Design and Synthesis of 1-Substituted-4-(4-Nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones as a New Class of Antihistaminic Agents

Russian Journal of Bioorganic Chemistry - Some new 1-substituted-4-(4-nitrophenyl)-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-ones were synthesized and screened for their H1-antihistaminic activity....     

Batch and continuous removal of arsenic using hyacinth roots

Arsenic is considered a primary pollutant in drinking water because of its high toxicity. The unique property of water hyacinth roots (Eichhornia crassipes) to remove heavy metals is of great signiicance for the development of a cost-effective phytoremediation technology. An experimental test program was conducted at the United States Environmental Protection (USEPA) Test and Evaluation (T&E) Facility in Cincinnati, Ohio, to investigate the potential of water hyacinth roots to remove arsenic from spiked drinking water samples. Water hyacinth roots were washed, dried, and powdered to provide dried hyacinth roots (DHR) for batch and continuous column experiments, Various quantities of DHR were added to water spiked with 300 micrograms per liter (microg/L) arsenic. A concentration of 20 g/L DHR was found adequate for greater than 90% arsenic removal in the batch tests. Based on the batch test results, continuous column experiments were performed using a 2-L column. In a continuous system, 15 L of water containing 300 microg/L arsenic were treated to below 20 microg/L using 50 g DHR, and 44 L of water containing 600 microg/L arsenic were treated to below 20 microg/L using 100 g DHR, giving a specific accumulation rate of approximately 260 microg As/g DHR.     

Cooperativity between inhibition of cytosolic K+ efflux and AMPK activation during suppression of hypoxia-induced cellular apoptosis

Cellular potassium homeostasis has recently emerged as a critical regulator of apoptosis in response to variety of stimuli. However, functional hierarchy of this phenomenon in the apoptotic cascade and therefore, its significance as a pathway for intervention is not fully established. Chronic hypoxia, a known threat to cell survival, also modulates cellular potassium homeostasis. In this study, we tested if hypoxia-induced apoptosis in lymphocytes can be prevented by modulating cellular K+ homeostasis. We observed that chronic hypoxia accelerated the rate of apoptosis in resting murine splenocytes concomitant with cytosolic K+ efflux. We tested several modalities including elevated extracellular potassium besides various K+ channel inhibitors to curtail hypoxia-induced K+ efflux and interestingly, established that the supplementation of KCl in extracellular medium was most effective in preventing hypoxia-induced apoptosis in these cells. Subsequent mechanistic dissection of pathways underlying this phenomenon revealed that besides effectively inhibiting hypoxia-induced efflux of K+ ion and its downstream cell-physiological consequences; elevated extracellular KCl modulated steady state levels of cellular ATP and culminated in stabilization of AMPKα with pro-survival consequences. Also, interestingly, global gene expression profiling revealed that KCl supplementation down regulated a distinct p53-regulated cellular sub-network of genes involved in regulation of DNA replication. Additionally, we present experimental evidence for the functional role of AMPK and p53 activation during suppression of hypoxia-induced apoptosis. In conclusion, our study highlights a novel bimodal effect wherein cooperativity between restoration of K+ homeostasis and a sustainable ‘metabolic quiescence’ induced by AMPK activation appeared indispensible for curtailing hypoxia-induced apoptosis.     

Combined arene ruthenium porphyrins as chemotherapeutics and photosensitizers for cancer therapy

Mononuclear 5-(4-pyridyl)-10,15,20-triphenylporphyrin and 5-(3-pyridyl)-10,15,20-triphenylporphyrin as well as tetranuclear 5,10,15,20-tetra(4-pyridyl)porphyrin (tetra-4-pp) and 5,10,15,20-tetra(3-pyridyl)porphyrin) (tetra-3-pp) arene ruthenium(II) derivatives (arene is C₆H₅Me or p-Pr ⁱ C₆H₄Me) were prepared and evaluated as potential dual photosensitizers and chemotherapeutics in human Me300 melanoma cells. In the absence of light, all tetranuclear complexes were cytotoxic (IC₅₀ ≤ 20 μM), while the mononuclear derivatives were not (IC₅₀ ≥ 100 μM). Kinetic studies of tritiated thymidine and tritiated leucine incorporations in cells exposed to a low concentration (5 μM) of tetranuclear p-cymene derivatives demonstrated a rapid inhibition of DNA synthesis, while protein synthesis was inhibited only later, suggesting arene ruthenium–DNA interactions as the initial cytotoxic process. All complexes exhibited phototoxicities toward melanoma cells when exposed to laser light of 652 nm. At low concentration (5 μM), LD₅₀ of the mononuclear derivatives was between 5 and 10 J/cm², while for the tetranuclear derivatives LD₅₀ was approximately 2.5 J/cm² for the [Ru₄(η⁶-arene)₄(tetra-4-pp)Cl₈] complexes and less than 0.5 J/cm² for the [Ru₄(η⁶-arene)₄(tetra-3-pp)Cl₈] complexes. Examination of cells under a fluorescence microscope revealed the [Ru₄(η⁶-arene)₄(tetra-4-pp)Cl₈] complexes as cytoplasmic aggregates, whereas the [Ru₄(η⁶-arene)₄(tetra-3-pp)Cl₈] complexes were homogenously dispersed in the cytoplasm. Thus, these complexes present a dual synergistic effect with good properties of both the arene ruthenium chemotherapeutics and the porphyrin photosensitizer.     

Quantitative evaluation of optical coherence tomography angiography images of diabetic retinopathy eyes before and after removal of projection artifacts

Projection artifacts (PAs) affect the quantification of vascular parameters in the deep layer optical coherence tomography (OCT) angiography image. This study eliminated PA and quantified its effect on imaging. 53 eyes (30 subjects) of normal Indian subjects and 113 eyes (92 patients) of type 2 diabetes mellitus with retinopathy (DR) underwent imaging with a scan area of 3 mm × 3 mm. In this study, a normalized cross‐correlation between superficial and deep layer was used to remove PA in deep layer. Local fractal analysis was done to compute vascular parameters such as foveal avascular zone area (mm²), vessel density (%), spacing between large vessels (%) and spacing between small vessels (%). Before PA removal, vessel density for mild nonproliferative (NPDR), moderate NPDR, severe NPDR and proliferative DR were 42.56 ±1.69%, 40.69 ±0.72%, 37.34 ±0.85% and 35.61 ±1.26%, respectively. After artifact removal, vessel density was 28.9 ±1.22%, 29.9 ±0.56%, 26.19 ±0.59% and 24.02 ±0.94%, respectively. All the vascular parameters were statistically significant (P <.001) between normal and disease eyes, irrespective of superficial and deep retinal layers. Parafoveal sectoral analyses showed that temporal zone had the lowest vessel density and may undergo DR‐related changes first. The current approach enabled rapid and accurate quantitative interpretation of DR eyes, without PA.      

A novel 13 residue acyclic peptide from the marine snail, Conus monile, targets potassium channels

A novel 13-residue peptide Mo1659 has been isolated from the venom of a vermivorous cone snail, Conus monile. HPLC fractions of the venom extract yielded an intense UV absorbing fraction with a mass of 1659Da. De novo sequencing using both matrix assisted laser desorption and ionization and electrospray MS/MS methods together with analysis of proteolytic fragments successfully yielded the amino acid sequence, FHGGSWYRFPWGY-NH(2). This was further confirmed by comparison with the chemically synthesized peptide and by conventional Edman sequencing. Mo1659 has an unusual sequence with a preponderance of aromatic residues and the absence of apolar, aliphatic residues like Ala, Val, Leu, and Ile. Mo1659 has no disulfide bridges distinguishing it from the conotoxins and bears no sequence similarity with any of the acyclic peptides isolated thus far from the venom of cone snails. Electrophysiological studies on the effect of Mo1659 on measured currents in dorsal root ganglion neurons suggest that the peptide targets non-inactivating voltage-dependent potassium channels.     

Partially saturated canthaxanthin purified from Aspergillus carbonarius induces apoptosis in prostrate cancer cell line

A mutant Aspergillus carbonarius selected for temperature tolerance after UV treatment, when grown in shake flasks, produced mycelia bearing yellow pigment. Since the mutant was affected in sterol biosynthetic pathway, the pigment was apparently produced to maintain membrane fluidity and rigidity for growth sustenance in low-pH culture broth. Nuclear magnetic resonance analyses characterizing the pigment as a partially saturated canthaxanthin, containing beta-ionone end rings, suggested its application as a retinoid. When tested for this property in retinoic acid receptor expressing prostate cancer cell line, LNCaP, the fungal partially saturated canthaxanthin induced apoptosis. Low apoptosis percentage in DU145 prostrate cancer cells that does not express functional retinoic acid receptor-beta (RAR-beta) suggested binding specificity of the partially saturated canthaxanthin for RAR-beta.     

The role of calcium channels in anthocyanin production in callus cultures of Daucus carota

The involvement of Ca²⁺ ATPases in anthocyanin accumulation in callus cultures of Daucus carota was investigated under the influence of calcium and calcium channel modulators. Ionophore (I) treatment enhanced callus growth and anthocyanin accumulation. Increasing the amount of calcium applied to cultures enhanced the anthocyanin level. Ionophore treatment influenced the enhancement of Ca²⁺ATPase and endogenous titres of PAs. Addition of the calcium channel blocker verapamil or the calmodulin antagonist chlorpromazine to the A23187 (ionophore) treated cells caused a reduction in anthocyanin levels. Channel blockers reduced Ca²⁺ATPase activity, which was restored by ionophore treatment, showing the importance of calcium in anthocyanin production. Higher ethylene levels were also found in treatment with ionophore or 2X calcium. Thus the influence of ionophore in anthocyanin production and its inhibition by calcium channel modulators suggests that calcium plays an important role in the production of anthocyanin by carrot callus cultures.     

Plasmodium berghei Calcium Dependent Protein Kinase 1 Is Not Required for Host Cell Invasion

Plasmodium Calcium Dependent Protein Kinase (CDPK1) is required for the development of sexual stages in the mosquito. In addition, it is proposed to play an essential role in the parasite’s invasive stages possibly through the regulation of the actinomyosin motor and micronemal secretion. We demonstrate that Plasmodium berghei CDPK1 is dispensable in the parasite’s erythrocytic and pre-erythrocytic stages. We successfully disrupted P. berghei CDPK1 (PbCDPK1) by homologous recombination. The recovery of erythrocytic stage parasites lacking PbCDPK1 (PbCDPK1-) demonstrated that PbCDPK1 is not essential for erythrocytic invasion or intra-erythrocytic development. To study PbCDPK1’s role in sporozoites and liver stage parasites, we generated a conditional mutant (CDPK1 cKO). Phenotypic characterization of CDPK1 cKO sporozoites demonstrated that CDPK1 is redundant or dispensable for the invasion of mammalian hepatocytes, the egress of parasites from infected hepatocytes and through the subsequent erythrocytic cycle. We conclude that P. berghei CDPK1 plays an essential role only in the mosquito sexual stages.     

Impacts of ambient solar uv (280-400 nm) radiation on three tropical legumes

Tropical regions receive the highest level of global solar ultraviolet (UV) radiation especially UV-B (280-320 nm). The average daily dose of the UV-B radiation in Madurai, South India (10°N) is 10 kJ m^-2. This is approximately 50% more than the average daily UV-B radiation in many European countries. A field study was conducted using selective filters to remove either the UV-B (< 320 nm) or UV-B/A (<400 nm) of the solar spectrum, and the effects were followed inCyamopsis tetragonoloba, Vigna mungo, andVigna radiata to determine their sensitivity to UV. When compared to ambient radiation, exclusion of solar UV-B increased the seedling height, leaf area, fresh weight and dry weight and the crop yield by 50% in the case ofCyamopsis, and the extent of such increase was slightly less under UV-B/A exclusion. InV. mungo a significant reduction was seen in solar UV excluded plants whileV. radiata was found to be unaffected.