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Trimetazidine exhibits great therapeutic potential in cardiovascular diseases and mitochondria-mediated cardioprotection by trimetazidine has been widely reported. In this study, to enhance its cardioprotection, the triphenylphosphonium-based modification of trimetazidine was conducted to deliver it specifically to mitochondria. Fifteen triphenylphosphonium (TPP) conjugated trimetazidine analogs were designed and synthesized. Their protective effects were evaluated in vivo using a tert-butyl hydroperoxide (t-BHP) induced zebrafish injury model. Structure-activity relationship correlations revealed the best way to couple the TPP moiety to trimetazidine, and led to a new conjugate (18a) with enhanced therapeutic properties. Compared to trimetazidine, 18a effectively protects against heart injury in the zebrafish model at a much lower concentration. Further study in t-BHP treated zebrafish and H9c2 cells demonstrated that 18a protects against cardiomyocyte death and damage by inhibiting excessive production of ROS, maintaining mitochondrial morphology, and preventing mitochondrial dysfunction. Consequently, 18a can be regarded as a potential therapeutic agent for cardioprotection.

A series of mitochondria-targeted triphenylphosphonium conjugated C-3 modified betulin were synthesized and evaluated against tumor cells. As a result, a new derivative 13 i, the conjugate of 3-O-(3'-acetylphenylacetate)-betulin with triphenylphosphonium, was identified as the one with the best anti-tumor effect. Conjugate 13 i significantly inhibited HCT116 cells with IC

Background Cysteinyl leukotriene (LT) has been proposed in the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). This study sought to examine the expression of the LT receptor (LTR) in CRSwNP patients and evaluate the potential role of LTR antagonist (LTRA) in the management of eosinophilic CRSwNP (ECRS) patients. Methods Nasal polyps and uncinate process tissues were collected from 18 ECRS patients, 13 non-eosinophilic CRSwNP (non-ECRS) patients, and 16 control subjects. The messenger RNA (mRNA) and protein expression of LTR (cysteinyl leukotriene receptor 1 [CysLT1R] and cysteinyl leukotriene receptor 2 [CysLT2R]) was examined using quantitative reverse-transcription polymerase chain reaction (qRT-PCR), immunohistochemistry, and Western blot analysis. Moreover, the effects of LTRA and steroids on total nasal symptom scores (TNSS) of uncontrolled ECRS patients were evaluated. Results The mRNA and protein expression of CysLT1R and CysLT2R was significantly increased in polyp tissues compared with healthy controls (p < 0.05). Compared with the non-ECRS subset, the ECRS subset showed significantly increased expression of CysLT1R and CysLT2R, as well as leukotriene C4 (LTC4) and leukotriene D4 (LTC4) levels (p < 0.05). Moreover, combined LTRA and steroids significantly decreased TNSS more than steroids alone in uncontrolled ECRS patients (p < 0.01). Conclusion Our findings indicate that LTR was differentially expressed between ECRS and non-ECRS patients, and that LTRA may be used as an additional therapy for ECRS patients.

Background Oxidative stress is characteristic of chronic airway inflammatory diseases such as asthma, chronic obstructive pulmonary disease and chronic rhinosinusitis with nasal polyps (CRSwNP). Heme oxygenase (HO)-1 has been proposed to be a cytoprotective enzyme against oxidative stress in CRSwNP. However, the expression and regulation of HO-1 in eosinophilic CRSwNP (ECRS) and non-eosinophilic CRSwNP (non-ECRS) subsets has not been well documented. Methods Nasal polyps and uncinate process tissues were enrolled from 40 CRSwNP patients (ECRS, 17; non-ECRS, 23) and 20 control subjects, respectively. The messenger RNA (mRNA) and protein expression of HO-1 was examined using qRT-PCR, immunohistochemistry, and Western blot staining. Moreover, the stimulatory effects of several cytokines (interferon γ [IFN-γ], interleukin [IL]-5, and IL-13, etc.) on HO-1 mRNA expression in cultured nasal explants were evaluated. Results The mRNA and protein expression of HO-1 was significantly increased in polyp tissues compared with healthy controls (p < 0.05), and the non-ECRS subset showed significantly increased HO-1 expression compared with the ECRS subset (p < 0.05). Moreover, in cultured nasal explant, HO-1 mRNA was significantly upregulated in the presence of IFN-γ, IL-27, IL-5, IL-13, and IL-17A, but was significantly inhibited by transforming growth factor β1 (TGF-β1) (p < 0.05). Conclusion Our findings indicate that HO-1 was differentially expressed and regulated in ECRS and non-ECRS patients.

Chronic rhinosinusitis (CRS) is characterized by inflammation of the mucosa of the nose and paranasal sinuses with a duration of at least 12 consecutive weeks and is a common otorhinolaryngologic disease that is frequently encountered in everyday practice (1). Although CRS is not a life-threatening disease, not all patients are cured or achieve control of their symptoms, even with maximal medical management or surgical intervention. The symptoms in CRS patients with (CRSwNP) and without nasal polyps (CRSsNP) are considerably overlapping, while patients with CRSwNP have higher symptom scores and more nasal symptoms (2). Patients with CRSwNP are particularly recalcitrant to usual therapies, and this type of CRS is increasingly prevalent (3). The persistent symptoms can result in facial pain/headache, impairments in general health, vitality and social functioning, stress disorders and other problems that affect patients’ lives and work (4–7). The European Position Paper on Rhinosinusitis and Nasal Polyps (EP3OS) group proposed clear guidelines for a symptom-based definition of rhinosinusitis that has been validated and accepted in epidemiological studies (1,8,9). The European postal survey of 57 128 adults in 12 countries reported that the overall prevalence of EP3OS-defined CRS was 10.9% and ranged from 6.9% to 27.1% in 19 centres (10). A recent survey reported a prevalence of EP3OS-defined CRS of 5.51% in Sao Paulo, Brazil (11). Some authors have used the data from the National Population Health Survey to estimate the prevalence of CRS and found prevalences of 6.95% in Korea (12) and 5.7% among female and 3.4% among male Canadians (13). The 2012 National Health Interview Survey of 34 525 adults found that 12% of adults have been told by a doctor or other health professional that they have sinusitis, and these self-reported doctor-diagnosed prevalences of sinusitis were 15% and 9% among males and females, respectively. The vital health statistic data revealed that CRS is more prevalent than other common chronic respiratory diseases, such as chronic obstructive pulmonary disease (3%) and asthma (8%) (14). Based on this high prevalence, some studies in the USA have claimed that CRS poses an enormous health and economic burden to individuals, the community and society (15). When accounting for the entire population into account, the health burden of CRS is speculated to be huge in Asia; nevertheless, little is known about the actual situation. A survey of 4554 Danes reported a CRS prevalence of 7.8% compared to the overall prevalence of 10.9% in 19 European centres (10,16). The National Health Interview Survey of US adults revealed a decreasing trend in CRS from 16% in 1997 to 14% in 2006 and 12% in 2012 (14,17,18). The literature suggests that the prevalence and patterns of CRS might vary by region and population and change over time due to environmental changes and the development of health care. The previous epidemiological data regarding CRS are mainly from western studies, and little is known regarding the potential socio-economic disparities. In Asia, large-scale epidemiological studies are required to update information about the prevalence of CRS, and such studies would provide information for the assessment of the disease burden and the development and promotion of public health policies associated with CRS. We conducted a cross-sectional investigation in seven major Chinese cities. This study aimed to provide a better understanding of the epidemiological characteristics of CRS, including its prevalence and associations with socio-economic factors and tobacco smoke.

Objectives/Hypothesis: The aim of this article was to describe our surgical technique for the treatment of nasal septal perforations with diameters of 1 to 2 cm. Study Design: Retrospective clinical research. Methods: We reviewed 13 patients with moderate nasal septal perforations (1–2 cm diameter) treated with a sandwich technique (bone or cartilage and quadriceps fascia graft as an interposition graft) by an endoscope-assisted intranasal approach from January 2008 to June 2011. Follow-up periods were 3 months. Results: Thirteen patients were treated with the sandwich technique. Twelve cases (92.3%) were completely healed. One case received incomplete closures without any postoperative symptoms. All patients were found not to have any complications after surgery. Conclusions: The transnasal endoscopic sandwich technique for repairing moderate nasal septal perforation (1–2 cm) has a high success rate and is easy to perform. Laryngoscope, 2012

Background: MicroRNAs (miRNAs) are known to regulate the inflammatory response in various cell types. However, the ability of miRNAs to modulate dendritic cells (DCs) function for allergen immunotherapy is unclear. Objective: To assess the role of miR-23b in the regulation of ovalbumin (OVA)-induced DC differentiation and function and to investigate the related molecular mechanisms. Methods: Bone marrow-derived dendritic cells (BMDCs) were generated from murine bone marrow progenitor cells and subsequently stimulated with OVA to examine the profile of miRNA expression. After transfection with miR-23b reagents, DCs were evaluated for endocytic ability, surface marker expression, cytokine secretion and CD4+ T-cell differentiation. The possible roles of the Notch and NF-κB signalling pathways were also evaluated. Human monocyte-derived dendritic cells (MDDCs) were similarly evaluated as well. Results: Significant upregulation of miR-23b was observed in BMDCs pulsed with OVA. Following miR-23b transfection, BMDCs showed decreased OVA uptake, increased IL-10 production, decreased IL-12 production and an enhanced capacity to promote FoxP3+ CD4+ T regulatory cells (Tregs) differentiation. In addition, inactivation of the Notch1 and NF-κB signalling pathways were observed. Conversely, inhibition of miR-23b in BMDCs resulted in the opposite effects. In human MDDCs, miRNA23b transfection similarly increased IL-10 and decreased IL-12 production, and that treated human MDDCs induced increased FoxP3+ CD4+ T cells. Conclusion: Our findings provide evidence that miR-23b is capable of inducing tolerogenic DC activity and Treg responses in vitro through the inhibition of the Notch1 and NF-κB signalling pathways; thus, miR-23b might represent a therapeutic target for the management of allergic diseases.

Background There is comparatively little information in the public domain on the diversity in prevalence and triggers/factors associated with allergic rhinitis (AR) or allergic rhinoconjunctivitis (AR/C) in countries beyond western-Europe and North America. Objective To review the prevalence and the sensitizing agents/triggers and factors associated with AR/C in several countries in Africa, the Asia-Pacific region, Australia, Eastern Europe, Latin America, Middle East and Turkey. Methods Articles published in English in peer-reviewed journals were assessed and selected for further review, following an extensive literature search using the Medline database. Results This review demonstrated that prevalence of AR and AR/C in these regions has predominantly been investigated in children; with studies indicating wide inter- and intra-regional variations ranging from 2.9% AR and 3.8% AR/C in 10–18-years-old children from one region in Turkey to 54.1% AR and 39.2% AR/C in 13–14-years-old children in one region in Nigeria. Moreover, the prevalence of AR and AR/C has increased markedly over the last decade particularly in some of the more affluent African countries, China-Taiwan and several Middle East countries, likely as a consequence of improved living standards leading to increased exposure to multiple traditional and non-traditional sensitizing agents and risk factors similar to those noted in western-Europe and North America. Conclusions and Clinical Relevance Our findings suggest that the greater diversity in prevalence of AR or AR/C in populations in these regions is in contrast to the lower diversity of AR or AR/C in the ‘western populations (USA and Europe), which tend to be more uniform. This review provides a comprehensive database of the important allergens and triggers which are likely to influence the prevalence of allergic rhinitis in these diverse regions, where the prevalence of allergic rhinitis is increasing and its adverse impact on the quality of life of affected individuals is increasingly recognised.

Summary Background The pathogenesis of nasal polyps is still unclear. There is increasing evidence indicating that Staphylococcal aureus (S. aureus) is associated with the formation of nasal polyps, but the mechanism has not been well documented to date. Methods We stimulated cultured nasal polyps and turbinate tissues with Staphylococcal exotoxin B (SEB), detected the expression of pro-inflammatory cytokines (IL-2, IL-6, and IL-8) and T cell cytokines (IFN-γ, IL-4, IL-5, IL-10, and IL-17) in the supernatants, and evaluated mRNA expression (T-bet, GATA-3, Foxp3, and RORγt) and frequencies of CD4+CD25+ T regulatory cells (Tregs) in nasal tissues. We also evaluated the effects of blocking IL-6 with monoclonal antibodies to T cell profiles in cultured nasal tissues stimulated by SEB. Results Levels of IL-6, IFN-γ and IL-4 increased significantly in SEB-stimulated nasal polyps. Meanwhile, mRNA expressions of T-bet and GATA-3 were significantly up-regulated, while Foxp3 was inhibited and the frequencies of CD4+CD25+ Tregs were decreased after SEB stimulation. After blocking IL-6, the levels of IL-10 and Foxp3 mRNA, as well as the frequencies of CD4+CD25+ Tregs, were significantly increased, while IFN-γ and IL-4 production and the mRNA expression of T-bet and GATA-3 were significantly inhibited. Conclusions SEB is able to modulate pro-inflammatory factors, T-helper type 1/Th2 profiles and suppress Treg activity in cultured nasal polyps, which were rescued by blocking IL-6 activity. Therefore, IL-6 is essential for SEB-induced Treg insufficiency in nasal polyps.

SUMMARY 1 The leucocyte-mediated inflammatory response plays a pivotal role in ischaemia–reperfusion injury. P-Selectin and CD11b are important mediators for the recruitment of leucocytes into the endothelium. However, the time-course of changes in P-selectin and CD11b expression during reperfusion is not defined. Magnesium has been shown to have a protective role in reperfusion injury, but the mechanism of its action is not yet clear. 2 In the present study, 90 male Sprague-Dawley rats were randomized into three groups, namely a sham-operated group, an IR group (subjected to 45 min of coronary occlusion followed by reperfusion for up to 6 h) and an MgSO4-treated group, which received an infusion of MgSO4 starting 30 min before occlusion and continuing until the onset of reperfusion. The expression of P-selectin on platelets and CD11b on leucocytes, endothelial P-selectin on cardiac microvessels and P-selectin mRNA in myocardial tissue were measured by flow cytometry, immunohistochemistry and reverse transcription–polymerase chain reaction, respectively, at different time points during reperfusion. The degree of myocardial necrosis and arrhythmia was assessed. 3 The present study shows that P-selectin expression on platelets and cardiac microvessels, P-selectin mRNA in myocardial tissue and CD11b expression on leucocytes in the IR group were significantly upregulated compared with the sham-operated group in a time-dependent manner during reperfusion. Treatment with MgSO4 attenuated the upregulation of P-selectin expression, in addition to inhibiting myocardial necrosis and arrhythmia, but had no effect on CD11b expression on leucocytes. 4 These results suggest that the expression of P-selectin and CD11b is upregulated after reperfusion and magnesium pretreatment plays a cardioprotective role in ischaemia–reperfusion injury, possibly by inhibiting the upregulation of P-selectin expression.

Background: It has been suggested that human hepatitis A virus cellular receptor, also known as T-cell immunoglobulin and mucin domain-1 (TIM-1), plays an important role in the development of allergic diseases on the basis of epidemiologic data, but the molecular mechanism has been unclear. In a murine model of ovalbumin (OVA)-sensitized allergic rhinitis (AR), we examined the expression of TIM-1 and its correlation with T helper1-associated transcription factor, T-bet, as a potential mediator of T-cell immunoglobulin expression. Methods: Mice were challenged intranasally with OVA to elicit AR. The expression of TIM-1 in nasal tissues was examined by real-time reverse-transcription polymerase chain reaction (RT-PCR), and the surface expression of TIM-1 in peripheral blood mononuclear cells was evaluated by means of flow cytometry. In addition, the expression of TIM-1 as well as T-bet in splenic lymphocytes was examined by Western blotting. Results: TIM-1 mRNA was increased significantly in nasal tissues (P < .05) as seen by real-time RT-PCR. Flow cytometry indicated a differential TIM-1 expression of 135.5 ± 34.2 in the AR group versus 51.1 ± 10.9 in the control group (P < .05). The mean values of normalized TIM-1 were 0.43 ± 0.18 and 0.21 ± 0.10 in AR and control groups, respectively, whereas the mean values of normalized T-bet were 0.22 ± 0.13 and 0.67 ± 0.17 in the AR and control groups, respectively. There was a significant difference in the production of TIM-1 as well as T-bet in AR mice versus control mice (P < .05). The increased production of TIM-1 correlated significantly with the decreased T-bet in spleen tissue of AR mice (r = −0.52, P < .05). Conclusion: Our experimental model recapitulates an increase in lymphocyte TIM-1 expression seen in AR both locally and systemically. Our results also demonstrate an inverse relationship between lymphocyte TIM-1 and T-bet expression, suggesting a possible mechanism that TIM-1 influences the development of AR.

With THIQ, secondary alcohols are obtained with moderate yields and generally good enantioselectivities.

Study of melt flow properties and mechanical properties of sulfonated butyl rubber ionomers showed that in the case of lithium ionomers addition of zinc stearate lowered obviously the melt viscosity, represented by torque value of a Brabender rheometer, and enhanced tensile strength of the ionomer up to 25% of zinc stearate, while in the case of ethylamine neutralized ionomer addition of zinc stearate lowered the melt viscosity not so obviously as in the case of lithium ionomer and slightly affected the tensile strength. Amine neutralized ionomers exhibited very low permanent sets, while the lithium ionomer showed much higher permanent set, which increased with sulfonate group and amount of zinc stearate added. Increase of neutralization degree below equivalent ratio of 1 significantly raised the melt viscosity and tensile strength. For monovalent cation ionomer, melt viscosity and tensile strength diminished with decreasing ionic potentials, but for divalent cation ionomers with increasing ionic potentials and with decreasing covalent character tensile strength decreased and melt viscosity increased. For different amine neutralized ionomers tensile strength decreased in the following orders: ethylamine > triethylamine > diethylamine; isopropylamine > ethylamine > tertiary butylamine > methylamine; ethylamine > hexylamine > dodecylamine > octadecylamine. Bei Untersuchungen der Schmelzfluseigenschaften und der mechanischen Eigenschaften von sulfonierten Butylkautschuk-Ionomeren mit einem Brabender-Plasticorder zeigte sich, das im Falle des Lithium-Ionomeren der Zusatz von Zinkstearat deutlich die Schmelzviskositat erniedrigt und die Zugfestigkeit bis zu 25% Zinkstearat-Zugabe erhoht, wahrend bei den mit Ethylamin neutralisierten Ionomeren Zinkstearat die Viskositat nur wenig erniedrigt und die Zugfestigkeit kaum beinflust. Amin-Ionomere zeigten sehr geringe bleibende Verformung, wahrend Lithium-Ionomere deutlich hohere Werte ergaben, die mit dem Gehalt an Sulfonat-Gruppen und an zugesetztem Zinkstearat anstiegen. Mit ansteigendem Neutralisationsgrad stiegen unterhalb der Aquivalenz die Schmelzviskositat und die Zugfestigkeit merklich an. Bei einwertigen Kationen nahm die Schmelzviskositut und die Zugfestigkeit mit fallendem Ionenpotential ab, bei zweiwertigen sank mit steigendem Ionenpotential und sinkendem covalenten Charakter die Zugfestigkeit, aber es stieg die Schmelzviskositat. Fur die verschiedenen Amine, die zur Neutralisation der Ionomeren verwendet wurden, nahm die Zugfestigkeit in folgenden Reihenfolgen ab: Ethylamin > Triethylamin > Diethylamin; Isopropylamin > Ethylamin > Tertiiirbutylamin > Methylamin; Ethylamin > Hexylamin > Dodecylamin > Octadecylamin.