PIM2 Induced COX-2 and MMP-9 Expression in Macrophages Requires PI3K and Notch1 Signaling

Activation of inflammatory immune responses during granuloma formation by the host upon infection of mycobacteria is one of the crucial steps that is often associated with tissue remodeling and breakdown of the extracellular matrix. In these complex processes, cyclooxygenase-2 (COX-2) plays a major role in chronic inflammation and matrix metalloproteinase-9 (MMP-9) significantly in tissue remodeling. In this study, we investigated the molecular mechanisms underlying Phosphatidyl-myo-inositol dimannosides (PIM2), an integral component of the mycobacterial envelope, triggered COX-2 and MMP-9 expression in macrophages. PIM2 triggers the activation of Phosphoinositide-3 Kinase (PI3K) and Notch1 signaling leading to COX-2 and MMP-9 expression in a Toll-like receptor 2 (TLR2)-MyD88 dependent manner. Notch1 signaling perturbations data demonstrate the involvement of the cross-talk with members of PI3K and Mitogen activated protein kinase pathway. Enforced expression of the cleaved Notch1 in macrophages induces the expression of COX-2 and MMP-9. PIM2 triggered significant p65 nuclear factor-kappa B (NF-kappa B) nuclear translocation that was dependent on activation of PI3K or Notch1 signaling. Furthermore, COX-2 and MMP-9 expression requires Notch1 mediated recruitment of uppressor of Hairless (CSL) and NF-kappa B to respective promoters. Inhibition of PIM2 induced COX-2 resulted in marked reduction in MMP-9 expression clearly implicating the role of COX-2 dependent signaling events in driving the MMP-9 expression. Taken together, these data implicate PI3K and Notch1 signaling as obligatory early proximal signaling events during PIM2 induced COX-2 and MMP-9 expression in macrophages.

Microglia play a major role in direct viral-induced demyelination

Microglia are the resident macrophage-like populations in the central nervous system (CNS). Microglia remain quiescent, unable to perform effector and antigen presentation (APC) functions until activated by injury or infection, and have been suggested to represent the first line of defence for the CNS. Previous studies demonstrated that microglia can be persistently infected by neurotropic mouse hepatitis virus (MHV) which causes meningoencephalitis, myelitis with subsequent axonal loss, and demyelination and serve as a virus-induced model of human neurological disease multiple sclerosis (MS). Current studies revealed that MHV infection is associated with the pronounced activation of microglia during acute inflammation, as evidenced by characteristic changes in cellular morphology and increased expression of microglia-specific proteins, Iba1 (ionized calcium-binding adaptor molecule 1), which is a macrophage/microglia-specific novel calcium-binding protein and involved in membrane ruffling and phagocytosis. During chronic inflammation (day 30 postinfection), microglia were still present within areas of demyelination. Experiments performed in ex vivo spinal cord slice culture and in vitro neonatal microglial culture confirmed direct microglial infection. Our results suggest that MHV can directly infect and activate microglia during acute inflammation, which in turn during chronic inflammation stage causes phagocytosis of myelin sheath leading to chronic inflammatory demyelination.

Anthrapyrazolone analogues intercept inflammatory JNK signals to moderate endotoxin induced septic shock

Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality. In the context of kinase specificities, an extensive library of anthrapyrazolone analogues has been investigated for the selective inhibition of c-JNK and thereby to gain control over the inflammation associated risks. In our comprehensive biochemical characterization, it is observed that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the obtained results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.

Solute induced liquid crystalline behaviour of a quaternary ammonium salt and its application to structure determination

A new liquid crystalline phase, induced by the addition of small amounts of a non-mesogenic solute (such as dimethyl sulphoxide or methyl iodide) to a quaternary ammonium salt, N-methyl-N,N,N-trioctadecylammonium iodide (MTAI), has been detected by NMR and optical microscopic studies. In some cases, there is a coexistence of nematic and smectic phases. Information on the ordering of the phases in the magnetic field of the spectrometer has been derived from NMR spectra of a dissolved molecule, C-13-enriched methyl iodide. The low order parameter of the pure thermotropic nematic phase of the salt provides first-order spectra of the dissolved oriented molecules. Analyses of spectra of cis,cis-mucononitrile exemplifies the utility of the MTAI nematic phase in the determination of structural parameters of the solute.

Gossypol-induced hypokalemia and role of exogenous potassium salt supplementation when used as an antispermatogenic agent in male langur monkey

In our earlier study, we have observed that hypokalemia in langur monkeys, following gossypol acetic acid (GAA) treatment (5 mg dose level) when used as an antispermatogenic agent, and potassium salt supplementation partially maintained body potassium level of the animals. The aims of the present investigation was to confirm further occurrence of hypokalemia in the monkey (comparatively at two higher dose levels) and the role of potassium salt in preventing occurrence of gossypol-induced hypokalemia. Highly purified gossypol acetic acid alone at two dose levels (7.5 and 10 mg/animal/day; oral) and in combination with potassium chloride (0.50 and 0.75 mg/animal/day; oral) was given for 180 days. Treatment with gossypol alone as well as with the supplementation of potassium salt resulted in severe oligospermia and azoospermia. Animals receiving gossypol alone showed significant potassium deficiency with signs of fatigue at both dose levels. Enhanced potassium loss through urine was found in potassium-deficient animals, whereas animals receiving gossypol acetic acid plus potassium salt showed normal serum potassium with a less significant increase in urine potassium level during treatment phases. Other parameters of the body remained within normal range except gradual and significant elevation in serum transaminases activity. The animals gradually returned to normalcy following 150 and 180 days of termination of the treatment.

N-acetyl cysteine enhances imatinib-induced apoptosis of Bcr-Abl(+) cells by endothelial nitric oxide synthase-mediated production of nitric oxide

Imatinib, a small-molecule inhibitor of the Bcr-Abl kinase, is a successful drug for treating chronic myeloid leukemia (CML). Bcr-Abl kinase stimulates the production of H2O2, which in turn activates Abl kinase. We therefore evaluated whether N-acetyl cysteine (NAC), a ROS scavenger improves imatinib efficacy. Effects of imatinib and NAC either alone or in combination were assessed on Bcr-Abl(+) cells to measure apoptosis. Role of nitric oxide (NO) in NAC-induced enhanced cytotoxicity was assessed using pharmacological inhibitors and siRNAs of nitric oxide synthase isoforms. We report that imatinib-induced apoptosis of imatinib-resistant and imatinib-sensitive Bcr-Abl(+) CML cell lines and primary cells from CML patients is significantly enhanced by co-treatment with NAC compared to imatinib treatment alone. In contrast, another ROS scavenger glutathione reversed imatinib-mediated killing. NAC-mediated enhanced killing correlated with cleavage of caspases, PARP and up-regulation and down regulation of pro- and anti-apoptotic family of proteins, respectively. Co-treatment with NAC leads to enhanced production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS). Involvement of eNOS dependent NO in NAC-mediated enhancement of imatinib-induced cell death was confirmed by nitric oxide synthase (NOS) specific pharmacological inhibitors and siRNAs. Indeed, NO donor sodium nitroprusside (SNP) also enhanced imatinib-mediated apoptosis of Bcr-Abl(+) cells. NAC enhances imatinib-induced apoptosis of Bcr-Abl(+) cells by endothelial nitric oxide synthase-mediated production of nitric oxide.

Field imperfection induced axial secular frequency shifts in nonlinear ion traps

This article develops a simple analytical expression that relates ion axial secular frequency to field aberration in ion trap mass spectrometers. Hexapole and octopole aberrations have been considered in the present computations. The equation of motion of the ions in a pseudopotential well with these superpositions has the form of a Duffing-like equation and a perturbation method has been used to obtain the expression for ion secular frequency as a function of field imperfections. The expression indicates that the frequency shift is sensitive to the sign of the octopole superposition and insensitive to the sign of the hexapole superposition. Further, for weak multipole superposition of the same magnitude, octopole superposition causes a larger frequency shift in comparison to hexapole superposition.

Cyclone-induced mixing does not cool SST in the post-monsoon north Bay of Bengal

High-resolution data from the TRMM satellite shows that sea surface temperature (SST) cools by 3 degrees C under the tracks of pre-monsoon tropical cyclones in the north Indian Ocean. However, even the strongest post-monsoon cyclones do not cool the open north Bay of Bengal. In this region, a shallow layer of freshwater from river runoff and monsoon rain caps a deep warm layer. Therefore, storm-induced mixing is not deep, and it entrains warm subsurface water. It is possible that the hydrography of the post-monsoon north Bay favours intense cyclones.

Pressure-Induced transitions in amorphous TlxSe100-x alloys

The electrical resistivity of bulk semiconducting amorphous TlxSe100-x alloys with 0 ≤ x ≤ 25 has been investigated up to a pressure of 14 GPa and down to liquidnitrogen temperature by use of a Bridgman anvil device. All the glasses undergo a discontinuous pressure-induced semiconducting-to-metal transition. X-ray diffraction studies on the pressure-recovered samples show that the high-pressure phase is the crystalline phase. The pressure-induced crystalline products are identified to be a mixture of Se having a hexagonal structure with a = 4·37 Aring and c = 4·95 Aring and TlSe having a tetragonal structure with a = 8·0 Aring and c = 7·0 Aring

Inhibition of Peroxidase-Catalyzed Iodination by Cephalosporins: Metallo-beta-Lactamase-Induced Antithyroid Activity of Antibiotics

Broad-spectrum antibiotics with heterocyclic side chains strongly inhibit peroxidase-catalyzed iodination in the presence of metallo--lactamase. This suggests that antibiotic resistance due to hydrolysis of the -lactam ring in antibiotics would have negative effects on thyroid activity.

Stress-induced martensitic phase transformation in Cu-Zr nanowires

A novel stress-induced martensitic phase transformation in an initial < 100 >/{100} B2-CuZr nanowire is reported for the first time in this letter. Such behavior is observed in a nanowire with cross-sectional dimensions of 19.44 x 19.44 angstrom(2) over a temperature range of 100-400 K and at a strain rate of 1 x 10(9) s(-1) using atomistic simulations. Phase transformation from an initial B2 phase to a BCT (Body-Centered-Tetragonal) phase is observed via nucleation and propagation of {100} twinning plane under high strain rate tensile deformation. (C) 2009 Elsevier B.V. All rights reserved.

Absorption of electromagnetic radiation by superconducting YBa2Cu3O7: an oxygen-induced phenomenon

In the superconducting state, YBa2Cu3O7 absorbs electromagnetic radiation over a wide range of frequencies (8 MHz-9 GHz). The absorption is extremely sensitive to temperature, particle size and the magnetic field and depends crucially on the presence of oxygen. A possible explanation for the phenomenon based on the formation of Josephson junctions is suggested.

Standardization and validation of an induced ovulation model system in buffalo cows: Characterization of gene expression changes in the periovulatory follicle

In bovines characterization of biochemical and molecular determinants of the dominant follicle before and during different time intervals after gonadotrophin surge requires precise identification of the dominant follicle from a follicular wave. The objectives of the present study were to standardize an experimental model in buffalo cows for accurately identifying the dominant follicle of the first wave of follicular growth and characterize changes in follicular fluid hormone concentrations as well as expression patterns of various genes associated with the process of ovulation. From the day of estrus (day 0), animals were subjected to blood sampling and ultrasonography for monitoring circulating progesterone levels and follicular growth. On day 7 of the cycle, animals were administered a PGF2α analogue (Tiaprost Trometamol, 750 μg i.m.) followed by an injection of hCG (2000 IU i.m.) 36 h later. Circulating progesterone levels progressively increased from day 1 of the cycle to 2.26 ± 0.17 ng/ml on day 7 of the cycle, but declined significantly after PGF2α injection. A progressive increase in the size of the dominant follicle was observed by ultrasonography. The follicular fluid estradiol and progesterone concentrations in the dominant follicle were 600 ± 16.7 and 38 ± 7.6 ng/ml, respectively, before hCG injection and the concentration of estradiol decreased to 125.8 ± 25.26 ng/ml, but concentration of progesterone increased to 195 ± 24.6 ng/ml, 24 h post-hCG injection. Inh-α and Cyp19A1 expressions in granulosa cells were maximal in the dominant follicle and declined in response to hCG treatment. Progesterone receptor, oxytocin and cycloxygenase-2 expressions in granulosa cells, regarded as markers of ovulation, were maximal at 24 h post-hCG. The expressions of genes belonging to the super family of proteases were also examined; Cathepsin L expression decreased, while ADAMTS 3 and 5 expressions increased 24 h post-hCG treatment. The results of the current study indicate that sequential treatments of PGF2α and hCG during early estrous cycle in the buffalo cow leads to follicular growth that culminates in ovulation. The model system reported in the present study would be valuable for examining temporo-spatial changes in the periovulatory follicle immediately before and after the onset of gonadotrophin surge.

Cation-induced crown porphyrin dimers of oxovanadium(IV)

Oxovanadium(1V) porphyrins appended with crown ether (benzo-15-crown-5) at the 5 (mono), the 5 and 10115 (cis/trans bis), the 5, 10, and 15 (tris), and the 5, 10, 15, and 20 (tetrakis) positions have been synthesized. The cation complexation behavior of these cavity-bearing porphyrins has been studied by using optical aborption and ESR spectral methods. The cations K+, Cs+, NH4+, and Ba2+, which require two crown ether cavities for complexation, induce dimerization of the porphyrins. The cation-induced dimerization constants for a representative tetrasubstituted porphyrin vary as K+ > Ba2+ > Cs+ - NH4+, and the relative stabilities of the dimers are dependent on the type of the substitution, tetrakis > tris > cis bis. ESR spectra recorded at a sample temperature of 77 K have low-field components attributed to Ah& = f 2 transitions, providing further evidence for the existence of dimers in solutions. The eclipsed sandwich dimers have V-V distances in the range 4.70 A. The relative distributions of oxovanadium crown porphyrins in terms of monomeric and dimeric forms rest on the geometric dispositions of the crown ether appendages.