Synthesis and Computational Exploration of Morpholine Bearing Halogenated Sulfonamides as Potential Tyrosinase Inhibitors

In the presented work, a new series of three different 4-((3,5-dichloro-2-[(2/4-halobenzyl)oxy]phenyl)sulfonyl)morpholines was synthesized and the structure of these compounds were corroborated by ¹H-NMR & ¹³C-NMR studies. The in vitro results established all the three compounds as potent tyrosinase inhibitors relative to the standard. The Kinetics mechanism plots established that compound 8 inhibited the enzyme non-competitively. The inhibition constants K_i calculated from Dixon plots for this compound was 0.0025 μM. Additionally, computational techniques were used to explore electronic structures of synthesized compounds. Fully optimized geometries were further docked with tyrosinase enzyme for inhibition studies. Reasonably good binding/interaction energies and intermolecular interactions were obtained. Finally, drug likeness was also predicted using the rule of five (RO5) and Chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) characteristics. It is anticipated that current experimental and computational investigations will evoke the scientific interest of the research community for the above-entitled compounds.     

Delivery of Beneficial Microbes via Seed Coating for Medicinal and Aromatic Plant Production: A Critical Review

Journal of Plant Growth Regulation - Medicinal and aromatic plants (MAPs) producing a myriad of chemicals can be utilized in numerous sectors such as pharmaceutical products, feed and food...     

Cascading effects of soil organic and inorganic fertilizers on tri-trophic interactions: Plant–aphid–parasitoid wasp as a study system

Understanding the mechanisms underlying tri-trophic interactions between insect herbivores, their host plants and natural enemies is an important aim in ecology. In the present study, the effect of urea fertilizer and vermicompost on a tri-trophic level cascade, comprising safflower, Carthamus tinctorius, safflower aphid, Uroleucon carthami and its primary parasitoid wasp, Praon yomenae, was investigated. Vermicompost increased the number of leaves, leaf area, fresh weight, dry weight, the total number of aphids and reduced the number of winged aphids and aphid load (Aphid load = number of aphids / plant fresh weight). Only two variables, plant phenol content and relative water content, were not significantly affected by vermicompost. Urea fertilizer had no impact on all variables except a significant effect on plant height. In another experiment, the effect of urea fertilizer and vermicompost on the wasp parasitoid was studied. The number of parasitoid mummies, mummification time, developmental time, the number of emerged adults, sex ratio, percentage of parasitism and hind tibia length was measured. Vermicompost had no significant effect on any of the measured parameters, but urea fertilizer increased the hind tibia length of the parasitoid. Vermicompost increased plant growth parameters and had an indirect and inhibiting effect on the safflower aphid itself. There was evidence of a bottom-up cascade to the third trophic level by adding fertilizers in this system: Urea fertilizer enhanced plant height but seemingly had no impact on the attacking herbivore. It is interesting that the effect of urea can be transferred to the third trophic level, that is parasitoid. This suggests that vermicompost could be used simultaneously with urea fertilizer, because urea fertilizer had a positive impact on the parasitoid and vermicompost had a positive impact on plant growth as well as the ability to reduce aphid load.     

Complete genome sequence of uropathogenic Proteus mirabilis, a master of both adherence and motility

The gram-negative enteric bacterium Proteus mirabilis is a frequent cause of urinary tract infections in individuals with long-term indwelling catheters or with complicated urinary tracts (e.g., due to spinal cord injury or anatomic abnormality). P. mirabilis bacteriuria may lead to acute pyelonephritis, fever, and bacteremia. Most notoriously, this pathogen uses urease to catalyze the formation of kidney and bladder stones or to encrust or obstruct indwelling urinary catheters. Here we report the complete genome sequence of P. mirabilis HI4320, a representative strain cultured in our laboratory from the urine of a nursing home patient with a long-term (> or =30 days) indwelling urinary catheter. The genome is 4.063 Mb long and has a G+C content of 38.88%. There is a single plasmid consisting of 36,289 nucleotides. Annotation of the genome identified 3,685 coding sequences and seven rRNA loci. Analysis of the sequence confirmed the presence of previously identified virulence determinants, as well as a contiguous 54-kb flagellar regulon and 17 types of fimbriae. Genes encoding a potential type III secretion system were identified on a low-G+C-content genomic island containing 24 intact genes that appear to encode all components necessary to assemble a type III secretion system needle complex. In addition, the P. mirabilis HI4320 genome possesses four tandem copies of the zapE metalloprotease gene, genes encoding six putative autotransporters, an extension of the atf fimbrial operon to six genes, including an mrpJ homolog, and genes encoding at least five iron uptake mechanisms, two potential type IV secretion systems, and 16 two-component regulators.     

Leishmania major: identification of developmentally regulated proteins in procyclic and metacyclic promastigotes

The differentiation from procyclic to metacyclic promastigotes (metacyclogenesis) has been correlated with an increased infectivity in a number of Leishmania species. We compared the proteomes of procyclic and metacyclic promastigotes of L. major. Lysates from either life cycle stage were resolved by 2D-PAGE, followed by Coomassie brilliant blue staining. Spots were analyzed by MALDI-TOF MS. 25 protein spots were found to be differentially expressed during metacyclogenesis. We found that proteins involved in protein synthesis were less abundant in metacyclic promastigotes, while proteins involved in motility, including paraflagellar rod protein 1D, α-tubulin and β-tubulin were more abundant. Also, two mitochondrial enzymes (succinyl-CoA synthetase β subunit and cytochrome c oxidase subunit IV) were differentially expressed in both life cycle stages. Down-regulation of proteins related to synthetic pathway in metacyclic promastigotes is consistent with the arrested growth in this life cycle stage, while up-regulation of proteins related to motility in metacyclic promastigotes is in agreement with the high motility observed in this stage.     

Surfactant protein A signaling pathways in human uterine smooth muscle cells

The present study investigated the ability of surfactant associated protein A1 (SFTPA1), a major component of lung surfactant, to bind and serve as a signal in human cultured myometrial cells. By using ligand blot analysis with 125I-SFTPA1, we consistently identified two myometrial SFTPA1 interacting proteins (55 and 200 kDa). We found that the SFTPA1 immunoreactive protein was present in myometrial cells. We also showed by indirect immunofluorescence the nuclear translocation of RELA (also known as NFkappaB p65 subunit) after activation of myometrial cells by SFTPA1. Neutralization of TLR4 did not reverse this effect. Moreover, SFTPA1 rapidly activated mitogen-activated protein kinase 1/3 (MAPK1/3) and protein kinase C zeta (PRKCZ). The prolonged treatment of myometrial cells with SFTPA1 upregulated PTGS2 (COX2) protein levels. We next evaluated whether SFTPA1 affected the actin dynamic. Stimulation of myometrial cells with SFTPA1 markedly enhanced the intensity of the filamentous-actin pool stained with fluorescein isothiocyanate-phalloidin. Inhibition of PRKC or Rho-associated, coiled-coil containing protein kinase 1 (ROCK) reduced the SFTPA1-mediated stress fiber formation. Our data support the hypothesis that human myometrial cells express functional SFTPA1 binding sites and respond to SFTPA1 to initiate activation of signaling events related to human parturition.     

13C relaxation studies of the DNA target sequence for hhai methyltransferase reveal unique motional properties

The goal of this work was to examine if sequence-dependent conformational flexibility in DNA plays a role in base extrusion, a common conformational change induced by many DNA-modifying enzymes. We studied the dynamics of the double-stranded DNA target of the HhaI methyltransferase by recording an extensive set of (13)C NMR relaxation parameters. We observe that the cytidine furanose rings experience fast (picosecond to nanosecond) motions that are not present in other nucleotides; the methylation site experiences particularly high mobility. We also observe that the bases of guanosine and cytidine residues within the HhaI recognition sequence GCGC experience motions on a much slower (1-100 micros) time scale. We compare these observations with previous solution and solid-state NMR studies of the EcoRI nuclease target sequence, and solid-state NMR studies of a similar HhaI target construct. While an increased mobility of cytidine furanose rings compared to those of other nucleotides is observed for both sequences, the slower motions are only observed in the HhaI target DNA. We propose that this inherent flexibility lowers the energetic barriers that must occur when the DNA binds to the HhaI methyltransferase and for extrusion of the cytidine prior to its methylation.     

VDUP1: a potential mediator of expansion-induced lung growth and epithelial cell differentiation in the ovine fetus

The degree of fetal lung expansion is a critical determinant of fetal lung growth and alveolar epithelial cell (AEC) differentiation, although the mechanisms involved are unknown. As VDUP1 (vitamin D3-upregulated protein 1) can modulate cell proliferation, can induce cell differentiation, and is highly expressed in the lung, we have investigated the effects of fetal lung expansion on VDUP1 expression and its relationship to expansion-induced fetal lung growth and AEC differentiation in fetal sheep. Alterations in fetal lung expansion caused profound changes in VDUP1 mRNA levels in lung tissue. Increased fetal lung expansion significantly reduced VDUP1 mRNA levels from 100+/-8% in control fetuses to 37+/-4, 46+/-4, and 45+/-9% of control values at 2, 4, and 10 days of increased fetal lung expansion, respectively. Reduced fetal lung expansion increased VDUP1 mRNA levels from 100+/-16% in control fetuses to 162+/-16% of control values after 7 days. VDUP1 was localized to airway epithelium in small bronchioles, AECs, and some mesenchymal cells. Its expression was inversely correlated with cell proliferation during normal lung development (R2=0.972, P<0.002) as well as in response to alterations in fetal lung expansion (R2=0.956, P<0.001) and was positively correlated with SP-B expression during normal lung development (R2=0.803, P<0.0001) and following altered lung expansion (R2=0.817, P<0.001). We suggest that VDUP1 may be an important mediator of expansion-induced lung cell proliferation and AEC differentiation in the developing lung.