Synthesis and anticancer evaluation of novel triazole linked N-(pyrimidin-2-yl)benzo[d]thiazol-2-amine derivatives as inhibitors of cell survival proteins and inducers of apoptosis in MCF-7 breast cancer cells.

A series of novel triazole linked N-(pyrimidin-2yl)benzo[d]thiazol-2-amine 5a-k were synthesized and evaluated for anticancer activity against breast (MCF-7), lung (A549) and skin (A375) cancer cell lines and their cytotoxic effects were compared against normal breast epithelial cells. The effect of compounds on cell cycle of MCF-7 breast cancer cell line was investigated by FACS. Result indicated G2/M cell cycle arrest of MCF-7 cells. Further promising compounds 5b, 5g, 5h and 5i were tested for their apoptosis inducing ability as well as inhibitory activity against key proteins NF-kB, Survivin, CYP1A1, and ERK1/2 which help in cancer cell survival and proliferation. The apoptotic aspect of these compounds is further evidenced by increase in the activity of caspase-9 in MCF-7 cells. Hence these small molecules have the potential to control both the cell proliferation as well as the invasion process in highly malignant breast cancers and can be selected for further biological studies.

Perampanel, an antagonist of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models.

Perampanel [Fycompa, 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile hydrate 4:3; Eisai Inc., Woodcliff Lake, NJ] is an AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor antagonist used as an adjunctive treatment of partial-onset seizures. We asked whether perampanel has AMPA receptor antagonist activity in both the cerebral cortex and hippocampus associated with antiepileptic efficacy and also in the cerebellum associated with motor side effects in rodent and human brains. We also asked whether epileptic or nonepileptic human cortex is similarly responsive to AMPA receptor antagonism by perampanel. In rodent models, perampanel decreased epileptic-like activity in multiple seizure models. However, doses of perampanel that had anticonvulsant effects were within the same range as those engendering motor side effects. Perampanel inhibited native rat and human AMPA receptors from the hippocampus as well as the cerebellum that were reconstituted into Xenopus oocytes. In addition, with the same technique, we found that perampanel inhibited AMPA receptors from hippocampal tissue that had been removed from a patient who underwent surgical resection for refractory epilepsy. Perampanel inhibited AMPA receptor-mediated ion currents from all the tissues investigated with similar potency (IC50 values ranging from 2.6 to 7.0 µM). Cortical slices from the left temporal lobe derived from the same patient were studied in a 60-microelectrode array. Large field potentials were evoked on at least 45 channels of the array, and 10 µM perampanel decreased their amplitude and firing rate. Perampanel also produced a 33% reduction in the branching parameter, demonstrating the effects of perampanel at the network level. These data suggest that perampanel blocks AMPA receptors globally across the brain to account for both its antiepileptic and side-effect profile in rodents and epileptic patients.

Lemon peels mediated synthesis of silver nanoparticles and its antidermatophytic activity.

There is an increasing commercial demand for nanoparticles due to their wide applicability in various areas. Metallic nanoparticles are traditionally synthesized by wet chemical techniques, where the chemicals used are quite often toxic and flammable. In this work, The extract of lemon peel was prepared and mixed with 1 mM AgNO3 solution .The bioreduction of Ag(+) ion in solution was monitored using UV-visible spectrometer, FESEM and EDAX analysis. Skin scales were collected from patients with suspected dermatophytosis and the dermatophytes were isolated and identified. The AgNPs produced from lemon peels showed good activity against the isolated dermatophytes. The present research work emphasizes the use of lemon peels for the effective synthesize of AgNPs and could be used against the dermatophytes which are found to develop drug resistant towards broad-spectrum antibiotics. The biosynthesis of AgNPs using lemon peel extract is very simple and economic. The use of environmentally benign and renewable plant material offers enormous benefits of eco-friendliness.

Rugulactone derivatives act as inhibitors of NF-κB activation and modulates the transcription of NF-κB dependent genes in MDA-MB-231cells.

Rugulactone and its analogues were synthesized following Horners-Wadsworth-Emmons and ring-closing metathesis as the key reactions. A library of new rugulactone analogues were designed, synthesized and evaluated for their anticancer activity in breast cancer cells. All analogues have shown anti-proliferative activity, while some of them exhibited significant cytotoxicity. In assays related to cell-cycle distribution, these conjugates induced G1 cell-cycle arrest in MDA-MB-231 cells. The cell cycle arrest nature was further confirmed by examining the effect on Cyclin E and Cdk2 proteins that acts at G1-S phase transition. Immunocytochemistry assay revealed that these compounds inhibited nuclear translocation of NF-κB protein, thereby activation of NF-κB was inhibited. The expression of NF-κB target genes such as Cyclin D1 and Bcl-xL were severely affected. Apart from acting on NF-κB, these compounds also regulate class I Histone deacetylase proteins such as (HDAC-3 and 8) that have a crucial and regulatory role in cell-proliferation. Simultaneously, the apoptotic inducing nature of these compounds was confirmed by activation of PARP protein, a protein that plays a key role in DNA damage and repair pathways. Among all compounds of this series 3g is the most potent compound and can be used for further studies.

Antimicrobial potential of Actinomycetes species isolated from marine environment.

OBJECTIVE: To evaluate the antimicrobial activity of Actinomycetes species isolated from marine environment. METHODS: Twenty one strains of Actinomycetes were isolated from samples of Royapuram, Muttukadu, Mahabalipuram sea shores and Adyar estuary. Preliminary screening was done using cross-streak method against two gram-positive and eight gram-negative bacteria. The most potent strains C11 and C12 were selected from which antibacterial substances were extracted. The antibacterial activities of the extracts were performed using Kirby-Bauer disc diffusion method. Molecular identification of those isolates was done. RESULTS: All those twenty one isolates were active against at least one of the test organisms. Morphological characters were recorded. C11 showed activity against Staphylococcus species (13.0±0.5 mm), Vibrio harveyi (11.0±0.2 mm), Pseudomonas species (12.0±0.3 mm). C12 showed activity against Staphylococcus species (16.0±0.4 mm), Bacillus subtilis (11.0±0.2 mm), Vibrio harveyi (9.0±0.1 mm), Pseudomonas species (10.0±0.2 mm). 16S rRNA pattern strongly suggested that C11 and C12 strains were Streptomyces species. CONCLUSIONS: The results of the present investigation reveal that the marine Actinomycetes from coastal environment are the potent source of novel antibiotics. Isolation, characterization and study of Actinomycetes can be useful in discovery of novel species of Actinomycetes.

Cowitch seed agar medium--a simple new medium for identification and melanin production of Cryptococcus neoformans.

A simple medium for identification and melanin production of Cryptococcus neoformans was developed using cowitch (Mucuna pruriens) seeds.

Effects of betahistine and of its metabolites on vestibular sensory organs.

Betahistine is widely used in the treatment of peripheral and central vestibular disorders. Till now the anti-vertigo effect of the drug was though to be mainly due to an action of betahistine on inner ear or cerebral microcirculation or on some structures of the CNS, chiefly the vestibular nuclei. Vertigo, however is, in most cases, of peripheral origin but it remains unknown whether betahistine, or some of its metabolities, may directly affect the vestibular system at peripheral level. Pharmacokinetic studies have in fact demonstrated that betahistine is transformed, mainly at the hepatic level, in aminoethylpyridine (M1), hydroxyethylpyridine (M2) and, finally, in pyridylacetic acid (M3) which is excreted with the urine. All these substances are therefore present in the body fluids of subjects treated with betahistine, and thus might have pharmacological effects. The goal of the present study was to investigate whether betahistine or some of its metabolites could exert any effect on vestibular receptors. To this end, the effects of the drugs (10(-7)-10(-2) M) have been examined on frog semicircular canals, an animal model well suited for this purpose. The effects of betahistine and of its metabolites have been evaluated by recording ampullar receptor activity both at rest and during mechanical stimulation of the sensory organ. The results demonstrated that both betahistine and one of its metabolites, the aminoethylpyridine (M1), exert effects quite similar on ampullar receptors; both these substances in fact could reduce greatly ampullar receptor resting discharge but had scanty effects on mechanically-evoked responses. This observation might justify betahistine and possibly M1 anti-vertigo effects. In fact vertigo is normally due to uncontrolled changes in vestibular receptor resting discharge. It is therefore probable that any factor able to reduce vestibular receptor resting firing rate and, in consequence, its variations, may have, as final effect, an anti-vertigo action. The observation that betahistine and M1 have similar effects might be of some clinical interest. In fact, on the basis of our data, the hypothesis may be put forward that the anti-vertigo action of betahistine is at first achieved by betahistine itself and then sustained and prolonged in time by M1.

Effects of betahistine metabolites on frog ampullar receptors.

Previous studies have demonstrated that betahistine, an histamine-like substance used widely as an anti-vertigo drug, can decrease ampullar receptor resting discharge without affecting their mechanically evoked responses. Pharmacokinetic studies have shown that this drug is transformed, mainly at the hepatic level, into aminoethylpyridine (M1), hydroxyethylpyridine (M2), then excreted with the urine as pyridylacetic acid (M3). The goal of the present study was to investigate whether betahistine metabolites are also able to affect vestibular receptor activity. Results demonstrated that, in the range tested (10(-7)-10(-2) M), M2 and M3 exerted no effect, whereas M1, at concentrations higher than 10(-6) M, was able to reduce the resting discharge of ampullar receptors without affecting the evoked responses. M1 therefore exerts effects similar to those of betahistine on ampullar receptors. This might be of some clinical interest. On the basis of our data, the hypothesis may be put forward that the anti-vertigo action of betahistine is at first achieved by betahistine itself and then sustained by M1.

Effects of caloric stimuli on frog ampullar receptors.

The observation that caloric nystagmus can be evoked even in microgravity conditions argues against Barany's convective theory. To justify this result, gravity-independent mechanisms (mainly endolymphatic volume changes and direct action of the temperature on vestibular sensors) are believed to contribute to caloric-induced activation of vestibular receptors. To define the importance of both gravity-dependent and gravity-independent mechanisms, the posterior semicircular canal of the frog was thermally stimulated by a microthermistor positioned close to the sensory organ. The stimulus produced a gravity-dependent transcupular pressure difference that, depending on the position of the heater, could result in either excitation or inhibition of ampullar receptor sensory discharge. When the heater was positioned on the ampulla, or when the canal rested on the horizontal plane, no responses could be evoked by thermal stimuli. These results suggest that, in our experimental conditions (DeltaT up to 1.5 degrees C), neither a thermally induced expansion of the endolymph nor a direct action of the temperature on vestibular sensors play any major role.

Caloric stimulation of ampullar receptors: a new method to produce mechanically-evoked responses in frog semicircular canals.

A microthermistor positioned close to the exposed posterior semicircular canal in isolated labyrinth preparations of the frog was used to stimulate the sensory organ. Our results indicated that, depending on the position of the heater, the induced endolymphatic convection currents may result in either excitatory or inhibitory cupular deflections and thus in a modulation of ampullar receptor resting activity. Other possible thermal-dependent mechanisms, such as a direct action of the stimulus on vestibular sensors or endolymphatic volume changes, had, in the present experimental conditions, a minor role. Caloric stimulation could therefore represent a novel method to stimulate the semicircular canals 'in situ'.

Effects of betahistine on vestibular receptors of the frog.

Betahistine is widely used in the symptomatic treatment of peripheral and central vestibular disorders. However, its remains unknown whether the drug can act directly on inner ear sensory organs. To this end, the effects of betahistine (10(-7)-10(-2) M) were examined on isolated preparations of frog semicircular canal mounted in a double-celled bath which allowed drug administration both in the endolymphatic and in the perilymphatic fluid. The effects of betahistine were evaluated by recording ampullar receptor potentials and nerve firing rate both at rest and during mechanical stimulation of the isolated preparation. The results demonstrated that endolymphatic administration of betahistine had no effect, whereas its perilymphatic administration could reduce greatly ampullar receptor resting discharge but had little effect on mechanically evoked responses. This observation may explain the anti-vertigo effects of betahistine. Vertigo is normally due to uncontrolled changes in vestibular receptor resting discharge. It is therefore probable that any factor able to reduce the resting firing rate of vestibular receptors and, in consequence, its variations, may have an anti-vertigo action.

Why do benign paroxysmal positional vertigo episodes recover spontaneously?

It is well known that most episodes of benign paroxysmal positional vertigo (BPPV), even in untreated, recover spontaneously in 2 to 6 weeks. In the present study, we put forward the hypothesis that this is mainly due to the fact that endolymph, owing to its low calcium content (20 microM) is able to dissolve otoconia. To support this, the fate of frog saccular otoconia immersed in normal endolymph (Ca2+ content 20 microM) and in Ca2+-rich endolymphatic fluids (up to 500 microM) was studied by observing the crystals at regular intervals for 3 weeks. The results demonstrated that normal endolymph can dissolve otoconia very rapidly (in about 20 hours). When the endolymphatic Ca2+ content was increased (50 to 200 microM) otoconia dissolution time was slowed down (about 100 to 130 hours, respectively) and completely stopped when the endolymphatic Ca2+ content was of 500 microM. The present results therefore suggest that the major process involved in the spontaneous recovery of BPPV episodes is the capability of the endolymph to dissolve dislodged otoconia.

[Incidence, mortality and survival in childhood tumors in meridional Sardinia. The Cagliari province, 1981-1988]. / Incidenza, mortalità e sopravvivenza per tumori infantili nella Sardegna meridionale. La provincia di Cagliari per gli anni 1982-1988.

Childhood cancer incidence, mortality and relative survival rates have been estimated in the province of Cagliari for the years 1982-86. Cases were collected from pediatric and non pediatric units operating either in the province or elsewhere. Deaths were identified through the registry offices of municipal administrations. A total of 151 cases were identified, corresponding to an incidence rate of 115.0 per million. Survival rate at three years of diagnosis was 63.3%.