Tricyclic dihydroquinazolinones as novel 5-HT2C selective and orally efficacious anti-obesity agents

Agonists of the 5-HT_2C receptor have been shown to suppress appetite and reduce body weight in animal models as well as in humans. However, agonism of the related 5-HT_2B receptor has been associated with valvular heart disease. Synthesis and biological evaluation of a series of novel and highly selective dihydroquinazolinone-derived 5-HT_2C agonists with no detectable agonism of the 5-HT_2B receptor is described. Among these, compounds (+)-2a and (+)-3c were identified as potent and highly selective agonists which exhibited weight loss in a rat model upon oral dosing.     

Mechanisms of plant defense against insect herbivores

Plants respond to herbivory through various morphological, biochemicals, and molecular mechanisms to counter/offset the effects of herbivore attack. The biochemical mechanisms of defense against the herbivores are wide-ranging, highly dynamic, and are mediated both by direct and indirect defenses. The defensive compounds are either produced constitutively or in response to plant damage, and affect feeding, growth, and survival of herbivores. In addition, plants also release volatile organic compounds that attract the natural enemies of the herbivores. These strategies either act independently or in conjunction with each other. However, our understanding of these defensive mechanisms is still limited. Induced resistance could be exploited as an important tool for the pest management to minimize the amounts of insecticides used for pest control. Host plant resistance to insects, particularly, induced resistance, can also be manipulated with the use of chemical elicitors of secondary metabolites, which confer resistance to insects. By understanding the mechanisms of induced resistance, we can predict the herbivores that are likely to be affected by induced responses. The elicitors of induced responses can be sprayed on crop plants to build up the natural defense system against damage caused by herbivores. The induced responses can also be engineered genetically, so that the defensive compounds are constitutively produced in plants against are challenged by the herbivory. Induced resistance can be exploited for developing crop cultivars, which readily produce the inducible response upon mild infestation, and can act as one of components of integrated pest management for sustainable crop production.     

Synthesis and DNA‐binding study of imidazole linked thiazolidinone derivatives

A novel series of imidazole‐linked thiazolidinone hybrid molecules were designed and synthesized through a feasible synthetic protocol. The molecules were characterized with Fourier transform infrared (FT‐IR), ¹H nuclear magnetic resonance (NMR), ¹³C NMR and high‐resolution mass spectrometry (HRMS) techniques. In vitro susceptibility tests against Gram‐positive (S. aureus and B. subtilis ) and Gram‐negative bacteria (E. coli and P. aeruginosa ) gave highly promising results. The most active molecule (3e) gave a minimal inhibitory concentration (MIC) value of 3.125 μg/mL which is on par with the reference drug streptomycin. Structure–activity relationships revealed activity enhancement by nitro and chloro groups when they occupied meta position of the arylidene ring in 2‐((3‐(imidazol‐1‐yl)propyl)amino)‐5‐benzylidenethiazolidin‐4‐ones. DNA‐binding study of the most potent molecule 3e with salmon milt DNA (sm‐DNA) under simulated physiological pH was probed with UV–visible absorption, fluorescence quenching, gel electrophoresis and molecular docking techniques. These studies established that compound 3e has a strong affinity towards DNA and binds at DNA minor groove with a binding constant (K_b) 0.18 × 10² L mol^?1. Molecular docking simulations predicted strong affinity of 3e towards DNA with a binding affinity (ΔG) ‐8.5 kcal/mol. Van der Waals forces, hydrogen bonding and hydrophobic interactions were predicted as the main forces of interaction. The molecule 3e exhibited specific affinity towards adenine–thiamine base pairs. Copyright © 2016 John Wiley & Sons, Ltd.     

Elevated CO<Subscript>2</Subscript> influences host plant defense response in chickpea against <Emphasis Type="Italic">Helicoverpa armigera</Emphasis>

Global atmospheric concentration of CO₂ is likely to increase from 350 to 750 ppm over the next 100 years. The present studies were undertaken to understand the effects of elevated CO₂ on enzymatic activity and secondary metabolites in chickpea in relation to expression of resistance to pod borer, Helicoverpa armigera. Fifteen-day-old chickpea plants [ICCL 86111—resistant and JG 11—commercial cultivar] grown in the greenhouse were transferred to open-top chambers (OTC) and kept under 350, 550 and 750 ppm of CO₂. Twenty neonates of H. armigera were released on each plant at 7 days after shifting the pots to the OTCs. Un-infested plants were maintained as controls. After 7 days of infestation, the activities of defensive enzymes [peroxidase (POD), polyphenol oxidase (PPO), phenylalanine ammonia lyase (PAL) and tyrosine ammonia lyase (TAL)] and amounts of total phenols and condensed tannins increased with an increase in CO₂ concentration in chickpea. The nitrogen balance index was greater in plants kept at 350 ppm CO₂ than in plants kept under ambient conditions. The H. armigera-infested plants had higher H₂O₂ content; amounts of oxalic and malic acids were greater at 750 ppm CO₂ than at 350 ppm CO₂. Plant damage was greater at 350 ppm than at 550 and 750 ppm CO₂. This information will be useful for understanding effects of increased levels of CO₂ on expression of resistance to insect pests to develop strategies to mitigate the effects of climate change.     

Effect of diet on serotonergic neurotransmission in depression

Depression is characterized by sadness, purposelessness, irritability, and impaired body functions. Depression causes severe symptoms for several weeks, and dysthymia, which may cause chronic, low-grade symptoms. Treatment of depression involves psychotherapy, medications, or phototherapy. Clinical and experimental evidence indicates that an appropriate diet can reduce symptoms of depression. The neurotransmitter, serotonin (5-HT), synthesized in the brain, plays an important role in mood alleviation, satiety, and sleep regulation. Although certain fruits and vegetables are rich in 5-HT, it is not easily accessible to the CNS due to blood brain barrier. However the serotonin precursor, tryptophan, can readily pass through the blood brain barrier. Tryptophan is converted to 5-HT by tryptophan hydroxylase and 5-HTP decarboxylase, respectively, in the presence of pyridoxal phosphate, derived from vitamin B₆. Hence diets poor in tryptophan may induce depression as this essential amino acid is not naturally abundant even in protein-rich foods. Tryptophan-rich diet is important in patients susceptible to depression such as certain females during pre and postmenstrual phase, post-traumatic stress disorder, chronic pain, cancer, epilepsy, Parkinson’s disease, Alzheimer’s disease, schizophrenia, and drug addiction. Carbohydrate-rich diet triggers insulin response to enhance the bioavailability of tryptophan in the CNS which is responsible for increased craving of carbohydrate diets. Although serotonin reuptake inhibitors (SSRIs) are prescribed to obese patients with depressive symptoms, these agents are incapable of precisely regulating the CNS serotonin and may cause life-threatening adverse effects in the presence of monoamine oxidase inhibitors. However, CNS serotonin synthesis can be controlled by proper intake of tryptophan-rich diet. This report highlights the clinical significance of tryptophan-rich diet and vitamin B₆ to boost serotonergic neurotransmission in depression observed in various neurodegenerative diseases. However pharmacological interventions to modulate serotonergic neurotransmission in depression, remains clinically significant. Depression may involve several other molecular mechanisms as discussed briefly in this report.     

Coexpression of human somatostatin receptor-2 (SSTR2) and SSTR3 modulates antiproliferative signaling and apoptosis

Background

Somatostatin (SST) via five G_i coupled receptors namely SSTR1-5 is known to inhibit cell proliferation by cytostatic and cytotoxic mechanisms. Heterodimerization plays a crucial role in modulating the signal transduction pathways of SSTR subtypes. In the present study, we investigated human SSTR2/SSTR3 heterodimerization, internalization, MAPK signaling, cell proliferation and apoptosis in HEK-293 cells in response to SST and specific agonists for SSTR2 and SSTR3.

Results

Although in basal conditions, SSTR2 and SSTR3 colocalize at the plasma membrane and exhibit heterodimerization, the cell surface distribution of both receptors decreased upon agonist activation and was accompanied by a parallel increase in intracellular colocalization. Receptors activation by SST and specific agonists significantly decreased cAMP levels in cotransfected cells in comparison to control. Agonist-mediated modulation of pERK1/2 was time and concentration-dependent, and pronounced in serum-deprived conditions. pERK1/2 was inhibited in response to SST; conversely receptor-specific agonist treatment caused inhibition at lower concentration and activation at higher concentration. Strikingly, ERK1/2 phosphorylation was sustained upon prolonged treatment with SST but not with receptor-specific agonists. On the other hand, SST and receptor-specific agonists modulated p38 phosphorylation time-dependently. The receptor activation in cotransfected cells exhibits G_i-dependent inhibition of cell proliferation attributed to increased PARP-1 expression and TUNEL staining, whereas induction of p21 and p27^Kip1 suggests a cytostatic effect.

Conclusion

Our study provides new insights in SSTR2/SSTR3 mediated signaling which might help in better understanding of the molecular interactions involving SSTRs in tumor biology.     

Degradation of chlorpyriphos and polyethylene by endosymbiotic bacteria from citrus mealybug

Chlorpyriphos is one of the major organophosphorus pesticides used widely to control a range of insect pests across several crops. This insecticide is hazardous to the environment and toxic to mammals, thus, it is essential to remove the same from the environment. Similarly, use of polythene is also increasing day by day. Therefore, it is highly important to identify ways to degrade chlorpyriphos and other pesticides from the environment. We studied the degradation of chlorpyriphos and polyethylene by Citrus mealybug (Planococcus citri) bacterial endosymbionts such as Bacillus licheniformis, Pseudomonas cereus, Pseudomonas putida and Bacillus subtilis. This investigation revealed that bacterial endosymbionts use the polythene as a source of carbon and solubilize them by their enzymatic machinery. The degradation of polyethylene by endosymbionts showed a significant reduction in weight of polyethylene sheet after 15, 30 and 45 days of treatment. The SEM images showed localized degradation of the polyethylene around the bacterial cells in the biofilm. Further, the tensile strength (percentage elongation) was significantly reduced after 45 days of incubation. The weight of paraffin wax showed significant reduction in B. cereus. A significant reduction in total amount of chlorpyriphos in soil was observed at an interval of 7, 14 and 21 days after treatment by the bacterial isolates. Among the bacteria, B. cereus and P. putida were found to be most effective. The results from this study show that endosymbionts can be significantly implicated in degrading chlorpyriphos and polyethylene from the environment.     

Complete Genome Sequence of Penicillium oxalicum Strain SGAir0226 Isolated from Outdoor Tropical Air in Singapore

Mycopathologia - Penicillium oxalicum strain SGAir0226 was isolated from a tropical air sample collected in Singapore. The complete genome was assembled from long reads obtained from...     

Pyrazole-based sulfonamide and sulfamides as potent inhibitors of mammalian 15-lipoxygenase

A series of inhibitors of mammalian 15-lipoxygenase (15-LO) based on a 3,4,5-tri-substituted pyrazole scaffold is described. Replacement of a sulfonamide functionality in the lead series with a sulfamide group resulted in improved physicochemical properties generating analogs with enhanced inhibition in cell-based and whole blood assays.     

Visualization of Atg3 during Autophagosome Formation in Saccharomyces cerevisiae

Macroautophagy (autophagy) is a highly conserved cellular recycling process involved in degradation of eukaryotic cellular components. During autophagy, macromolecules and organelles are sequestered into the double-membrane autophagosome and degraded in the vacuole/lysosome. Autophagy-related 8 (Atg8), a core Atg protein essential for autophagosome formation, is a marker of several autophagic structures: the pre-autophagosomal structure (PAS), isolation membrane (IM), and autophagosome. Atg8 is conjugated to phosphatidylethanolamine (PE) through a ubiquitin-like conjugation system to yield Atg8-PE; this reaction is called Atg8 lipidation. Although the mechanisms of Atg8 lipidation have been well studied in vitro, the cellular locale of Atg8 lipidation remains enigmatic. Atg3 is an E2-like enzyme that catalyzes the conjugation reaction between Atg8 and PE. Therefore, we hypothesized that the localization of Atg3 would provide insights about the site of the lipidation reaction. To explore this idea, we constructed functional GFP-tagged Atg3 (Atg3-GFP) by inserting the GFP portion immediately after the handle region of Atg3. During autophagy, Atg3-GFP transiently formed a single dot per cell on the vacuolar membrane. This Atg3-GFP dot colocalized with 2× mCherry-tagged Atg8, demonstrating that Atg3 is localized to autophagic structures. Furthermore, we found that Atg3-GFP is localized to the IM by fine-localization analysis. The localization of Atg3 suggests that Atg3 plays an important role in autophagosome formation at the IM.