Dietary Phytochemicals as Neurotherapeutics for Autism Spectrum Disorder: Plausible Mechanism and Evidence.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with symptoms ranging from lack of social interaction and communication deficits to rigid, repetitive, and stereotypic behavior. It has also been associated with comorbidities such as anxiety, aggression, epilepsy, deficit in sensory processing, as well as ADHD (attention deficit hyperactivity disorder). Apart from several behavioral and cognitive complications arising as a result of central nervous system dysfunction, there are various physiological comorbidities such as immune system deregulation, neuroinflammation, oxidative stress, mitochondrial dysfunction, and gastrointestinal complications which can worsen existing behavioral complications. There are no available treatments for these physiological comorbidities. The prevalence of gastrointestinal complications in ASD ranges from 9% to 70% and it correlates with behaviors consistent with the autistic endophenotype indicating that these are one of the major comorbidities associated with ASD. A strong connection of gut-brain cross talk occurs as a result of gut dysbiosis responsible for excessive production of short-chain fatty acids such as propanoic acid (PPA) by abnormal gut flora in ASD patients. This worsens behavioral, neurochemical, and mitochondrial dysfunction occurring in ASD. These physiological comorbidities are responsible for the generation of free radical species that cause immune system dysfunction leading to synthesis of various pro-inflammatory cytokines and chemokines. This in turn causes activation of microglia. Dietary phytochemicals are thought to be safer and useful as an alternative neurotherapeutic moiety. These compounds provide neuroprotection by modulating signaling pathways such as Nrf2, NF-κB, MAPK pathway or Sirtuin-FoxO pathway. There has been recent evidence in scientific literature regarding the modulation of gut-brain cross talk responsible for behavioral, biochemical, and mitochondrial dysfunction as well as cellular and behavioral sensory alterations by dietary phytochemicals such as curcumin, resveratrol, naringenin, and sulforaphane. These dietary phytochemicals can be formulated in novel brain-targeted delivery systems which overcome their limitation of low oral bioavailability and short half-life leading to prolonged action. Till date, not much work has been done on the development of brain-targeted neurotherapeutics for ASD. In this chapter we discuss plausible mechanisms and evidence from our own and other scientific research for the utilization of curcumin, resveratrol, naringenin, and sulforaphane as neurotherapeutics for ASD.

A compound isolated from Alpinia officinarum Hance. inhibits swarming motility of Pseudomonas aeruginosa and down regulates virulence genes.

AIM: The study was aimed at purifying the active principle from Alpinia officinarum rhizomes responsible for inhibition of swarming motility of Pseudomonas aeruginosa and analysing the mechanism of action. METHODS AND RESULTS: The active compound from methanol extract of A. officinarum was purified by silica gel column chromatography followed by elution from Amberlite resin. The compound 1-(3,5-dihydroxyphenyl)-2-(methylamino)ethan-1-one, inhibited swarming motility at 12·5 µg ml-1 . This inhibition was independent of rhamnolipid production. Real-time PCR analysis showed significant down-regulation of virulence-associated genes including T3SS exoS, exoT and flagella master regulator fleQ. CONCLUSIONS: The compound from A. officinarum inhibited swarming motility and significantly down-regulated the expression of type III secretory system effector genes exoS and exoT and flagellar master regulator fleQ genes. SIGNIFICANCE AND IMPACT OF THE STUDY: The study identifies a potent swarming inhibitory compound from the common medicinal plant A. officinarum and reinstates the potential of plant-derived compounds in tackling virulence properties of pathogenic bacteria.

Integration of physicochemical and pharmacokinetic parameters in lead optimization: a physiological pharmacokinetic model based approach.

There have been major strides in the development of novel ways of investigating drug like properties of new chemical entities (NCE) in the last three decades. Identification of ideal properties of a clinical candidate that would give a clinical proof of concept (POC) is the most critical step in the discovery process. Besides the biological dose-response relationship, the pharmacokinetic parameters play the most vital role in influencing the therapeutic response or toxicity of NCE. While there are numerous techniques to understand various drug-like properties individually, the behavior of an NCE in a dynamic in vivo system which influences its therapeutic or toxic effects is a composite function of its various physicochemical and pharmacokinetic parameters. This implies the need to understand the collective influence of various measured parameters, and knowing how variations made in them can result in favorable pharmacodynamic or toxicokinetic properties. Understanding this behavior holds the key to a successful and time efficient lead optimization process. Physiological based pharmacokinetic models (PBPK) are of great interest in this context as they involve a natural way of integrating the individual compound property to physiological properties, providing a rational approach to predict drug like behavior (an ideal behavior identified may be addressed generally as Target Product Profile) in vivo. In the current review, various physiological pharmacokinetic models addressing absorption, tissue distribution and clearance are discussed along with their application in integrating various physicochemical and ADME parameters to predict human pharmacokinetics helping lead optimization.

Tracking metastatic tumor cell extravasation with quantum dot nanocrystals and fluorescence emission-scanning microscopy.

Metastasis is an impediment to the development of effective cancer therapies. Our understanding of metastasis is limited by our inability to follow this process in vivo. Fluorescence microscopy offers the potential to follow cells at high resolution in living animals. Semiconductor nanocrystals, quantum dots (QDs), offer considerable advantages over organic fluorophores for this purpose. We used QDs and emission spectrum scanning multiphoton microscopy to develop a means to study extravasation in vivo. Although QD labeling shows no deleterious effects on cultured cells, concern over their potential toxicity in vivo has caused resistance toward their application to such studies. To test if effects of QD labeling emerge in vivo, tumor cells labeled with QDs were intravenously injected into mice and followed as they extravasated into lung tissue. The behavior of QD-labeled tumor cells in vivo was indistinguishable from that of unlabeled cells. QDs and spectral imaging allowed the simultaneous identification of five different populations of cells using multiphoton laser excitation. Besides establishing the safety of QDs for in vivo studies, our approach permits the study of multicellular interactions in vivo.

Calcium regulates the expression of a Dictyostelium discoideum asparaginyl tRNA synthetase gene.

In a screen for calcium-regulated gene expression during growth and development of Dictyostelium discoideum we have identified an asparaginyl tRNA synthetase (ddAsnRS) gene, the second tRNA synthetase gene identified in this organism. The ddAsnRS gene shows many unique features. One, it is repressed by lowering cellular calcium, making it the first known calcium-regulated tRNA synthetase. Two, despite the calcium-dependence, its expression is unaltered during the cell cycle, making this the first D. discoideum gene to show a calcium-dependent but cell cycle phase-independent expression. Finally, the N-terminal domain of the predicted ddAsnRS protein shows higher sequence similarity to Glutaminyl tRNA synthetases than to other Asn tRNA synthetases. These unique features of the AsnRS from this primitive eukaryote not only point to a novel mechanism regulating the components of translation machinery and gene expression by calcium, but also hint at a link between the evolution of GlnRS and AsnRS in eukaryotes.