Inflammation is a predominant aspect of neurodegenerative diseases and experimental studies performed in animal models of Parkinson’s disease (PD) suggesting that a sustained neuroinflammation exacerbates the nigrostriatal degeneration pathway. The central role of microglia in neuroinflammation has been studied as a target for potential neuroprotective drugs for PD, for example nonsteroidal anti-inflammatory drugs (NSAIDs) and matrix metalloproteinases (MMP) inhibitors that regulates microglial activation and migration. The aim of this study was to investigate the neuroprotective response of the iminosugar 1-deoxynojirimycin (1-DNJ) and compare its effect with a combined treatment with ibuprofen. MPTP-treated mice were orally dosed with ibuprofen and/or 1-DNJ 1. Open-field test was used to evaluate behavioral changes. Immunohistochemistry for dopaminergic neurons marker (TH+) and microglia markers (Iba-1+; CD68+) were used to investigate neuronal integrity and microglial activation in the substantia nigra pars compacta (SNpc). The pro-inflammatory cytokines TNF-α and IL-6 were analysed by qPCR. Treatments with either 1-DNJ or Ibuprofen alone did not reduce the damage induced by MPTP intoxication. However, combined treatment with 1-DNJ and ibuprofen prevents loss of mesencephalic dopaminergic neurons, decreases the number of CD68+/ Iba-1+ cells, the microglia/neurons interactions, and the pro-inflammatory cytokines, and improves behavioral changes when compared with MPTP-treated animals. In conclusion, these data demonstrate that the combined treatment with a MMPs inhibitor (1-DNJ) plus an anti-inflammatory drug (ibuprofen) has neuroprotective effects open for future therapeutic interventions.
The molecular distribution of insulin-like growth factor I (IGF-I) and IGF-II among the IGF binding proteins (IGFBPs) was studied before and during IGF-I therapy in Ecuadorean adults with growth hormone receptor deficiency (GHRD). Of the total circulating IGF-I and IGF-II, 70% was carried by the 150 kDa complex in normal subjects, while in patients with GHRD, 50% of serum IGF-I, but only 30–35% of serum IGF-II, was measured within the 150 kDa IGFBP-3 region. Administration of IGF-I altered the concentration of IGF-I and IGF-II, although the percentage of total IGF measured within each IGFBP region was not affected, as the increase in IGF-I and the decrease in IGF-II were proportional. Similarly, serum concentrations of IGFBP-3 and the acid-labile subunit, measured by radioimmunoassay, were unaltered. Thus, administration of IGF-I to patients with GHRD was unable to correct the aberrant distribution of IGFs among the IGFBPs. 相似文献
OBJECTIVE: To assess whether physical growth is affected in early treated Dutch patients with phenylketonuria (PKU). METHODS: The birth weights of all 137 early detected patients with PKU born in the period from 1974 to 1988 in the Netherlands were compared with reference values. Height, head circumference, and weight were measured at the age at which treatment started (commonly about 2-3 weeks), at 6 months of age, and yearly from the child's first birthday up to the age of 10 years. These measurements were compared with reference values. RESULTS: The adjusted birth weight in patients with PKU was 141 g (95% confidence interval (CI) 66 to 216 g) less than Dutch reference values by Kloosterman and 103 g (95% CI 9 to 196 g) less compared with the birth weight of another reference group. At the age at which treatment started, z scores of patients for height by age were -0.23 (95% CI -0.44 to -0.02) and z scores for head circumference by the age were -0.25 (95% CI -0.44 to -0.06). From the age at which treatment started up to the age of 3 years z scores for height by age further decreased to -0.74 (95% confidence interval -0.93 to -0.56), after which no additional decrease occurred. In contrast, z scores for head circumference increased from -0.25 at the first visit to 0.08 (95% CI -0.14 to 0.30) at the age of 1 year, after which they remained close to zero. Weight by height was close to the expected centiles for all ages. CONCLUSION: Patients with PKU are growth retarded at birth and have smaller head circumferences than the normal population. In Dutch patients further growth retardation occurs in the first three years of life. 相似文献
Classical phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of hepatic phenylalanine hydroxylase (PAH). Three different vector systems have been developed to examine the potential of somatic gene therapy for the treatment of PKU. Recombinant retroviral vectors and DNA/protein complexes can efficiently transduce PAH-deiicient hepatocytes in vitro, but their present phenylketonuria, retrovirus application is limited by their low transduction efficiency in vivo. In contrast, infusion of a recombinant adenoviral vector expressing the human PAH cDNA into the portal circulation of PAH-deficient mice restores 10-80% of normal hepatic PAH activity and completely normalizes serum phenylalanine levels. At present, this effect is transient and re-administration has no further effect. However, this result suggests that PKU can be completely corrected by somatic gene therapy as more persistent vectors are developed. 相似文献
Pneumococcal disease causes significant morbidity and mortality in at-risk individuals, and is complicated by emerging antibiotic
resistance. An effective, safe and cost-effective vaccine is available, but despite this many patients who would benefit from
pneumococcal vaccination remain unvaccinated. The purpose of this study was to determine the rates of missed opportunities
to provide pneumococcal vaccination to patients being discharged from a tertiary center medical teaching unit and to determine
if a nurse coordinator-based intervention would increase rates of pneumococcal vaccination prior to discharge home. 相似文献
8-Oxo-2'-deoxyguanosine (8-oxo-dG) is emerging as a useful marker for
oxidative DNA damage. Reported basal levels determined by 32P- postlabeling
(PPL) method were 10-fold or more higher than those obtained with
HPLC/electrochemical detection (ECD). This discrepancy was investigated. In
commercial calf thymus DNA, levels of 4 +/- 1 and 64 +/- 14 8-oxo-dG per
10(6) 2'-deoxynucleosides (dN) were measured by the standard HPLC/ECD and
PPL methods, respectively. DNA digestion by micrococcal nuclease/spleen
phosphodiesterase and nuclease P1 (as used in the standard PPL method),
followed by ECD analysis resulted in a level of 8 +/- 3. In calf thymus DNA
spiked with chemically synthesized 8-oxo-dGp to give an increment of 9
8-oxo-dG/10(6) dN, the added standard produced a significant increase with
HPLC/ECD but not PPL. After spiking the DNA with 90 8-oxo-dG/10(6) dN, the
added 8-oxo-dGp was detectable also with PPL, with a labeling efficiency of
65%. In order to investigate the role of ionizing radiation from 32P for
the higher 8-oxo-dG levels in PPL, incubation times and amounts of
radioactivity in the phosphorylation reaction with commercial dGp were
increased, and external irradiation of commercial dG with 32P was
investigated. All modifications resulted in higher values of 8-oxo-dG
measured, but the effect was not large enough to fully explain the
discrepancy between PPL and HPLC/ECD. Using [gamma-33P]ATP instead of
[gamma-32P]ATP or adding [33P]phosphate to a 32P-PPL assay resulted in even
higher levels of 8-oxo-dG measured. The increase in 8-oxo-dG levels during
the PPL workup is attributed to the presence and oxidation of unmodified
dGp in the reaction mixture. For a determination of true basal levels, the
PPL method will have to be modified, including the removal of dGp prior to
the phosphorylation reaction.
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