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- Localized delivery of doxorubicin in vivo from polymer-modified thermosensitive liposomes with MR-guided focused ultrasound-mediated heating. [JOURNAL ARTICLE]
- J Control Release 2014 Aug 21.
Thermosensitive liposomes have emerged as a viable strategy for localized delivery and triggered release of chemotherapy. MR-guided focused ultrasound (MRgFUS) has the capability of heating tumors in a controlled manner, and when combined with thermosensitive liposomes can potentially reduce tumor burden in vivo. However, the impact of this drug delivery strategy has rarely been investigated. We have developed a unique liposome formulation modified with p(NIPAAm-co-PAA), a polymer that confers sensitivity to both temperature and pH. These polymer-modified thermosensitive liposomes (PTSL) demonstrated sensitivity to focused ultrasound, and required lower thermal doses and were more cytotoxic than traditional formulations in vitro. A set of acoustic parameters characterizing optimal release from PTSL in vitro was applied in the design of a combined MRgFUS/PTSL delivery platform. This platform more effectively reduced tumor burden in vivo when compared to free drug and traditional formulations. Histological analysis indicated greater tumor penetration, more extensive ECM remodeling, and greater cell destruction in tumors administered PTSL, correlating with improved response to the therapy.
- Tetramethylpyrazine promotes SH-SY5Y cell differentiation into neurons through epigenetic regulation of Topoisomerase IIβ [JOURNAL ARTICLE]
- Neuroscience 2014 Aug 19.
Tetramethylpyrazine (TMP) is an active compound extracted from the traditional Chinese medicinal herb Chuanxiong Recently, it has been reported that TMP enhances neurogenesis, and promotes neural stem cell differentiation towards neurons. However, its molecular basis remains unknown. Topoisomerase IIβ (TopoIIβ) is a nuclear enzyme with an essential role in neuronal development. This study aimed to investigate whether TopoIIβ is involved in TMP-induced neuronal differentiation. We examined the effect of TMP on neuronal differentiation of SH-SY5Y cells. It was found that TMP inhibited cell proliferation and induced G0/G1 cell cycle arrest. TMP promoted SH-SY5Y cells to differentiate towards post-mitotic neurons characterized by long, out-branched neurites and up-regulated neuronal markers, microtubule-associated protein 2 (MAP2) and tau. Meanwhile, we demonstrated that TopoIIβ was highly expressed following TMP treatment. To unravel how TMP affects TopoIIβ expression, two chromatin active markers, acetylated histone H3 (Ac-H3) and acetylated histone H4 (Ac-H4) were examined in this study. Our data showed that the levels of Ac-H3 and Ac-H4 were positively correlated with TopoIIβ expression in the processes of neuronal differentiation. We further performed chromatin immunoprecipitation (ChIP) analysis and identifiedthat TMP enhanced the recruitment of Ac-H3 and Ac-H4 to the TopoIIβ gene promoter region. Therefore, we concluded that TMP may stimulate neuronal differentiation of SH-SY5Y cells through epigenetic regulation of TopoIIβ. These results suggest a novel molecular mechanism underlying TMP-promoted neuronal differentiation.
- Expression of soluble vascular endothelial growth factor receptor-1 and placental growth factor in fetal growth restriction cases and intervention effect of tetramethylpyrazine. [Journal Article]
- Asian Pac J Trop Med 2014 Aug; 7(8):663-7.
To investigate the expression of soluble vascular endothelial growth factor receptor-1 (sFlt-1) and placental growth factor (PLGF) in the fetal growth restriction (FGR) cases and the intervention mechanism of tetramethylpyrazine.A total of 60 fetal growth restriction cases that admitted to our hospital were randomly divided into ligustrazine intervention group (group A) and nutritional support group (group B). A total of 50 healthy pregnant women were also enrolled as control group (group C). Expression level of maternal serum sFlt1, PLGF and fetal growth parameters including HC, AC, FL, BPD, EFW as well as placenta PLGF, sFlt-1 mRNA expression were recorded and compared among the three groups. A total of 15 SD rats were selected and were divided into three groups, TMP group, alcohol and tobacco group and blank control group. Three groups of rats were dissected on the twentieth day of gestation.Expression level of sFlt-1 and PLGF in group A was not significantly different from that of group C (P>0.05); but significant difference in SFlt1 and PLGF expression level was observed between group C and group B (P<0.05). Before treatment, HC, AC, FL, BPD and EFW of group A and group B were significant lower than those of group C, but after treatment, those parameters in group A were significantly improved (P<0.05). In the animal experiment there was no significant difference in sFlt-1 between treatment group and FGR group without treatment or control group (P>0.05). There was significant difference in PLGF between FGR group with treatment and FGR group without treatment or control group (P<0.01).PLGF level is decreased and sFlt-1 increased in patients suffered from fetal growth restriction, and FGR rats show increased sFlt-1 and decreased PLGF, thus they can be indicator of the fetal growth restriction. Ligustrazine can effectively improve sFlt-1, PLGF expression level in fetal growth restriction cases, which can be used as treatment for FGR.
- The neuroprotective effect of 17β-estradiol Is independent of its antioxidantive properties. [JOURNAL ARTICLE]
- Brain Res 2014 Aug 19.
17β-estradiol (E2) is neuroprotective in experimental models of stroke. While some postulate a mainly antioxidative action due to E2's free C3 hydroxyl group at its A-ring, others suggest that neuroprotection is mediated by a hormonal, receptor mediated effect. The aim of the current study was to clarify this issue by testing whether E2 analogues lacking hormonal activity are also neuroprotective following cerebral ischemia.Focal cerebral ischemia was induced in male C57/BL6 mice by laser-Doppler-controlled endovascular occlusion of the middle cerebral artery for 40min. Mice received either 1) memantine, a NMDA-receptor antagonist, as a positive control, 2) E2 (1400µg/kg b.w.), or 3) 2,4,6-trimethylphenol (TMP), an E2 analogue without hormonal activity (1400, 140, or 14µg/kg b.w.). Motor function was tested 3h and 24h after ischemia. Thereafter mice were sacrificed and brain damage was quantified by histomorphometry.Treatment with memantine or E2 significantly reduced infarct volume by >40% and significantly improved neurological function while treatment with TMP had no effect.E2 is equally neuroprotective as antagonization of NMDA receptors while E2 analogues without hormonal activity are not neuroprotective. Therefore the current data suggest that the neuroprotection activity of E2 is independent of its free-radical scavenging properties.
- Nox2-dependent signaling between macrophages and sensory neurons contributes to neuropathic pain hypersensitivity. [JOURNAL ARTICLE]
- Pain 2014 Aug 16.
Emerging lines of evidence indicate that production of reactive oxygen species (ROS) at distinct sites of the nociceptive system contributes to the processing of neuropathic pain. However, the mechanisms underlying ROS production during neuropathic pain processing are not fully understood. We here detected the ROS-generating NADPH oxidase isoform Nox2 in macrophages of dorsal root ganglia (DRGs) in mice. In response to peripheral nerve injury, Nox2-positive macrophages were recruited to DRGs, and ROS production was increased in a Nox2-dependent manner. Nox2-deficient mice displayed reduced neuropathic pain behavior after peripheral nerve injury, whereas their immediate responses to noxious stimuli were normal. Moreover, injury-induced upregulation of tumor necrosis factor α was absent and ATF3-induction was reduced in DRGs of Nox2-deficient mice suggesting an attenuated macrophage-neuron signaling. These data suggest that Nox2-dependent ROS production in macrophages recruited to DRGs contributes to neuropathic pain hypersensitivity, underlining the observation that Nox-derived ROS exert specific functions during the processing of pain.
- Abnormalities in renal tubular phosphate handling in children with sickle cell disease. [JOURNAL ARTICLE]
- Pediatr Blood Cancer 2014 Aug 17.
The mechanisms responsible for the hyperphosphatemia in patients with sickle cell disease (SCD) and preserved glomerular filtration rate (GFR) are not fully understood. The role of fibroblast growth factor 23 (FGF23), a phosphaturic hormone has not been investigated in SCD. Hence, we evaluated parameters of renal tubular phosphorus handling and their relation to prevailing FGF23 levels in a cohort of young SCD patients.Renal tubular phosphate handling and circulating levels of various analytes including FGF23 and parathyroid hormone (PTH) were measured in 24 children with SCD and normal estimated GFR in a cross sectional study. Correlation and regression analysis were employed to derive relationships between serum phosphorus and several variables.Most children showed elevated age- adjusted serum phosphorus (5.1 ± 0.7 mg/dl) levels. Tubular re-absorption of phosphorus(TRP) (96.3 ± 2.1%) and tubular maximum re-absorption of phosphorus per unit volume of GFR (TMP/GFR) (4.9 ± 0.6 mg/dl) were both elevated. Plasma intact FGF23 concentrations were elevated (81 ± 38 pg/ml) while the average PTH values were normal in most patients (50 ± 27 pg/ml). Univariate analysis showed significant correlations of serum phosphorus with TMP/GFR, alkaline phosphatase, age, lactate dehydrogenase (LDH), and log intact FGF23. TMP/GFR correlated with log intact FGF23 (r = 0.5, P< or = 0.01) but not with PTH. Multiple regression analysis yielded an independent relationship of serum phosphorus with TMP/GFR.The elevated serum phosphorus concentrations with simultaneously increased TMP/GFR and elevated FGF23 levels collectively suggest that patients with SCD display proximal tubular resistance to the action of FGF23 before any decline in GFR. Pediatr Blood Cancer © 2014 Wiley Periodicals, Inc.
- Chiral chromatography-tandem mass spectrometry applied to the determination of pro-resolving lipid mediators. [JOURNAL ARTICLE]
- J Chromatogr A 2014 Jul 29.
Pro-resolving lipid mediators are a class of endogenously synthesized molecules derived from different fatty acids, such as arachidonic, docosahexaenoic or eicosapentaenoic acid, which are derived into four different product families: lipoxins, resolvins, maresins and protectins. For quantitation of these compounds, a sensitive, selective and robust liquid chromatography-tandem mass spectrometry method was developed and validated for the simultaneous quantitation of lipoxin A4, 6-epi-lipoxin A4, lipoxin B4 and lipoxin A5, the D-series resolvins D1 and D2 as well as aspirin-triggered lipoxin A4 and resolvin D1, maresin and protectin and the pathway markers 17(S)-hydroxy-docosahexaenoic acid and 17(R)-hydroxy-docosahexaenoic acid in cell culture supernatants. For this purpose, a chiral column was connected in series with a reversed-phase column to achieve efficient analyte separation and high sensitivity. Sample pre-treatment included a fast and simple liquid-liquid extraction procedure. Limits of quantitation in the range of 0.1-0.5ng/mL cell culture media, absolute recoveries between 90 and 115%, intra- and interday precision of less than 13% and an accuracy of less than 11% were obtained. Stability of the samples after 60 days storage at -80°C, three freeze/thaw cycles and 4h at room temperature has been demonstrated for all analytes. Sample extracts can be stored at 7°C for 24h without degradation of the analytes. Deviations of less than 13% in the accuracy, evaluated in terms of relative error, were obtained. The suitability of the method has been demonstrated in cell culture supernatants of human polymorphonuclear leukocytes, stimulated with 15R-hydroxy-eicosatetraenoic acid and in cell culture media of human polymorphonuclear leukocytes co-incubated with human platelets. From all studied analytes, lipoxin A4 and 6-epi-lipoxin A4 were found in cell culture media under both incubation conditions, while 15-epi-lipoxin A4 was additionally detected in cell culture supernatants of polymorphonuclear leukocytes stimulated with 15R-hydroxy-eicosatetraenoic acid.
- Design, Synthesis, and Biological Evaluation of Stable Colchicine Binding Site Tubulin Inhibitors as Potential Anticancer Agents. [JOURNAL ARTICLE]
- J Med Chem 2014 Aug 14.
To block the metabolically labile sites of novel tubulin inhibitors targeting the colchicine binding site based on SMART, ABI, and PAT templates, we have designed, synthesized, and biologically tested three focused sets of new derivatives with modifications at the carbonyl linker, the para-position in the C ring of SMART template, and modification of A ring of the PAT template. Structure-activity relationships of these compounds led to the identification of new benzimidazole and imidazo[4,5-c]pyridine -fused ring templates, represented by compounds 4 and 7, respectively, which showed enhanced antitumor activity and substantially improved the metabolic stability in liver microsomes compared to SMART. MOM group replaced TMP C ring generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Further modification of PAT template yielded another potent analogue 33 with 5-indolyl substituent at A ring.
- Air-Stable Solid Aryl and Heteroaryl Organozinc Pivalates: Syntheses and Applications in Organic Synthesis. [JOURNAL ARTICLE]
- Chemistry 2014 Aug 12.
A wide range of air-stable, solid, polyfunctional aryl and heteroarylzinc pivalates were efficiently prepared by either magnesium insertion or Hal/Mg exchange followed by transmetalation with Zn(OPiv)2 (OPiv=pivalate). By reducing the amount of LiCl the air stability could be significantly enhanced compared with previously prepared reagents. An alternative route is directed magnesiation using TMPMgCl⋅LiCl (TMP=2,2,6,6-tetramethylpiperidyl) followed by transmetalation with Zn(OPiv)2 or, for very sensitive substrates, direct zincation by using TMPZnOPiv. These zinc reagents not only show excellent stability towards air, but they also undergo a broad range of CC bond-formation reactions, such as allylation and carbocupration reactions, as well as addition to aldehydes and 1,4-addition reactions. Acylation reactions can be performed by using an excess of TMSCl to overcome side reactions of the omnipresent pivalate anion.
- Otitis media in children vaccinated during consecutive 7-valent or 10-valent pneumococcal conjugate vaccination schedules. [JOURNAL ARTICLE]
- BMC Pediatr 2014 Aug 11; 14(1):200.
In 2001 when 7-valent pneumococcal conjugate vaccine (PCV7) was introduced, almost all (90%) young Australian Indigenous children living in remote communities had some form of otitis media (OM), including 24% with tympanic membrane perforation (TMP). In late 2009, the Northern Territory childhood vaccination schedule replaced PCV7 with 10-valent pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10).We conducted regular surveillance of all forms of OM in children in remote Indigenous communities between September 2008 and December 2012. This analysis compares children less than 36months of age who received a primary course of at least two doses of PCV7 or PHiD-CV10, and not more than one dose of another pneumococcal vaccine.Mean ages of 444 PCV7- and 451 PHiD-CV10-vaccinated children were 20 and 18 1months, respectively. Bilaterally normal middle ears were detected in 7% and 9% respectively. OM with effusion was diagnosed in 41% and 51% (Risk Difference 10% [95% Confidence Interval 3 to 17] p = 0.002), any suppurative OM (acute OM or any TMP) in 51% versus 39% (RD -12% [95%CI -19 to -5] p = 0.0004], and TMP in 17% versus 14% (RD -3% [95%CI -8 to 2] p = 0.2), respectively. Multivariate analyses described a similar independent negative association between suppurative OM and PHiD-CV10 compared to PCV7 (Odds Ratio = 0.6 [95%CI 0.4 to 0.8] p = 0.001). Additional children in the household were a risk factor for OM (OR = 2.4 [95%CI 2 to 4] p = 0.001 for the third additional child), and older age and male gender were associated with less disease. Other measured risk factors were non-significant. Similar clinical results were found for children who had received non-mixed PCV schedules.Otitis media remains a significant health and social issue for Australian Indigenous children despite PCV vaccination. Around 90% of young children have some form of OM. Children vaccinated in with PHiD-CV10 had less suppurative OM than children vaccinated with PCV7. Ongoing surveillance during the PCV13 era, and trials of early intervention including earlier and mixed vaccine schedules are warranted.