Nitrogen-bridged substituted 8-arylquinolines as potent PDE IV inhibitors

Potent inhibitors of the human PDE IV enzyme are described. Substituted 8-arylquinoline analogs bearing nitrogen-linked side chain were identified as potent inhibitors based on the SAR described herein. The pharmacokinetic profile of the best analog and the in vivo efficacy in an ovalbumin-induced bronchoconstriction assay in conscious guinea pigs are reported.     

STIL,a peculiar molecule from styles,specifically dephosphorylates the pollen receptor kinase LePRK2 and stimulates pollen tube growth <Emphasis Type="Italic">in vitro</Emphasis>

Background  

LePRK1 and LePRK2 are two pollen receptor kinases localized to the plasma membrane, where they are present in a high molecular weight complex (LePRK complex). LePRK2 is phosphorylated in mature and germinated pollen, but is dephosphorylated when pollen membranes are incubated with tomato or tobacco style extracts.     

STEAP, a prostate tumor antigen, is a target of human CD8+ T cells

STEAP is a recently identified protein shown to be particularly overexpressed in prostate cancer and also present in numerous human cancer cell lines from prostate, pancreas, colon, breast, testicular, cervical, bladder and ovarian carcinoma, acute lymphocytic leukemia and Ewing sarcoma. This expression profile renders STEAP an appealing candidate for broad cancer immunotherapy. In order to investigate if STEAP is a tumor antigen that can be targeted by specific CD8⁺ T cells, we identified two high affinity HLA-A*0201 restricted peptides (STEAP_86–94 and STEAP_262–270). These peptides were immunogenic in vivo in HLA-A*0201 transgenic HHD mice. Peptide specific murine CD8 T cells recognized COS-7 cells co-transfected with HHD (HLA-A*0201) and STEAP cDNA constructs and also HLA-A*0201⁺ STEAP⁺ human tumor cells. Furthermore, STEAP_86–94 and STEAP_262–270 stimulated specific CD8⁺ T cells from HLA-A*0201⁺ healthy donors, and these peptide specific CD8⁺ T cells recognized STEAP positive human tumor cells in an HLA-A*0201-restricted manner. Importantly, STEAP_86–94-specific T cells were detected and reactive in the peripheral blood mononuclear cells in NSCLC and prostate cancer patients ex vivo. These results show that STEAP can be a target of anti-tumor CD8⁺ T cells and that STEAP peptides can be used for a broad-spectrum-tumor immunotherapy.     

Alloxan reduces amplitude of ventricular myocyte shortening and intracellular Ca2+ without altering L-type Ca2+ current, sarcoplasmic reticulum Ca2+ content or myofilament sensitivity to Ca2+ in Wistar rats

Alloxan is widely used to induce diabetes mellitus in experimental animals. Recent studies have provided evidence that alloxan has direct actions on cardiac muscle contraction. The aim of this study was to further investigate the mechanisms underlying the effects of alloxan on ventricular myocyte shortening and intracellular Ca²⁺ transport. Amplitude of myocyte shortening was reduced in a dose-dependent manner as the concentration of alloxan was increased in the range 10^?7–10^?4 M. Amplitude of shortening was reduced (56.8 ± 6.6%, n = 27) by 10^?6 M alloxan and was partially reversed during a 10 min washout. Amplitude of the Ca²⁺ transient was also reduced (79.7 ± 2.9%, n = 29) by 10^?6 M alloxan. Caffeine-evoked sarcoplasmic reticulum Ca²⁺ release, fractional release of Ca²⁺, assessed by comparing the amplitude of electrically evoked with that of caffeine-evoked Ca²⁺ transients, and fura-2-cell length trajectory during the late stages of relaxation of myocyte twitch contraction were not significantly altered by alloxan. The amplitude of L-type Ca²⁺ current was not altered by alloxan. Alterations in sarcoplasmic reticulum Ca²⁺ transport, myofilament sensitivity to Ca²⁺, and L-type Ca²⁺ current do not appear to underlie the negative inotropic effects of alloxan.     

Raman spectral analysis of the 1300 cm−1 region for lipid and membrane studies

The Raman spectra of fatty acids, fatty acid methyl esters and several membrane lipids are analyzed in the 1300 cm^?1 region. The ratio of peak intensities at 1303/1267 cm^?1 varies linearly with the ratio of methylene to vinyl groups in the hydrocarbon chain. This parameter should be useful for estimating the degree of unsaturation in isolated lipids and lipids in membranes.     

^14CO2 Fixation and Translocation of Photoassimilates as Selection Criteria of Egyptian Taro Genotypes

The growth characterlstlcs, different physlological parameters, photosynthetic activity （^14CO2 fixation）, and the translocatlon rate of photoassimllates In different taro （Colocasia esculenta L. Schott） genotypes was studled In order to determlne the posslble use of these parameters as selectlon crlterla for dlfferent wldely used genotypes of taro （Delta No. 9, 15, 20, 21, and balady）. The results obtalned suggest that Delta No. 21 shows the most slgnlflcant increase In all parameters tested compared wlth the control （balady）, followed by Delta No. 9, 15, and 20, respectively. The results show a positive correlation between photosynthetlc actlvlty, translocatlon efflclency, and total yield. The selected clone Delta No. 21 Is recommended for cultlvatlon In the delta reglon of Egypt.     

Prostaglandin E2 acts at two distinct pathways of T lymphocyte activation: inhibition of interleukin 2 production and down-regulation of transferrin receptor expression

The mechanism by which prostaglandin E2 (PGE2) inhibits human T lymphocyte activation and proliferation was studied. We analyzed the effect of physiologic concentrations of PGE2 on interleukin 2 (IL 2) production, expression of IL 2 receptor (Tac antigen), and expression of the transferrin receptor after in vitro activation with phytohemagglutinin. PGE2 inhibited T lymphocyte proliferation by 80 to 90% of control values. This was associated with a similar degree of inhibition of IL 2 production while the expression of IL 2 receptor was not affected. This was in marked contrast to the expression of the transferrin receptor, which was inhibited 65% after 72 hr of in vitro activation. The addition of exogenous, purified IL 2 reconstituted lymphocyte proliferation to 50% of control values, but had no effect on transferrin receptor expression. Because PGE2 is known to increase the intracellular concentration of 3',5' cyclic adenosine monophosphate (cAMP), we investigated the effect of another adenylate cyclase activator, i.e., isoproterenol, as well as the effect of extracellular administration of the cAMP derivative dibutyryl cAMP (dBcAMP) on IL 2 production, Tac antigen expression, and transferrin receptor expression. It was demonstrated that isoproterenol, as well as dBcAMP, inhibited transferrin receptor expression on PHA-activated T lymphocytes to the same extent as PGE2, and exogenous IL 2 could not counteract the down-regulation of the receptor expression. In contrast, neither isoproterenol nor dBcAMP had any significant effect on IL 2 receptor expression. Prostaglandin F2 alpha (PGF2 alpha), which has been reported to elevate intracellular cyclic GMP levels, had no effect on lymphocyte activation and proliferation, and did not counteract the PGE2-induced depression in IL 2 production. In contrast to its effect on peripheral blood lymphocytes, PGE2 had no effect on transferrin receptor expression or cell proliferation by IL 2-dependent T cell clones and IL 2-independent T cell lines. These studies demonstrate that PGE2 exerts its inhibitory effects on T cell activation and proliferation via two distinct pathways: inhibition of IL 2 production and inhibition of transferrin receptor expression. The transferrin receptor inhibition is mediated via the cAMP pathway and is IL 2-independent.     

Phagocytosis of autologous lymphocytes by cervical preneoplastic and neoplastic cells

Eighty-nine random Pap smears of the uterine cervix were examined to evaluate the phagocytic abnormal cells (PACs) of atypical, dysplastic and neoplastic tissues against infiltrated blood cells. The results revealed that none of the PACs have been identified in atypical (II) and mild dysplastic cells (IIIa). Low levels (1.2%) of PACs were initially demonstrated in patients with moderate dysplasia (IIIb) that increased 1.7-fold in subsequent severe dysplasia (IIIc) and further increased 2.8-fold in invasive carcinomas of the cervix (V). In addition, the data showed age-related responsiveness toward the development of PACs, where 82% of old patients have developed phagocytic activity in moderate dysplastic cells compared with 27% of young patients. However, the difference became less significant at the subsequent classes of the disease. These data further demonstrated that PACs are class-dependent and it may explain one mechanism by which precancerous cells escape immunosurveillance.