BackgroundExposures to environmental toxins are now thought to contribute to the development of autism spectrum disorder. Propionic acid (PA) found as a metabolic product of gut bacteria has been reported to mimic/mediate the neurotoxic effects of autism. Results from animal studies may guide investigations on human populations toward identifying environmental contaminants that produce or drugs that protect from neurotoxicity. Forty-eight young male Western Albino rats were used in the present study. They were grouped into six equal groups 8 rats each. The first group received a neurotoxic dose of buffered PA (250 mg/Kg body weight/day for 3 consecutive days). The second group received only phosphate buffered saline (control group). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for one week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for one week prior to PA (protected groups). Heat shock protein70 (Hsp70), Gamma amino-butyric acid (GABA), serotonin, dopamine, oxytocin and interferon γ-inducible protein 16 together with Comet DNA assay were measured in brain tissues of the six studied groups.ResultsThe obtained data showed that PA caused multiple signs of brain toxicity revealed in depletion of GABA, serotonin, and dopamine, are which important neurotransmitters that reflect brain function, interferon γ-inducible protein 16 and oxytocin. A high significant increase in tail length, tail DNA% damage and tail moment was reported indicating the genotoxic effect of PA. Administration of melatonin or coenzyme Q showed both protective and therapeutic effects on PA–treated rats demonstrated in a remarkable amelioration of most of the measured parameters.ConclusionIn conclusion, melatonin and coenzyme Q have potential protective and restorative effects against PA-induced brain injury, confirmed by improvement in biochemical markers and DNA double strand breaks.

BackgroundAbnormalities in fatty acid metabolism and membrane fatty acid composition play a part in a wide range of neurodevelopmental and psychiatric disorders. Altered fatty acid homeostasis as a result of insufficient dietary supplementation, genetic defects, the function of enzymes involved in their metabolism, or mitochondrial dysfunction contributes to the development of autism.ObjectiveThis study evaluates the association of altered brain lipid composition and neurotoxicity related to autism spectrum disorders in propionic acid (PA)–treated rats.DesignForty-eight young male western albino rats were used in this study. They were grouped into six equal groups with eight rats in each. The first group received only phosphate buffered saline (control group). The second group received a neurotoxic dose of buffered PA (250 mg/kg body weight/day for 3 consecutive days). The third and fourth groups were intoxicated with PA as described above followed by treatment with either coenzyme Q (4.5 mg/kg body weight) or melatonin (10 mg/kg body weight) for 1 week (therapeutically treated groups). The fifth and sixth groups were administered both compounds for 1 week prior to PA (protected groups). Methyl esters of fatty acid were extracted with hexane, and the fatty acid composition of the extract was analyzed on a gas chromatography.ResultsThe obtained data proved that fatty acids are altered in brain tissue of PA-treated rats. All saturated fatty acids were increased while all unsaturated fatty acids were significantly decreased in the PA-treated group and relatively ameliorated in the pre–post melatonin and coenzyme Q groups.ConclusionsMelatonin and coenzyme Q were effective in restoring normal level of most of the impaired fatty acids in PA-intoxicated rats which could help suggest both as supplements to ameliorate the autistic features induced in rat pups.

A series of novel naphthopyrano[2,3-d]pyrimidin-11(12H)-one containing isoxazole nucleus 4 was synthesized under microwave irradiation and classical conditions in moderate to excellent yields upon 1,3-dipolar cycloaddition reaction using various arylnitrile oxides under copper(I) catalyst. A one-pot, three-component reaction, N-propargylation and Dimroth rearrangement were used as the key steps for the preparation of the dipolarophiles3. The structures of the synthesized compounds were established by 1H NMR, 13C NMR and HRMS-ES means. The present study aims to also predict the theoretical assembly of the COVID-19 protease (SARS-CoV-2 Mpro) and to discover in advance whether this protein can be targeted by the compounds 4a–1 and thus be synthesized. The docking scores of these compounds were compared to those of the co-crystallized native ligand inhibitor (N3) which was used as a reference standard. The results showed that all the synthesized compounds (4a–l) gave interesting binding scores compared to those of N3 inhibitor. It was found that compounds 4a, 4e and 4i achieved greatly similar binding scores and modes of interaction than N3, indicating promising affinity towards SARS-CoV-2 Mpro. On the other hand, the derivatives 4k, 4h and 4j showed binding energy scores (−8.9, −8.5 and −8.4 kcal/mol, respectively) higher than the Mpro N3 inhibitor (−7.0 kcal/mol), revealing, in their turn, a strong interaction with the target protease, although their interactions were not entirely comparable to that of the reference N3.

Neuropeptides play a major role in maintaining normal brain development in children. Dysfunction of some specific neuropeptides can lead to autism spectrum disorders (ASD) in terms of social interaction and repetitive behavior, but the exact underlying etiological mechanisms are still not clear. In this study, we used an animal model of autism to investigate the role of bee pollen and probiotic in maintaining neuropeptide levels in the brain. We measured the Alpha-melanocyte-stimulating hormone (α-MSH), Beta-endorphin (β-End), neurotensin (NT), and substance P (SP) in brain homogenates of six studied groups of rats. Group I served as control, given only PBS for 30 days; Group II as an autistic model treated with 250 mg PPA/kg BW/day for 3 days after being given PBS for 27 days. Groups III-VI were denoted as intervention groups. G-III was treated with bee pollen (BP) 250 mg/kg body weight/day; G-IV with Lactobacillus paracaseii (LB) (109 CFU/mL) suspended in PBS; G-V with 0.2 g/kg body weight/day Protexin®, a mixture of probiotics (MPB); and G-VI was transplanted with stool from normal animals (FT) for 27 days prior to the induction of PPA neurotoxicity on the last 3 days of study (days 28–30). The obtained data were analyzed through the use of principal component analysis (PCA), discriminant analysis (DA), hierarchical clustering, and receiver operating characteristic (ROC) curves as excellent statistical tools in the field of biomarkers. The obtained data revealed that brain levels of the four measured neuropeptides were significantly reduced in PPA-treated animals compared to healthy control animals. Moreover, the findings demonstrate the ameliorative effects of bee pollen as a prebiotic and of the pure or mixed probiotics. This study proves the protective effects of pre and probiotics against the neurotoxic effects of PPA presented as impaired levels of α-MSH, β-End, NT, and SP.

The allosteric regulation of ADP-glucose pyrophosphorylase is critical for the biosynthesis of glycogen in bacteria and starch in plants. The enzyme from Agrobacterium tumefaciens is activated by fructose 6-phosphate (Fru6P) and pyruvate (Pyr). The Pyr site has been recently found, but the site where Fru6P binds has remained unknown. We hypothesize that a sulfate ion previously found in the crystal structure reveals a part of the regulatory site mimicking the presence of the phosphoryl moiety of the activator Fru6P. Ser72 interacts with this sulfate ion and, if the hypothesis is correct, Ser72 would affect the interaction with Fru6P and activation of the enzyme. Here, we report structural, binding, and kinetic analysis of Ser72 mutants of the A. tumefaciens ADP-glucose pyrophosphorylase. By X-ray crystallography, we found that when Ser72 was replaced by Asp or Glu side chain carboxylates protruded into the sulfate-binding pocket. They would present a strong steric and electrostatic hindrance to the phosphoryl moiety of Fru6P, while being remote from the Pyr site. In agreement, we found that Fru6P could not activate or bind to S72E or S72D mutants, whereas Pyr was still an effective activator. These mutants also blocked the binding of the inhibitor AMP. This could potentially have biotechnological importance in obtaining enzyme forms insensitive to inhibition.