Analysis of the action of euxanthone, a plant-derived compound that stimulates neurite outgrowth

We have investigated the neurite growth-stimulating properties of euxanthone, a xanthone derivative isolated from the Chinese medicinal plant Polygala caudata. Euxanthone was shown to exert a marked stimulatory action on neurite outgrowth from chick embryo dorsal root ganglia explanted in collagen gels, in the absence of added neurotrophins. It was also shown to promote cell survival in explanted chick embryo ganglia, and to stimulate neurite outgrowth from isolated adult rat primary sensory neurons in vitro. The further finding that euxanthone stimulates neurite outgrowth from explants of chick embryo retina and ventral spinal cord suggests an action on signaling pathways downstream of neuronal receptors for specific neurotrophic factors. Consistent with this, euxanthone did not promote neurite outgrowth from non-transfected PC12 cells, or from PC12 cells transfected with TrkB or TrkC, under conditions in which these cells extended neurites in response to, respectively, the neurotrophins nerve growth factor, brain-derived neurotrophic factor and neurotrophin 3. Western blot analysis of euxanthone-stimulated dorsal root ganglion explants showed that expression of phospho-mitogen-activated protein (MAP) kinase was up-regulated after 1 h of euxanthone-treatment. Inhibition of the MAP kinase pathway using PD98059, a specific inhibitor of MAP kinase kinase, blocked all euxanthone-stimulated neurite outgrowth. However, analysis of phospho-Akt expression indicated that the phosphatidylinositol-3 kinase-Akt pathway, another major signaling pathway engaged by neurotrophins, is not significantly activated by euxanthone. These results suggest that euxanthone promotes neurite outgrowth by selectively activating the MAP kinase pathway.     

First case of cryptococcosis in a new species of bandicoot (Bandicota indica) caused by Cryptococcus neoformans var. grubii.

The first case of cryptococcosis caused by Cryptococcus neoformans var. grubii in a new species of bandicoot (Bandicota indica) is described. The animal was trapped in a bamboo thicket in a park located in the city of Jabalpur, India. On necropsy, pathological lesions were seen in the lungs and liver and C. neoformans var. grubii was isolated from the lungs, liver, kidneys, spleen and brain but not the heart or intestine. The soil of the animal's burrow and bamboo debris around it also revealed the presence of C. neoformans var. grubii. We hypothesize that the bandicoots may potentially act as sentinel animals for environmental human pathogenic Cryptococcus species.     

Blood pressure levels among cross-cultural populations of Visakhapatnam district,Andhra Pradesh,India

BACKGROUND: Elevated blood pressure is a leading cause of morbidity and mortality throughout the world, as a major contributor to cardiovascular diseases. Blood pressure tends to vary cross-culturally and studies to address the influence of acculturization/modernization on blood pressure are limited from India, particularly from Andhra Pradesh. AIM: To provide information on blood pressure levels and variability across population groups from the State of Andhra Pradesh, India, and to examine the influence of acculturization/modernization on blood pressure levels. SUBJECTS AND METHODS: The blood pressure levels among 1316 individuals (646 men and 670 women) belonging to two tribal (Khondh and Valmiki) and two caste groups (Wadabalija and Settibalija) from rural and urban areas from Andhra Pradesh were collected. Analysis of covariance (ANCOVA) was used to examine the effect of age and sex, and population differences. RESULTS: The distribution of blood pressure showed significant variability among these population groups. Higher levels of blood pressure were noticed in an acculturizing tribe, the Valmiki, than among the Khondh, a traditional tribal population. The results indicate that age had significant effect on both systolic and diastolic blood pressure levels. Also, the systolic blood pressure was relatively more sensitive than diastolic blood pressure to the effect of age. The sex did not contribute significantly to the variability of blood pressure. CONCLUSIONS: The study revealed significant population differences in the variability of blood pressure, with higher levels among acculturizing tribal population than the non-acculturizing group. But no significant variation was noticed between rural and urban slum dwellers. Age had a significant effect on blood pressure levels.     

Improvement of Bioavailability and Anti-Inflammatory Potential of Curcumin in Combination with Emu Oil

The purpose of the present study is to evaluate the effect of emu oil on bioavailability of curcumin when co-administered and to evaluate the property that enhances the anti-inflammatory potential of curcumin. Oral bioavailability of curcumin in combination with emu oil was determined by measuring the plasma concentration of curcumin by HPLC. The anti-inflammatory potential was evaluated in carrageenan-induced paw edema model (acute model) and in Freund’s complete adjuvant (FCA)-induced arthritis model (chronic model) in male SD rats. The anti-inflammatory potential of curcumin in combination with emu oil has been significantly increased in both acute and chronic inflammatory models as evident from inhibition of increase in paw volume, arthritic score, and expression of pro-inflammatory cytokines. The increased anti-inflammatory activity in combination therapy is due to enhanced bioavailability (5.2-fold compared to aqueous suspension) of curcumin by emu oil. Finally, it is concluded that the combination of emu oil with curcumin will be a promising approach for the treatment of arthritis.     

B1 but not B2 bradykinin receptor agonists promote DU145 prostate cancer cell proliferation and migration

Background

The kallikrein-kinin system (KKS) is an endogenous pathway involved in angiogenesis and tumourigenesis, both vital for cancer growth and progression.

Objectives

To investigate the effect of two bradykinin receptor (B1R and B2R) agonists on growth and motility of prostate tumour (DU145) and micro-vascular endothelial cells (dMVECs).

Methods

Increasing concentrations of selective B1R and B2R agonists were added to cultured cells. Cell proliferation and migration were assessed using the 3-[4,5 dimethylthiazol-2-yl]-2,5-diphenyl-tetrazolium bromide (MTT) and modified Boyden Chamber assays, respectively. Where significant stimulation was found, the influence of an antagonist was also investigated.

Results

Neither growth nor motility of endothelial cells was affected by either agonist. In DU145 cells, while the B2R agonist was without any significant effect, the B1R agonist stimulated proliferation and migration at concentrations of 10nM and 50nM respectively. Further, this effect was abrogated when cells were pre-incubated with a B1R antagonist.

Conclusions

Unlike the physiologically-active B2R, the pathologically-inducible B1R may be implicated in prostate tumourigenic events. The involvement of the KKS in malignant prostate pathology supports on-going exploration of bradykinin receptor antagonists as target candidates in the development of alternate approaches to cancer therapy.     

Correlates of sensitization to Blomia tropicalis and Dermatophagoides pteronyssinus in asthma in Barbados

BACKGROUND: Sensitivity to the mite Blomia tropicalis is related to asthma in tropical climates, but correlates of sensitivity to B. tropicalis and its relationship to Dermatophagoides pteronyssinus sensitivity have not been widely examined in families with asthma. The main objective of this study was to determine prevalence and correlates of sensitivity to these mites in families with asthma and characteristics of persons sensitized to both. METHODS: Antibodies to major antigens (Blo t 5 and Der p 1) of these mites were measured by immunochemiluminescent assay in 481 members of 29 families from Barbados ascertained through two asthmatic siblings. RESULTS: Blo t 5 sensitivity was present in 261 subjects (46%) and was associated with younger age, higher total serum IgE level, and more than a three-fold increased prevalence of asthma (42 vs. 13%). Der p 1 sensitivity was less common (27%) and showed similar associations with age, IgE, and asthma. Of the 261 subjects sensitized to Blo t 5, 116 were also sensitized to Der p 1; they were younger, had higher total and Blo t 5 specific IgE levels, and had more than twice the asthma prevalence as those sensitized to Blo t 5 alone (59 vs. 29%). Der p 1 sensitivity without Blo t 5 sensitivity was uncommon; 90% of those sensitized to Der p 1 were also sensitized to Blo t 5. Geometric mean total IgE levels were lowest in the 207 participants without any mite sensitization (102 U/ml), intermediate in 158 sensitized to either Blo t 5 OR Der p 1 (609 U/ml), and highest in 116 sensitized to both (1,869 U/ml). CONCLUSIONS: Blo t 5 is the predominant sensitizing mite allergen in these Barbadian families with correlates similar to Der p 1. Concomitant sensitization to Der p 1 appears to identify a more reactive subgroup of individuals at a higher risk of asthma.     

Galactose residues on the lipooligosaccharide of Moraxella catarrhalis 26404 form the epitope recognized by the bactericidal antiserum from conjugate vaccination

Lipooligosaccharide (LOS) from Moraxella catarrhalis has the potential to elicit bactericidal antibodies against the pathogen. We generated LOS-based conjugate vaccines that elicited bactericidal antibodies in animal models. However, epitopes on the LOS recognized by the functional anti-LOS antibodies remain unidentified. In this study, a mutant strain, D4, which lost the recognition by a bactericidal anti-LOS rabbit serum in Western blotting was generated from a serotype C strain 26404 by random transposon mutagenesis. Sequence analysis revealed there was an insertion of a kanamycin resistance gene in the lgt2 gene of D4, which encodes beta(1-4)-galactosyltransferase. An isogenic lgt2 mutant, 26404lgt2, was constructed. Structural analysis indicated that the mutant strain produced a truncated LOS lacking terminal galactoses from 4- and 6-linked oligosaccharide chains of strain 26404. Further studies showed that the antiserum lost the recognition of both mutant cells and LOSs in Western blotting, an enzyme-linked immunosorbent assay (ELISA), or a flow cytometry assay. The antiserum also lost the ability to kill the mutant strain in a bactericidal assay, whereas it showed a bactericidal titer of 1:80 to strain 26404. In an inhibition ELISA, d-(+)-galactose or 26404lgt2 LOS showed no inhibition. However, the 26404 LOS and a serotype A O35E LOS with terminal galactoses on its 6-linked oligosaccharide chain showed >90% inhibition, while a serotype B 26397 LOS showed >60% inhibition. These studies suggest that the terminal alpha-Gal-(1-->4)-beta-Gal on the 6-linked oligosaccharide chain of 26404 LOS plays a critical role in forming the epitope recognized by the bactericidal antiserum induced by immunization with our conjugate vaccine.     

Carvedilol attenuates neuroleptic-induced orofacial dyskinesia: possible antioxidant mechanisms

1. Tardive dyskinesia (TD), a syndrome of potentially irreversible, involuntary hyperkinetic disorder occurring in 20 - 40% of the patient population undergoing chronic neuroleptic treatment is a major limitation of neuroleptic therapy. 2. Oxidative stress and products of lipid peroxidation are implicated in the pathophysiology of various neurological disorders including tardive dyskinesia. 3. Chronic treatment with neuroleptics leads to the development of abnormal oral movements in rats known as vacuous chewing movements (VCMs). Vacuous chewing movements in rats are widely accepted as an animal model of tardive dyskinesia. 4. All the antipsychotics were administered i.p. once daily for 21 days, whereas carvedilol (also i.p.) was administered twice daily. Rats chronically treated with haloperidol (1.0 mg kg(-1)) or chlorpromazine (5 mg kg(-1)) but not clozapine (2 mg kg(-1)) significantly developed vacuous chewing movements and tongue protrusions. Carvedilol dose dependently (0.5 - 2 mg kg(-1)) reduced the haloperidol or chlorpromazine-induced vacuous chewing movements and tongue protrusions. 5. Biochemical analysis revealed that chronic haloperidol or chlorpromazine but not clozapine treatment significantly induced lipid peroxidation and decreased the glutathione (GSH) levels in the forebrains of rats. Chronic haloperidol or chlorpromazine but not clozapine treated rats showed decreased forebrain levels of antioxidant defence enzymes, superoxide dismutase (SOD) and catalase. 6. Co-administration of carvedilol (0.5-2 mg kg(-1)) significantly reduced the lipid peroxidation and restored the decreased glutathione levels by chronic haloperidol or chlorpromazine treatment. Co-administration of carvedilol (1-2 mg kg(-1)) significantly reversed the haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels in rats. However, lower dose of carvedilol (0.5 mg kg(-1)) failed to reverse chronic haloperidol or chlorpromazine-induced decrease in forebrain SOD and catalase levels. 7. The major findings of the present study suggest that oxidative stress might play a significant role in neuroleptic-induced orofacial dyskinesia. In conclusion, carvedilol could be a useful drug for the treatment of neuroleptic-induced orofacial dyskinesia.