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- Regulation of ceramide synthase 6 in a spontaneous experimental autoimmune encephalomyelitis model is sex dependent. [JOURNAL ARTICLE]
- Biochem Pharmacol 2014 Aug 27.
Ceramides (Cer) are mediators of inflammatory processes. In a chronic experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we observed a significant elevation of C16-Cer and its synthesizing enzyme, ceramide synthase(CerS)6, in the lumbar spinal cord. In the present study, we have confirmed that C16-Cer and CerS6 are also upregulated in the lumbar spinal cord in a spontanous relapse-remitting EAE model, using SJL mice overexpressing a transgenic T cell receptor (TCR1640). CerS6 was found to be expressed in macrophages, T cells and B cells in EAE lesions. In macrophages, we demonstrated that interferon gamma (IFN-γ)-induced CerS6 upregulation was amplified by 17β-estradiol, an action that was further accompanied by increased upregulation of tumor necrosis factor alpha (TNF-α). Accordingly, CerS6 and TNF-α expression was upregulated predominantly in the spinal cord in female TCR1640 mice, which usually develop the relapse-remitting form of EAE, while male TCR1640 mice showed an attenuated regulation of CerS6 and TNF-α and exhibit mostly chronic disease progression. Furthermore, expression of TNFR2, one of two receptors of TNF-α, which is linked to neuroprotection and remyelination, was also upregulated to a greater extent during EAE in female TCR1640 mice in comparison to male TCR1640 mice. Taken together, our results confirm the upregulation of CerS6 and C16-Cer in an adjuvant-independent, physiological EAE model and further suggest an anti-inflammatory role of CerS6 in the regulation of the disease course in female TCR1640 mice via TNF-α/TNFR2.
- Predictors of Traditional Medicines Utilisation in the Ghanaian Health Care Practice: Interrogating the Ashanti Situation. [JOURNAL ARTICLE]
- J Community Health 2014 Aug 31.
Traditional medicine (TRM) use remains universal among individuals, families and communities the world over but the predictive variables of TRM use is still confounding. This population-based study analysed the predictors of TRM use in Ashanti Region, Ghana. A retrospective cross-sectional quantitative survey involving systematic random sampled participants (N = 324) was conducted. Structured interviewer-administered questionnaires were used as research instruments. Data were analysed with logit regression, Pearson's Chi square and Fisher's exact tests from the PASW for Windows application (V. 17.0). Overall, 86.1 % (n = 279) reported use of TRM with biologically-based and distant/prayer therapies as the major forms of TRM utilised in the previous 12 months. Among the general population, TRM use was predicted by having low-income levels [odds ratio (OR) 2.883, confidence interval (CI) 1.142-7.277], being a trader (OR 2.321, CI 1.037-5.194), perceiving TRM as effective (OR 4.430, CI 1.645-11.934) and safe (OR 2.730, CI 0.986-4.321), good affective behaviour of traditional medical practitioner (TMP) (OR 2.943, CI 0.875-9.896) and having chronic ill-health (OR 3.821, CI 1.213-11.311). The prevalence of TRM use is high. The study provides evidence that people's experience, personal attributes, health beliefs, attitude to TRM, attitude of TMP to clients and medical history are largely accountable for the upsurge use of TRM rather than socio-demographic factors. Understanding the health-seeking behaviour of individuals is exigent to ascribe appropriate medical care by health care providers.
- Antibiotic prophylaxis in the management of vesicoureteric reflux: a randomized double-blind placebo-controlled trial. [JOURNAL ARTICLE]
- Pediatr Nephrol 2014 Aug 31.
The benefits of long-term low-dose antibiotics in preventing urinary tract infection (UTI) and renal damage in children with primary vesicoureteric reflux (VUR) are unclear.Children aged between 1 and 12 years with VUR grade I-IV and a microbiologically proven UTI were randomized into two groups to receive either antibiotic prophylaxis [2 mg/kg trimethoprim + sulfamethoxazole (TMP-SMX)] daily or placebo, respectively, for 12 months. Primary outcome was microbiologically confirmed symptomatic UTI. Intention-to-treat analysis using time-to-event data was performed.A total of 93 children (66.7 % boys) with a median age of 4.6 years were enrolled in this study; VUR grade III-IV was present in 73.1 % of these children. At least one symptomatic UTI occurred in ten (21.3 %) patients receiving antibiotic prophylaxis and in three (6.5 %) patients receiving placebo [hazard ratio in antibiotic group 3.9; 95 % confidence interval (CI) 1- 14; log rank test P = 0.02). Compared to the group receiving placebo, the antibiotic group had a 14.8 % increased risk for developing UTI (95 % CI 1-28; P = 0.03). Of the total number of episodes of UTI, 58.3 % of those in the antibiotic group were caused by TMP-SMX-resistant bacteria compared to 20 % in the placebo group (P = 0.15). A renal scan at 12 months revealed that six of 37 (16.2 %) patients in the antibiotic group and seven of 43 (16.3 %) patients in the placebo group had new or worsening of pre-existing scar.Long-term antibiotic prophylaxis with TMP-SMX is associated with increased risk of symptomatic UTI compared to placebo in children with grade I-IV VUR.
- Early effect of NTBC on renal tubular dysfunction in hereditary tyrosinemia type 1. [JOURNAL ARTICLE]
- Mol Genet Metab 2014 Aug 1.
Hereditary tyrosinemia type 1 (HT1) is characterized by severe progressive liver disease and renal tubular dysfunction. NTBC therapy has revolutionized the management of HT1 but its effect on renal tubular function has so far been poorly investigated. The aim of this study was to describe the early effect of NTBC on renal tubular disease in patients with HT1.Five HT1 patients (age between 5 and 53months) with different types of presentation were evaluated before and during the first 2weeks of therapy with NTBC in a retrospective case analysis for phosphate metabolism and renal tubular function.Before starting NTBC therapy, all children manifested signs of renal dysfunction which included hypophosphatemia, acidosis, reduced phosphate reabsorption, aminoaciduria, glycosuria (Fanconi syndrome), and variable degree of proteinuria. Some patients also presented increased urinary calcium/creatinine ratio and raised fractional excretion of sodium. Starting of NTBC therapy resulted in the rapid normalization of plasma phosphate within one week from its initiation in majority of patients and in all patients during the second week of therapy. TmP/GFR normalized in 48h, while the other markers of renal dysfunction showed an improving trend over 2weeks.NTBC is an efficient treatment for renal tubular dysfunction in HT1, allowing the return to normal function within a few weeks. Its early effect on renal tubular cells appeared to be very rapid, particularly in normalizing plasma phosphate and TmP/GFR. In our series of patients, the TmP/GFR resulted as the most reliable index of tubular function.
- Reduction of sulfamethoxazole hydroxylamine (SMX-HA) by the mitochondrial amidoxime reducing component (mARC). [JOURNAL ARTICLE]
- Chem Res Toxicol 2014 Aug 29.
Under high dose treatment with sulfamethoxazole (SMX) / trimethoprim (TMP) hypersensitivity reactions occur with a high incidence. Mechanism of this adverse drug reaction is not fully understood. Several steps in toxification pathway of SMX were investigated. The aim of our study was to investigate the reduction of sulfamethoxazole hydroxylamine (SMX-HA) in this toxification pathway, which can possibly be catalyzed by the mARC-containing N-reductive enzyme system. Western blot analyses of subcellular fractions of porcine tissue were performed with antibodies against mARC-1, mARC-2, cytochrome b5 type B and NADH cytochrome b5 reductase. Incubations of porcine and human subcellular tissue fractions and of the heterologous expressed human components of the N-reductive enzyme system were carried out with SMX-HA. mARC-1 and mARC-2 knockdown was performed in HEK-293 cells. Kinetic parameters of the heterologous expressed human protein variants V96L, A165T, M187K, C246S, D247H and M268I of mARC-1, G244S and C245W of mARC-2, and N-reductive activity of 2SF, D14G, K16E and T22A of cytochrome b5 type B were analyzed. Western blot analyses were consistent with the hypothesis that the mARC-containing N-reductive enzyme system might be involved in the reduction of SMX-HA. In agreement with these results highest reduction rates were found in mitochondrial subcellular fractions of porcine tissue and in the outer membrane vesicle (OMV) of human liver tissue, respectively. Knockdown studies in HEK-293 cells demonstrated that mARC-1 and mARC-2 were capable of reducing SMX-HA in cell metabolism. Investigations with the heterologous expressed human mARC-2 protein showed a higher catalytic efficiency towards SMX-HA than mARC-1 but none of the investigated human protein variants showed statistically significant differences of its N-reductive activity and was therefore likely to participate in the pathogenesis of hypersensitivity reaction under treatment with SMX.
- Clindamycin-primaquine for pneumocystis jiroveci pneumonia in renal transplant patients. [JOURNAL ARTICLE]
- Infection 2014 Aug 29.
Trimethoprim/sulfamethoxazole (TMP/SMX) is considered first-line therapy for pneumocystis jiroveci pneumonia (PCP) in renal transplant patients. Alternatives have not been formally studied. Clindamycin-primaquine (C-P) is effective in HIV-associated PCP, but data in renal transplant patients are lacking.Retrospective cohort study of 57 consecutive renal transplant patients who developed PCP and were treated with C-P (n = 23) or TMP/SMX (n = 34).A non-significantly higher failure rate was observed in patients on C-P due to lack of efficacy (30.4 versus 20.6 %, p = 0.545). The difference was more pronounced in severe PCP (60 versus 37.5 %, p = 0.611) and a significantly lower efficacy of C-P was seen when used as salvage therapy. The two patients who had received C-P after not responding to TMP/SMX failed this regimen, but all seven patients who had failed initial treatment with C-P and had been switched to TMP/SMX were cured (p = 0.028). No treatment-limiting adverse reactions were reported for patients on C-P while six patients (17.6 %) on TMP/SMX developed possibly related treatment-limiting toxicity (p = 0.071). However, in only two patients adverse events were definitely related to TMP/SMX (5.9 %).Clindamycin-primaquine appears to be safe and well tolerated for treating PCP in renal transplant patients but is probably less effective than TMP/SMX, the standard regimen. However, our data indicates that C-P represents an acceptable alternative for patients with contraindications or treatment emergent toxicities during TMP/SMX use. Notably, TMP/SMX was also acceptably tolerated in most patients. TMP/SMX remains an effective salvage regimen in case of C-P failure.
- Bioelectricity generation in an integrated system combining microbial fuel cell and tubular membrane reactor: Effects of operation parameters performing a microbial fuel cell-based biosensor for tubular membrane bioreactor. [JOURNAL ARTICLE]
- Bioresour Technol 2014 Aug 13.:483-490.
A bio-cathode microbial fuel cell (MFC) with tubular membrane was integrated to construct a microbial fuel cell-tubular membrane bioreactor (MFC-TMBR) system, in which the bio-cathode MFC was developed as a biosensor for COD real-time monitoring in TMBR and the performance was analyzed in terms of its current variation caused by operation parameters. With a constant anode potential, the effect of HRT demonstrated that higher rate of mass transport increased the response of the system. The system was further explored an inverse relationship between TMP and current peak by using EPS concentration under the different MLSS concentration. The sensor output had a linear relationship with COD up to 1000mg/L (regression coefficient, R(2)=0.97) and MLSS (regression coefficient, R(2)=0.94). The simple and compact bio-cathode MFC biosensor for TMBR using MFC-TMBR integrated system showed promising potential for direct and economical COD online monitoring, and provided an opportunity to widen the application of MFC-based biosensor.
- 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 20.
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 toward 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 toward 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 identified that 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.