94.1% of TAC. Antioxidant properties detected by DPPH, FRAP, and ORAC methods all showed wide variations ranging from 4.8 to 65.3 µg/100 mL (expressed as EC(50)), from 17.5 to 105.8 units/g, and from 42.5 to 1834.6 µmol Trolox equivalent/g, respectively. Sixty varieties were classified into four groups by hierarchical clustering analysis, and group 4 consisting of nine varieties had the highest phytochemicals content and antioxidant activity.

Phenolic profiles and antioxidant activity of black rice bran of different commercially available varieties.

Increased consumption of whole grains has been associated with reduced risk of developing major chronic diseases. These health benefits have been attributed in part to their unique phytochemicals. Previous studies on black rice mainly focused on anthocyanins. Little is known about the phytochemical profiles and antioxidant activities of different black rice varieties. The objective of this study was to determine the phytochemical profiles and antioxidant activity of rice bran samples from 12 diverse varieties of black rice. The free, bound, and total phenolic contents of black rice bran samples ranged from 2086 to 7043, from 221.2 to 382.7, and from 2365 to 7367 mg of gallic acid equiv/100 g of dry weight (DW), respectively. The percentage contribution of free phenolics to the total ranged from 88.2 to 95.6%. The average values of free, bound, and total phenolic contents of black rice bran were 8, 1.5, and 6 times higher than those of white rice bran, respectively (p < 0.05). The free, bound, and total flavonoid contents of black rice bran samples ranged from 3462 to 12061, from 126.7 to 386.9, and from 3596 to 12448 mg of catechin equiv/100 g of DW, respectively. The percentage contribution of free flavonoids to the total ranged from 96.3 to 97.6%. The average values of free, bound, and total flavonoid contents of black rice bran were 7.4, 1.9, and 6.7 times higher than those of white rice bran, respectively (p < 0.05). The free, bound, and total anthocyanin contents of black rice bran samples ranged from 1227 to 5096, from 4.89 to 8.23, and from 1231 to 5101 mg of cyanidin-3-glucoside equiv/100 g of DW, respectively. The percentage contribution of free anthocyanins to the total ranged from 99.5 to 99.9%. Cyanidin-3-glucoside, cyanidin-3-rutinoside, and peonidin-3-glucoside were detected in black rice bran samples and ranged from 736.6 to 2557, from 22.70 to 96.62, and from 100.7 to 534.2 mg/100 g of DW, respectively. The free, bound, and total antioxidant activities of black rice bran samples ranged from 476.9 to 180, from 47.91 to 79.48, and from 537.5 to 1876 mumol of Trolox equiv/g of DW, respectively. The percentage contribution of free antioxidant activity to the total ranged from 88.7 to 96.0%. The average values of free, bound, and total antioxidant activity of black rice bran were more than 8, 1.5, and 6 times higher than those of white rice bran, respectively (p < 0.05). The total antioxidant activity of black rice bran was correlated to the content of total phenolics, total flavonoids, and total anthocyanins and also was significantly correlated to the contents of cyanidin-3-glucoside, cyanidin-3-rutinoside, and peonidin-3-glucoside. These results indicate that there are significant differences in phytochemical content and antioxidant activity among the different black rice varieties. Black rice bran has higher content of phenolics, flavonoids, and anthocyanins and has higher antioxidant activity when compared to white rice bran. Interestingly, the phenolics, flavonoids, and anthocyanins of black rice bran are mainly present in free form. Knowing the phytochemical profile and antioxidant activity of black rice bran gives insights to its potential application to promote health.

[Effect of Rhizoma pinelliae on vomiting in minks].

OBJECTIVE: To study emetic and anti-emetic effects of Rhizoma pinelliae in minks. METHOD: The emetic effect of raw pinellia 2 g kg(-1) (i.g.) was investigated. Three preparations of Rhizoma pinelliae (processed with ginger) were made by ethanol extraction, water extraction and water decoction respectively and their effects on emesis model induced by cisplatin (7.5 mg kg(-1), i.p.) or apomorphine (1.6 mg kg(-1), s.c.) were then studied; the effect of the decoction of ginger-processed Rhizoma pinelliae on rotation-induced emesis model in minks was also observed. RESULT: The emesis was induced by raw pinellia in minks (P < 0.01); ginger-processed Rhizoma pinelliae, metoclopramide and ondansetron significantly inhibit the emesis induced by cisplatin and apomorphine (P < 0.05). CONCLUSION: Ginger-processed Rhizoma pinelliae exhibits a anti-emetic effect in minks, which may be mediated by inhibiting the function of the vomiting center in central nervous system.