Ali Alshehri

Ceramide generation during curcumin-induced apoptosis is controlled by crosstalk among Bcl-2, Bcl-xL, caspases and glutathione.

Curcumin exhibits anti-cancer properties manifested by activation of pro-apoptotic signaling. We have demonstrated earlier that apoptosis of HL-60 human leukemia cells induced by curcumin is controlled by ceramide generated by neutral sphingomyelinase (nSMase) which contributes to sphingomyelin synthase (SMS) inhibition favoring accumulation of ceramide in cells. Here we report that the activity of nSMase, ceramide accumulation and death of HL-60 cells are inhibited by overexpression of Bcl-xL or Bcl-2 proteins, while down-regulation of nSMase interferes with degradation of Bcl-2 but not Bcl-xL. Activation of nSMase in curcumin-treated cells requires the activity of apoptosis initiator caspase-8 and executioner caspase-3, whereas nSMase depletion prevents activation of caspase-3, but not caspase-8. These data place nSMase activation downstream of caspase-8 and Bcl-xL and indicate a mutual regulation between nSMase and caspase-3 activity on one hand, and Bcl-2 level on the other hand in curcumin-treated cells. The activation of nSMase and ceramide accumulation also depended on the depletion of glutathione. The depletion of glutathione required the activity of caspase-8 and caspase-3 as well as the down-regulation of Bcl-2 and Bcl-xL. Together, the data indicate a crosstalk among Bcl-2, Bc-xL, caspases and glutathione during curcumin-induced apoptosis and point to the superior role of caspase-8 activity, Bcl-xL down-regulation and glutathione depletion in the pro-apoptotic cascade leading to nSMase activation and generation of ceramide.

TH1/TH2 chemokines/cytokines profile in rats treated with tetanus toxoid and Euphorbia tirucalli

Natural products, including their purified materials, play a remarkable role in drug development. The Euphorbiaceae family, mainly Euphorbia tirucalli, is used in some traditional medicine, and has evidence that its latex comprises immunomodulatory properties and cytokine production. This study aimed to measure the in vivo production of chemokines (IL-1α, IL-1β, IL-12, and RANTES), TH1 cytokines (IFN-γ, TNF-α, GM-CSF, and IL-2) and TH2 cytokines (IL-4, IL-6, IL-10, and IL-13) in rats after treatments with ethanol latex extract of E. tirucalli. Vaccine treated and untreated rats were divided into seven groups to assess antimicrobial activities of the extracted components. After completion of the treatment schedule, blood was withdrawn and sera were collected. The results showed that the main component of the extract was a euphol compound. The extract showed antimicrobial activity and had the ability to modulate innate and adaptive immunity. Animals treated with extract for only 7 days before vaccination showed higher levels of antibody production. The extract showed antibacterial and antifungal activities. The extract could stimulate both adaptive and innate immunity. Pre-treatment with the extract increased immune responses in vaccinated animals, indicating the usefulness of the extract before immunization.

Efficient procedure with new fused pyrimidinone derivatives, Schiff base ligand and its La and Gd complexes by green chemistry

In this study, a convenient synthesis of a series of pyrimido[4,5-d]pyrimidine, pyrimidine acetohydrazide, and thieno[3,2-d]pyrimidine-7-carbohydrazide derivatives, via the reactions of versatile, readily accessible electrophilic and nucleophilic reagents with 2-thioxodihydropyrimidine-4,6(1H,5H)-dione 1, is described. Different biologically active moieties such as thiophene and pyridine are introduced in order to investigate their anticancer activity in vitro. In addition, a Schiff base ligand derived from the reaction of 5-bromosalicylaldehyde with 6-aminothieno[3,2-d]pyrimidine carbohydrazide 8 and its La(III) and Gd(III) complexes (in the bulk and at the nanoscale) were prepared and characterized by elemental analyses, IR spectra, magnetic measurement, and electronic absorption data. Chemical shifts of the different types of protons in the NMR spectra of the prepared Schiff base and its metal complexes are also reported. The nanocomplexes were characterized with a scanning electron microscope. The cytotoxicity of all newly synthesized compounds was demonstrated and they were tested for their activity against common pathogenic organisms and anticancer activity against human epithelial colorectal adenocarcinoma cells (Caco2). Some of the newly synthesized compounds had the best recorded anticancer activity against Caco2 cells. In addition, the three active compounds were tested for antibacterial activity. The three structures succeeded in affecting and stopping the growth of Klebsiella pneumoniae strain and the results revealed promising activity.