FORMULATION AND IN VITRO EVALUATION OF OIL ENTRAPPED BUOYANT BEADS FOR STOMACH SPECIFIC DELIVERY OF METRONIDAZOLE

Objective: This work focused on the development of floating alginate beads for stomach specific delivery of Metronidazole towards the effective eradication of Helicobacter pylori, a major causative agent of peptic ulcers.Methods: Different formulations of sunflower oil entrapped gel beads were prepared by emulsion gelation technique using sodium alginate as gelling agent. The prepared beads were evaluated for size, surface morphology, drug entrapment efficiency, in vitro floatuing and in vitro drug release properties.Results: It was found that the percentage of oil plays an important role in controlling the floating of oil-entrapped alginate beads. All batches of beads floated for >24 hours with a very short lag time of 151–187 seconds. Scanning electron microscopy (SEM) revealed that the beads were spherical in shape with small pores on the surface. SEM of the cross section of the beads demonstrated minute oil globules throughout the inner portion of the beads confirming oil entrapment. The results clearly indicated that amount of polymer (% w/v) and amount of sunflower oil (% v/v) affected the bead size, floating, encapsulation efficiency and drug release of the beads. It was observed that the drug release kinetics was best fitted with the Higuchi model and drug release from the polymer matrix system was non fickian (anomalous transport) type.Conclusion: The results provide evidence that formulated gel beads may be used to incorporate antimicrobials like Metronidazole and may be effective when administered locally in the stomach to cure Helicobacter pylori infection.Â

IDO1 and Inflammatory Neovascularization: Bringing New Blood to Tumor-Promoting Inflammation

In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the \u27Hallmarks of Cancer\u27, it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFNγ blocks the antagonistic effect of IFNγ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies

IDO1 and inflammatory neovascularization: bringing new blood to tumor-promoting inflammation

In parallel with the genetic and epigenetic changes that accumulate in tumor cells, chronic tumor-promoting inflammation establishes a local microenvironment that fosters the development of malignancy. While knowledge of the specific factors that distinguish tumor-promoting from non-tumor-promoting inflammation remains inchoate, nevertheless, as highlighted in this series on the ‘Hallmarks of Cancer’, it is clear that tumor-promoting inflammation is essential to neoplasia and metastatic progression making identification of specific factors critical. Studies of immunometabolism and inflamometabolism have revealed a role for the tryptophan catabolizing enzyme IDO1 as a core element in tumor-promoting inflammation. At one level, IDO1 expression promotes immune tolerance to tumor antigens, thereby helping tumors evade adaptive immune control. Additionally, recent findings indicate that IDO1 also promotes tumor neovascularization by subverting local innate immunity. This newly recognized function for IDO1 is mediated by a unique myeloid cell population termed IDVCs (IDO1-dependent vascularizing cells). Initially identified in metastatic lesions, IDVCs may exert broader effects on pathologic neovascularization in various disease settings. Mechanistically, induction of IDO1 expression in IDVCs by the inflammatory cytokine IFNγ blocks the antagonistic effect of IFNγ on neovascularization by stimulating the expression of IL6, a powerful pro-angiogenic cytokine. By contributing to vascular access, this newly ascribed function for IDO1 aligns with its involvement in other cancer hallmark functionalities, (tumor-promoting inflammation, immune escape, altered cellular metabolism, metastasis), which may stem from an underlying role in normal physiological functions such as wound healing and pregnancy. Understanding the nuances of how IDO1 involvement in these cancer hallmark functionalities varies between different tumor settings will be crucial to the future development of successful IDO1-directed therapies

High Precision Measurements of Interstellar Dispersion Measure with the upgraded GMRT

Pulsar radio emission undergoes dispersion due to the presence of free electrons in the interstellar medium (ISM). The dispersive delay in the arrival time of pulsar signal changes over time due to the varying ISM electron column density along the line of sight. Correcting for this delay accurately is crucial for the detection of nanohertz gravitational waves using Pulsar Timing Arrays. In this work, we present in-band and inter-band DM estimates of four pulsars observed with uGMRT over the timescale of a year using two different template alignment methods. The DMs obtained using both these methods show only subtle differences for PSR 1713+0747 and J1909$-$3744. A considerable offset is seen in the DM of PSR J1939+2134 and J2145$-$0750 between the two methods. This could be due to the presence of scattering in the former and profile evolution in the latter. We find that both methods are useful but could have a systematic offset between the DMs obtained. Irrespective of the template alignment methods followed, the precision on the DMs obtained is about $10^{-3}$ pc cm$^{-3}$ using only BAND3 and $10^{-4}$ pc cm$^{-3}$ after combining data from BAND3 and BAND5 of the uGMRT. In a particular result, we have detected a DM excess of about $5\times10^{-3}$ pc cm$^{-3}$ on 24 February 2019 for PSR J2145$-$0750. This excess appears to be due to the interaction region created by fast solar wind from a coronal hole and a coronal mass ejection (CME) observed from the Sun on that epoch. A detailed analysis of this interesting event is presented.Comment: 11 pages, 6 figures, 2 tables. Accepted by A&

The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia Type 3 pathogenesis

DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.This research was supported by USPHS grant NS073976 (TKH) and P30 ES 06676 that support the NIEHS Center Cell Biology Core and Molecular Genomics Core of UTMB’s NIEHS Center for DNA sequencing. TKP is supported by CA129537 and CA154320. This work was also supported by Fundação para a Ciência e Tecnologia through the project [PTDC/SAU-GMG/101572/2008] and through fellowships [SFRH/BPD/91562/2012 to ASF, SFRH/BD/51059/2010 to ANC]. IB is supported by NIEHS R01 ES018948 and NIAID/AI06288