Effects of buthionine sulfoximine nifurtimox and benznidazole upon trypanothione and metallothionein proteins in Trypanosoma cruzi

Proteins rich in sulfhydryl groups, such as metallothionein, are present in several strains of the parasite Trypanosoma cruzi, the etiological agent of Chagas' disease. Metallothionein-like protein concentrations ranged from 5.1 to 13.2 pmol/mg protein depending on the parasite strain and growth phase. Nifurtimox and benznidazole, used in the treatment of Chagas' disease, decreased metallothionein activity by approximately 70%. T. cruzi metallothionein was induced by ZnCl2. Metallothionein from T. cruzi was partially purified and its monobromobimane derivative showed a molecular weight of approximately 10,000 Da by SDS-PAGE analysis. The concentration of trypanothione, the major glutathione conjugate in T. cruzi, ranged from 3.8 to 10.8 nmol/mg protein, depending on the culture phase. The addition of buthionine sulfoximine to the protozoal culture considerably reduced the concentration of trypanothione and had no effect upon the metallothionein concentration. The possible contribution of metallothionein-like proteins to drug resistance in T. cruzi is discussed.     

Synthesis, radiolabeling, and preliminary biological evaluation of [3H]-1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine, a potent antagonist radioligand for the P2X7 receptor

The design, synthesis, and preliminary biological evaluation of the first potent radioligand antagonist for the P2X(7) receptor, named [(3)H]-1-[(S)-N,O-bis-(isoquinolinesulfonyl)-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine (compound 13), are reported. This compound bound to human P2X(7) receptors expressed in HEK transfected cells with K(D) and B(max) value of 3.46+/-0.1 nM and 727+/-73 fmol/mg of protein, respectively. The high affinity and facile labeling makes it a promising radioligand for a further characterization of P2X(7) receptor subtype.     

MiR‐342 controls Mycobacterium tuberculosis susceptibility by modulating inflammation and cell death

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb) that places a heavy strain on public health. Host susceptibility to Mtb is modulated by macrophages, which regulate the balance between cell apoptosis and necrosis. However, the role of molecular switches that modulate apoptosis and necrosis during Mtb infection remains unclear. Here, we show that Mtb‐susceptible mice and TB patients have relatively low miR‐342‐3p expression, while mice with miR‐342‐3p overexpression are more resistant to Mtb. We demonstrate that the miR‐342‐3p/SOCS6 axis regulates anti‐Mtb immunity by increasing the production of inflammatory cytokines and chemokines. Most importantly, the miR‐342‐3p/SOCS6 axis participates in the switching between Mtb‐induced apoptosis and necrosis through A20‐mediated K48‐linked ubiquitination and RIPK3 degradation. Our findings reveal several strategies by which the host innate immune system controls intracellular Mtb growth via the miRNA‐mRNA network and pave the way for host‐directed therapies targeting these pathways.     

Benzoyl and cinnamoyl nitrogen mustard derivatives of benzoheterocyclic analogues of the tallimustine: synthesis and antitumour activity

A series of benzoyl and cinnamoyl nitrogen mustards tethered to different benzoheterocycles and to oligopyrroles structurally related to netropsin consisting of two pyrrole-amide units and terminating with an amidine moiety have been synthesised and a structure--activity relationship determined. Derivatives 3--10 have been evaluated for their sequence selective alkylating properties and cytotoxicity against human K562 leukaemia cells. They are 2- to 50-fold less cytotoxic than tallimustine, with compound 8 being the most potent member of this series. Among tallimustine isosters, the compounds with an indole 3 or benzothiophene 6 are 4-fold less cytotoxic than tallimustine, while the compounds with an N-methyl indole or benzofuran showed a 7- and 14-fold reduced cytotoxic potency, respectively. Our preliminary results indicate that these derivatives preferentially bind to AT-rich sequence with a sequence selectivity similar to tallimustine.     

Genetics of amyotrophic lateral sclerosis: an update

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.     

A common cortical substrate activated by horizontal and vertical sound movement in the human brain

Perception of movement in acoustic space depends on comparison of the sound waveforms reaching the two ears (binaural cues) as well as spectrotemporal analysis of the waveform at each ear (monaural cues). The relative importance of these two cues is different for perception of vertical or horizontal motion, with spectrotemporal analysis likely to be more important for perceiving vertical shifts. In humans, functional imaging studies have shown that sound movement in the horizontal plane activates brain areas distinct from the primary auditory cortex, in parietal and frontal lobes and in the planum temporale. However, no previous work has examined activations for vertical sound movement. It is therefore difficult to generalize previous imaging studies, based on horizontal movement only, to multidimensional auditory space perception. Using externalized virtual-space sounds in a functional magnetic resonance imaging (fMRI) paradigm to investigate this, we compared vertical and horizontal shifts in sound location. A common bilateral network of brain areas was activated in response to both horizontal and vertical sound movement. This included the planum temporale, superior parietal cortex, and premotor cortex. Sounds perceived laterally in virtual space were associated with contralateral activation of the auditory cortex. These results demonstrate that sound movement in vertical and horizontal dimensions engages a common processing network in the human cerebral cortex and show that multidimensional spatial properties of sounds are processed at this level.     

α‐Lipoic acid inhibits testicular and epididymal oxidative damage and improves fertility efficacy in arsenic‐intoxicated rats

The present study evaluates the protective effect of α‐lipoic acid (LA) against arsenic‐induced testicular and epididymal oxidative damage in rats. Arsenic caused significant reduction in the reproductive organ weights, serum testosterone levels, testicular daily sperm count, epididymal sperm count, sperm motility, sperm viability, and sperm membrane integrity. Significant reduction in the activity levels of superoxide dismutase, catalase, and glutathione levels with a concomitant increase in the lipid peroxidation and protein carbonyl content in the testis and the cauda epididymis of arsenic‐exposed rats. Arsenic intoxication also enhanced the testicular caspase‐3 mRNA levels, disorganization of testicular and cauda epididymal architecture as well as increased arsenic content in the testis and the cauda epididymis of rats. Arsenic exposure also deteriorated fertility ability in male rats over controls. Conversely, α‐LA negated the testicular and cauda epididymal oxidative stress and restored the male reproductive health in arsenic‐exposed rats.     

Uncoupling Warburg effect and stemness in CD133<Superscript>+ve</Superscript> cancer stem cells from Saos-2 (osteosarcoma) cell line under hypoxia

Cancer stem cells (CSCs) which are known to be residing deep inside the core of the tumor in its hypoxia niche is responsible for relapse of cancers. Owing to this hypoxic niche, the residing CSCs simultaneously fuel their stemness, cancerous and drug resistance properties. Attributes of CSCs are still not properly understood in its hypoxia niche. Addressing this, we sorted CSCs from Saos-2 (osteosarcoma) cell line using CD133 antibody. The CD133^+ve CSCs exhibited quiescent cell proliferation in DNA doubling, Ca²⁺ signaling and cell cycle analysis. CD133^+ve CSCs exhibited increased production of ATP and lactate dehydrogenase (LDH) activity under hypoxia. CD133^+ve cells exhibited decreased glucose uptake compared to ATP levels under hypoxia. Moreover, there was only negligible LDH activity in CD133^+ve cells under normoxia which do not rely on Warburg effect. Stemness markers (such as c-Myc, SOX2, Oct4 and TERT), metastasis marker (CD44) and drug resistance marker (ABCG2) were highly expressed in CD133^+ve cells. In summary, both CD133^+ve/?ve cells of Saos-2 (osteosarcoma) cell line did not exhibit Warburg effect under normoxic condition. Moreover, this significantly indicates an uncoupling between stemness and Warburg effect in CD133^+ve. This work provides a novel insight into the metabolic and functional features of CSCs in a hypoxic environment which could open new avenues for therapeutic strategies aimed to target CSCs.     

Multisensory contributions to the 3-D representation of visuotactile peripersonal space in humans: evidence from the crossmodal congruency task.

In order to determine precisely the location of a tactile stimulus presented to the hand it is necessary to know not only which part of the body has been stimulated, but also where that part of the body lies in space. This involves the multisensory integration of visual, tactile, proprioceptive, and even auditory cues regarding limb position. In recent years, researchers have become increasingly interested in the question of how these various sensory cues are weighted and integrated in order to enable people to localize tactile stimuli, as well as to give rise to the 'felt' position of our limbs, and ultimately the multisensory representation of 3-D peripersonal space. We highlight recent research on this topic using the crossmodal congruency task, in which participants make speeded elevation discrimination responses to vibrotactile targets presented to the thumb or index finger, while simultaneously trying to ignore irrelevant visual distractors presented from either the same (i.e., congruent) or a different (i.e., incongruent) elevation. Crossmodal congruency effects (calculated as performance on incongruent-congruent trials) are greatest when visual and vibrotactile stimuli are presented from the same azimuthal location, thus providing an index of common position across different sensory modalities. The crossmodal congruency task has been used to investigate a number of questions related to the representation of space in both normal participants and brain-damaged patients. In this review, we detail the major findings from this research, and highlight areas of convergence with other cognitive neuroscience disciplines.