Drug and Alcohol Rehabilitation: Towards an Understanding of the Function of the Phytochelatin Synthase of Schistosoma Mansoni.

Towards an Understanding of the Function of the Phytochelatin Synthase of Schistosoma mansoni.

Filed under: Drug and Alcohol Rehabilitation

PLoS Negl Trop Dis. 2013 Jan; 7(1): e2037
Rigouin C, Nylin E, Cogswell AA, Schaumlöffel D, Dobritzsch D, Williams DL

Phytochelatin synthase (PCS) is a protease-like enzyme that catalyzes the production of metal chelating peptides, the phytochelatins, from glutathione (GSH). In plants, algae, and fungi phytochelatin production is important for metal tolerance and detoxification. PCS proteins also function in xenobiotic metabolism by processing GSH S-conjugates. The aim of the present study is to elucidate the role of PCS in the parasitic worm Schistosoma mansoni. Recombinant S. mansoni PCS proteins expressed in bacteria could both synthesize phytochelatins and hydrolyze various GSH S-conjugates. We found that both the N-truncated protein and the N- and C-terminal truncated form of the enzyme (corresponding to only the catalytic domain) work through a thiol-dependant and, notably, metal-independent mechanism for both transpeptidase (phytochelatin synthesis) and peptidase (hydrolysis of GSH S-conjugates) activities. PCS transcript abundance was increased by metals and xenobiotics in cultured adult worms. In addition, these treatments were found to increase transcript abundance of other enzymes involved in GSH metabolism. Highest levels of PCS transcripts were identified in the esophageal gland of adult worms. Taken together, these results suggest that S. mansoni PCS participates in both metal homoeostasis and xenobiotic metabolism rather than metal detoxification as previously suggested and that the enzyme may be part of a global stress response in the worm. Because humans do not have PCS, this enzyme is of particular interest as a drug target for schistosomiasis.
HubMed – drug

Neglected tropical diseases of oceania: review of their prevalence, distribution, and opportunities for control.

Filed under: Drug and Alcohol Rehabilitation

PLoS Negl Trop Dis. 2013 Jan; 7(1): e1755
Kline K, McCarthy JS, Pearson M, Loukas A, Hotez PJ

Among Oceania’s population of 35 million people, the greatest number living in poverty currently live in Papua New Guinea (PNG), Fiji, Vanuatu, and the Solomon Islands. These impoverished populations are at high risk for selected NTDs, including Necator americanus hookworm infection, strongyloidiasis, lymphatic filariasis (LF), balantidiasis, yaws, trachoma, leprosy, and scabies, in addition to outbreaks of dengue and other arboviral infections including Japanese encephalitis virus infection. PNG stands out for having the largest number of cases and highest prevalence for most of these NTDs. However, Australia’s Aboriginal population also suffers from a range of significant NTDs. Through the Pacific Programme to Eliminate Lymphatic Filariasis, enormous strides have been made in eliminating LF in Oceania through programs of mass drug administration (MDA), although LF remains widespread in PNG. There are opportunities to scale up MDA for PNG’s major NTDs, which could be accomplished through an integrated package that combines albendazole, ivermectin, diethylcarbamazine, and azithromycin, in a program of national control. Australia’s Aboriginal population may benefit from appropriately integrated MDA into primary health care systems. Several emerging viral NTDs remain important threats to the region.
HubMed – drug

Epidermal Growth Factor Protects Squamous Cell Carcinoma against Cisplatin-Induced Cytotoxicity through Increased Interleukin-1? Expression.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(2): e55795
Ko SC, Huang CR, Shieh JM, Yang JH, Chang WC, Chen BK

The expression of cytokines, such as IL-1?, and the activation of the epidermal growth factor receptor (EGFR) are crucial regulators in the process of carcinogenesis. The correlation between growth factor and activated cytokine signals in the control of tumor development is a critical issue to be clarified. In our study, we found that the IL-1? gene and protein expression were induced by EGF in squamous cell carcinoma. To clarify the mechanism involved in EGF-regulated IL-1? expression, we examined the transcriptional activity and mRNA stability of IL-1? in EGF-treated cells. We found that EGF induced the expression of IL-1? and was mediated through transcriptional activation, but not through mRNA stability. The involvement of Akt and NF-?B signaling pathways in the EGF-induced IL-1? gene expression was confirmed by knockdown of RelA and Akt in cells or treating cells with Akt and NF-?B inhibitors, LY294002 and parthenolide, respectively. The expression of dominant negative I?B also repressed the activation of NF-?B and inhibited EGF-induced IL-1? expression. Using immunofluorescence staining assay, the EGF-stimulated nuclear translocation of NF-?B (p65) was inhibited by pre-treating cells with LY294002 and parthenolide. Furthermore, EGF increased the binding of NF-?B to the NF-?B binding site of the IL-1? promoter through the activation of the Akt/NF-?B pathway, which resulted in activating IL-1? promoter activity. The expression and secretion of IL-1? induced by EGF considerably reduced chemotherapeutic drug cisplatin-induced cell death. These results showed that EGF enhanced the expression of IL-1?, which was mediated by the Akt/NF-?B pathway. The activation of EGF signaling and increase of IL-1? contributed to chemotherapeutic resistance of cancer cells, suggesting that the expression of IL-1? may be used as a biomarker to evaluate successful cancer treatment.
HubMed – drug

Admixed Phylogenetic Distribution of Drug Resistant Mycobacterium tuberculosis in Saudi Arabia.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2013; 8(2): e55598
Varghese B, Supply P, Allix-Béguec C, Shoukri M, Al-Omari R, Herbawi M, Al-Hajoj S

The phylogeographical structure of Mycobacterium tuberculosis is generally bimodal in low tuberculosis (TB) incidence countries, where genetic lineages of the isolates generally differ with little strain clustering between autochthonous and foreign-born TB patients. However, less is known on this structure in Saudi Arabia-the most important hub of human migration as it hosts a total population of expatriates and pilgrims from all over the world which is equal to that of its citizens.We explored the mycobacterial phylogenetic structure and strain molecular clustering in Saudi Arabia by genotyping 322 drug-resistant clinical isolates collected over a 12-month period in a national drug surveillance survey, using 24 locus-based MIRU-VNTR typing and spoligotyping.In contrast to the cosmopolitan population of the country, almost all the known phylogeographic lineages of M. tuberculosis complex (with noticeable exception of Mycobacterium africanum/West-African 1 and 2) were detected, with Delhi/CAS (21.1%), EAI (11.2%), Beijing (11.2%) and main branches of the Euro-American super-lineage such as Ghana (14.9%), Haarlem (10.6%) and Cameroon (7.8%) being represented. Statistically significant associations of strain lineages were observed with poly-drug resistance and multi drug resistance especially among previously treated cases (p value of HubMed – drug

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