Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis

Alzheimer's disease (AD) is the most common form of neurodegeneration and the major cause of dementia. This multifactorial disorder is clinically defined by progressive behavioural and cognitive deficits, and neuropathologically characterized by β‐amyloid aggregation, hyperphosphorylated tau and neuroinflammation. Oridonin, a diterpenoid isolated from Chinese herb Rabdosia rubescens, has multiple biological properties, especially anti‐inflammatory and neuroregulatory activities. Potential therapeutic effects of Oridonin were investigated in an animal model of cerebral amyloidosis for AD, transgenic APP/PS1 mice. Oridonin was suspended in carboxymethylcellulose or loaded with a nanostructured emulsion, and was orally administrated or injected. Before, during and following the experimental treatments, behavioural tests were performed with these transgenic mice and their naive littermates. Following relatively short‐term treatments of 10 days, brain tissue of mice were removed for immunohistochemical assays. The results indicate that both oral treatment and injection of Oridonin significantly attenuated β‐amyloid deposition, plaque‐associated APP expression and microglial activation in brain of transgenic mice. Furthermore, injection of Oridonin‐nanoemulsion ameliorated deficits in nesting, an important affiliative behaviour, and in social interaction. Additional in vitro studies indicated that Oridonin effectively attenuated inflammatory reaction of macrophage and microglial cell lines. Our results suggest that Oridonin might be considered a promising therapeutic option for human AD or other neurodegenerative diseases.     

Palifermin for the protection and regeneration of epithelial tissues following injury: new findings in basic research and pre‐clinical models

Keratinocyte growth factor (KGF) is a paracrine‐acting epithelial mitogen produced by cells of mesenchymal origin, that plays an important role in protecting and repairing epithelial tissues. Pre‐clinical data initially demonstrated that a recombinant truncated KGF (palifermin) could reduce gastrointestinal injury and mortality resulting from a variety of toxic exposures. Furthermore, the use of palifermin in patients with hematological malignancies reduced the incidence and duration of severe oral mucositis experienced after intensive chemoradiotherapy. Based upon these findings, as well as the observation that KGF receptors are expressed in many, if not all, epithelial tissues, pre‐clinical studies have been conducted to determine the efficacy of palifermin in protecting different epithelial tissues from toxic injury in an attempt to model various clinical situations in which it might prove to be of benefit in limiting tissue damage. In this article, we review these studies to provide the pre‐clinical background for clinical trials that are described in the accompanying article and the rationale for additional clinical applications of palifermin.     

Epigenetic silencing of the WNT antagonist Dickkopf 3 disrupts normal Wnt/β‐catenin signalling and apoptosis regulation in breast cancer cells

Dickkopf‐related protein 3 (DKK3) is an antagonist of Wnt ligand activity. Reduced DKK3 expression has been reported in various types of cancers, but its functions and related molecular mechanisms in breast tumorigenesis remain unclear. We examined the expression and promoter methylation of DKK3 in 10 breast cancer cell lines, 96 primary breast tumours, 43 paired surgical margin tissues and 16 normal breast tissues. DKK3 was frequently silenced in breast cell lines (5/10) by promoter methylation, compared with human normal mammary epithelial cells and tissues. DKK3 methylation was detected in 78% of breast tumour samples, whereas only rarely methylated in normal breast and surgical margin tissues, suggesting tumour‐specific methylation of DKK3 in breast cancer. Ectopic expression of DKK3 suppressed cell colony formation through inducing G0/G1 cell cycle arrest and apoptosis of breast tumour cells. DKK3 also induced changes of cell morphology, and inhibited breast tumour cell migration through reversing epithelial‐mesenchymal transition (EMT) and down‐regulating stem cell markers. DKK3 inhibited canonical Wnt/β‐catenin signalling through mediating β‐catenin translocation from nucleus to cytoplasm and membrane, along with reduced active‐β‐catenin, further activating non‐canonical JNK signalling. Thus, our findings demonstrate that DKK3 could function as a tumour suppressor through inducing apoptosis and regulating Wnt signalling during breast tumorigenesis.     

Apolipoprotein E,brain injury and neurodevelopmental outcome of children

Apolipoprotein E plays an important role in neurodegenerative processes in adulthood, whereas its neurodevelopmental role is uncertain. We aimed to study the effect of apolipoprotein E on neurodevelopment in a cohort liable to neurodevelopmental changes. The cohort consisted of very preterm (<32 gestational weeks) and/or very low birth weight (<1500 g) children, and the longitudinal follow‐up protocol included sequential cranial ultrasounds during infancy, brain magnetic resonance imaging at term‐equivalent age, neurological and cognitive assessment (Mental Developmental Index) at the corrected age of 2 years and cognitive and neuropsychological assessments (Wechsler Preschool and Primary Scale of Intelligence and Developmental NEuroPSYchological Assessment) at the chronological age of 5 years. Apolipoprotein E genotypes were determined from 322 children. Ultrasound and magnetic resonance imaging data were available for 321 (99.7%) and 151 (46.9%) children, respectively. Neurodevelopmental assessment data were available for 138 (42.9%) to 171 (53.1%) children. Abnormal findings in ultrasounds and magnetic resonance imaging were found in 163 (50.8%) and 64 (42.4%) children, respectively. Mild cognitive delay at the corrected age of 2 years and the chronological age of 5 years was suspected in 21 (12.3%) of 171 and 19 (13.8%) of 138 children, respectively. In the Developmental NEuroPSYchological Assessment, 47 (32.6%) of 144 children had significantly impaired performances in more than one study subtest. No associations between the apolipoprotein E genotypes and imaging findings or measured neurodevelopmental variables were found. Apolipoprotein E genotypes do not appear to have major impact on brain vulnerability or neurodevelopment in children .     

Genetic variation in dopamine‐related gene expression influences motor skill learning in mice

Several neurodevelopmental disorders with a strong genetic basis, including attention‐deficit/hyperactivity disorder, autism spectrum disorders and developmental coordination disorder, involve deficits in fine motor skills. This phenotype may depend on heritable variation in components of the dopamine (DA) system, which is known to play a critical role in motor skill learning. In this study, we took advantage of two inbred strains of mice (BALB/c and C57BL/6) that differ markedly in the number of midbrain DA neurons in order to investigate the influence of such naturally occurring genetic variation on the acquisition and performance of fine motor skills. Gene expression analysis of midbrain, frontal cortex and striatum showed significant differences in the expression of presynaptic and postsynaptic dopaminergic (DAergic) markers (e.g. tyrosine hydroxylase, DA transporter, DA D4 receptor, DA D5 receptor and DARPP‐32) between these two strains. BALB/c mice had lower learning rate and performance scores in a complex skilled reaching task when compared with C57BL/6 mice. A negative correlation was found between the motor learning rate and level of DARPP‐32 mRNA expression in the frontal cortex contralateral to the trained forelimb. The rate of motor learning was also negatively correlated with the levels of DARPP‐32 and DA D1 receptor mRNAs in the striatum. Our results suggest that genetically driven variation in frontostriatal DAergic neurotransmission is a major contributor to individual differences in motor skill learning. Moreover, these findings implicate the D1R/cAMP/DARPP‐32 signaling pathway in those neurodevelopmental disorders that are associated with fine motor skill deficits.     

Odor Qualities and Thresholds of Physiological Metabolites of 1,8‐Cineole as an Example for Structure?Activity Relationships Considering Chirality Aspects

The present study aimed at analyzing the odor properties of a group of physiological human metabolites of the odorant 1,8‐cineole: 2,3‐dehydro‐, α2,3‐epoxy‐, α/β2‐hydroxy‐, α3‐hydroxy‐, 4‐hydroxy‐, 7‐hydroxy‐, 9‐hydroxy‐, 2‐oxo‐, and 3‐oxo‐1,8‐cineole. These metabolites constitute a group of structurally closely related molecules, which differ mainly in nature and position of O‐containing functional groups. They thus offer the possibility to correlate odor properties with molecular structure, i.e., to establish structure? odor relationships of compounds that are biologically generated from a potent odorant as parent substance. Generally, the metabolites preserved the eucalyptus‐like odor quality of 1,8‐cineole but showed additional odor notes such as sweet, citrus‐like, plastic‐like, earthy, musty, and faecal, which made them distinguishable. The individual enantiomers of chiral molecules also exhibited different odors. With the exception of 2,3‐dehydro‐1,8‐cineole, all metabolites showed a highly decreased odor threshold in comparison to 1,8‐cineole. The determination of odor qualities and odor thresholds was accomplished by gas chromatography/olfactometry (GC/O) on achiral and chiral GC capillaries. The results were correlated with common theories on structure? odor relationships.     

Chemical Composition and Antimicrobial Activity of the Essential Oil from the Edible Aromatic Plant Aristolochia delavayi

The essential oil obtained by hydrodistillation from the aerial parts of Aristolochia delavayi Franch. (Aristolochiaceae), a unique edible aromatic plant consumed by the Nakhi (Naxi) people in Yunnan, China, was investigated using GC/MS analysis. In total, 95 components, representing more than 95% of the oil composition, were identified, and the main constituents found were (E)‐dec‐2‐enal (52.0%), (E)‐dodec‐2‐enal (6.8%), dodecanal (3.35%), heptanal (2.88%), and decanal (2.63%). The essential oil showed strong inhibitory activity (96% reduction) of the production of bacterial volatile sulfide compounds (VSC) by Klebsiella pneumoniae, an effect that was comparable with that of the reference compound citral (91% reduction). Moreover, the antimicrobial activity of the essential oil and the isolated major compound against eight bacterial and six fungal strains were evaluated. The essential oil showed significant antibacterial activity against Providencia stuartii and Escherichia coli, with minimal inhibitory concentrations (MIC) ranging from 3.9 to 62.5 μg/ml. The oil also showed strong inhibitory activity against the fungal strains Trichophyton ajelloi, Trichophyton terrestre, Candida glabrata, Candida guilliermondii, and Cryptococcus neoformans, with MIC values ranging from 3.9 to 31.25 μg/ml, while (E)‐dec‐2‐enal presented a lower antifungal activity than the essential oil.     

Variability of the Needle Essential Oils of Juniperus deltoides R.P.Adams from Different Populations in Serbia and Croatia

The essential‐oil compositions of one Croatian and three Serbian populations of Juniperus deltoides R.P.Adams have been determined by GC/MS analysis. In total, 147 compounds were identified, representing 97.3–98.3% of the oil composition. The oils were dominated by monoterpenes, which are characteristic components for the species of the section Juniperus. Two monoterpenes, α‐pinene and limonene, were the dominant constituents, with a summed‐up average content of 49.45%. Statistical methods were used to determine the diversity of the terpene classes and the common terpenes between the newly described J. deltoides populations from Serbia and Croatia. Only reports on several specimens from this species have been reported so far, and there are no studies that treat population diversity. Cluster analysis of the oil contents of 21 terpenes showed high correlation with the geographical distribution of the populations, separating the Croatian from the Serbian populations. The comparison of the essential‐oil compositions obtained in the present study with literature data, showed the separation of J. deltoides and J. oxycedrus ssp. oxycedrus from the western Mediterranean region.     

Synthesis,Characterization, and Anti‐Amoebic Activity of N‐(Pyrimidin‐2‐yl)benzenesulfonamide Derivatives

A new series of N‐(pyrimidin‐2‐yl)benzenesulfonamide derivatives, 3a – 3i and 4a – 4i , was synthesized from pyrimidin‐2‐amines, 2a – 2i , with the aim to explore their effects on in vitro growth of Entamoeba histolytica. The chemical structures of the compounds were elucidated by elemental analysis, FT‐IR, ¹H‐ and ¹³C‐NMR, and ESI mass‐spectral data. In vitro anti‐amoebic activity was evaluated against HM1 : IMSS strain of Entamoeba histolytica. The IC₅₀ values were calculated by using the double dilution method. The results were compared with the IC₅₀ value of the standard drug ‘metronidazole’. The selected compounds were tested for their cytotoxic activities by cell‐viability assay using H9C2 cardiac myoblasts cell line, and the results indicated that all the compounds displayed remarkable >80% viabilities to a concentration of 100 μg/ml.