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  1. Article ; Online: Mutations associated with autism lead to similar synaptic and behavioral alterations in both sexes of male and female mouse brain

    Manish Kumar Tripathi / Shashank Kumar Ojha / Maryam Kartawy / Igor Khaliulin / Wajeha Hamoudi / Haitham Amal

    Scientific Reports, Vol 14, Iss 1, Pp 1-

    2024  Volume 10

    Abstract: Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder based on synaptic abnormalities. The estimated prevalence rate of male individuals diagnosed with ASD prevails over females is in a proportion of 4:1. Consequently, males remain the ...

    Abstract Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder based on synaptic abnormalities. The estimated prevalence rate of male individuals diagnosed with ASD prevails over females is in a proportion of 4:1. Consequently, males remain the main focus in ASD studies in clinical and experimental settings. Meanwhile, some studies point to an underestimation of this disorder in females. In this work, we studied the sex differences of the synaptic and behavioral phenotypes of ASD mouse models. Juvenile male and female Shank3Δ4–22 and Cntnap2−/− mutant mice and their WT littermates were used in the experiments. The animals were subjected to a Three-Chamber Sociability Test, then euthanized, and the whole cortex was used for the evaluation of the synaptic phenotype. Protein levels of glutamatergic (NR1) and GABAergic (GAD1 and VGAT) neuronal markers were measured. Protein level of synaptophysin (Syp) was also measured. Dendritic spine density in somatosensory neurons was analyzed by Golgi staining methods. Spine Density and GAD1, NR1, VGAT, and Syp levels were significantly reduced in Shank3Δ4–22 and Cntnap2−/− mice compared to the control group irrespective of sex, indicating impaired synaptic development in the mutant mice. These results were consistent with the lack of differences in the three-chamber sociability test between male and female mice. In conclusion, female ASD mice of both mutations undergo similar synaptic aberrations as their male counterparts and need to be studied along with the male animals. Finally, this work urges the psychiatry scientific community to use both sexes in their investigations.
    Keywords Medicine ; R ; Science ; Q
    Subject code 590
    Language English
    Publishing date 2024-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Systems Biology Reveals S-Nitrosylation-Dependent Regulation of Mitochondrial Functions in Mice with Shank3 Mutation Associated with Autism Spectrum Disorder

    Maryam Kartawy / Igor Khaliulin / Haitham Amal

    Brain Sciences, Vol 11, Iss 677, p

    2021  Volume 677

    Abstract: Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. ...

    Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder manifested in repetitive behavior, abnormalities in social interactions, and communication. The pathogenesis of this disorder is not clear, and no effective treatment is currently available. Protein S-nitrosylation (SNO), the nitric oxide (NO)-mediated posttranslational modification, targets key proteins implicated in synaptic and neuronal functions. Previously, we have shown that NO and SNO are involved in the ASD mouse model based on the Shank3 mutation. The energy supply to the brain mostly relies on oxidative phosphorylation in the mitochondria. Recent studies show that mitochondrial dysfunction and oxidative stress are involved in ASD pathology. In this work, we performed SNO proteomics analysis of cortical tissues of the Shank3 mouse model of ASD with the focus on mitochondrial proteins and processes. The study was based on the SNOTRAP technology followed by systems biology analysis. This work revealed that 63 mitochondrial proteins were S-nitrosylated and that several mitochondria-related processes, including those associated with oxidative phosphorylation, oxidative stress, and apoptosis, were enriched. This study implies that aberrant SNO signaling induced by the Shank3 mutation can target a wide range of mitochondria-related proteins and processes that may contribute to the ASD pathology. It is the first study to investigate the role of NO-dependent mitochondrial functions in ASD.
    Keywords autism spectrum disorder ; nitric oxide ; S-nitrosylation ; proteomics mitochondria ; systems biology ; Neurosciences. Biological psychiatry. Neuropsychiatry ; RC321-571
    Subject code 612
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: The role of nitric oxide in brain disorders

    Manish Kumar Tripathi / Maryam Kartawy / Haitham Amal

    Redox Biology, Vol 34, Iss , Pp 101567- (2020)

    Autism spectrum disorder and other psychiatric, neurological, and neurodegenerative disorders

    2020  

    Abstract: Nitric oxide (NO) is a multifunctional signalling molecule and a neurotransmitter that plays an important role in physiological and pathophysiological processes. In physiological conditions, NO regulates cell survival, differentiation and proliferation ... ...

    Abstract Nitric oxide (NO) is a multifunctional signalling molecule and a neurotransmitter that plays an important role in physiological and pathophysiological processes. In physiological conditions, NO regulates cell survival, differentiation and proliferation of neurons. It also regulates synaptic activity, plasticity and vesicle trafficking. NO affects cellular signalling through protein S-nitrosylation, the NO-mediated posttranslational modification of cysteine thiols (SNO). SNO can affect protein activity, protein-protein interaction and protein localization. Numerous studies have shown that excessive NO and SNO can lead to nitrosative stress in the nervous system, contributing to neuropathology. In this review, we summarize the role of NO and SNO in the progression of neurodevelopmental, psychiatric and neurodegenerative disorders, with special attention to autism spectrum disorder (ASD). We provide mechanistic insights into the contribution of NO in diverse brain disorders. Finally, we suggest that pharmacological agents that can inhibit or augment the production of NO as well as new approaches to modulate the formation of SNO-proteins can serve as a promising approach for the treatment of diverse brain disorders.
    Keywords Nitric oxide ; S-nitrosylation ; Autism spectrum disorder ; Alzheimer's disease ; Psychiatry ; Neurodegeneration ; Medicine (General) ; R5-920 ; Biology (General) ; QH301-705.5
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Elsevier
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Sex Differences in Biological Processes and Nitrergic Signaling in Mouse Brain

    Igor Khaliulin / Maryam Kartawy / Haitham Amal

    Biomedicines, Vol 8, Iss 124, p

    2020  Volume 124

    Abstract: Nitric oxide (NO) represents an important signaling molecule which modulates the functions of different organs, including the brain. S-nitrosylation (SNO), a post-translational modification that involves the binding of the NO group to a cysteine residue, ...

    Abstract Nitric oxide (NO) represents an important signaling molecule which modulates the functions of different organs, including the brain. S-nitrosylation (SNO), a post-translational modification that involves the binding of the NO group to a cysteine residue, is a key mechanism of nitrergic signaling. Most of the experimental studies are carried out on male animals. However, significant differences exist between males and females in the signaling mechanisms. To investigate the sex differences in the SNO-based regulation of biological functions and signaling pathways in the cortices of 6–8-weeks-old mice, we used the mass spectrometry technique, to identify S-nitrosylated proteins, followed by large-scale computational biology. This work revealed significant sex differences in the NO and SNO-related biological functions in the cortices of mice for the first-time. The study showed significant SNO-induced enrichment of the synaptic processes in female mice, but enhanced SNO-related cytoskeletal processes in the male mice. Proteins, which were S-nitrosylated in the cortices of mice of both groups, were more abundant in the female brain. Finally, we investigated the shared molecular processes that were found in both sexes. This study presents a mechanistic insight into the role of S-nitrosylation in both sexes and provides strong evidence of sex difference in many biological processes and signalling pathways, which will open future research directions on sex differences in neurological disorders.
    Keywords sex ; proteomics ; S-nitrosylation ; nitric oxide ; posttranslational modification ; cell signaling ; Biology (General) ; QH301-705.5
    Subject code 572
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: Preconditioning or Postconditioning with 8-Br-cAMP-AM Protects the Heart against Regional Ischemia and Reperfusion

    Igor Khaliulin / Raimondo Ascione / Leonid N. Maslov / Haitham Amal / M. Saadeh Suleiman

    Cells, Vol 10, Iss 1223, p

    A Role for Mitochondrial Permeability Transition

    2021  Volume 1223

    Abstract: The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied ... ...

    Abstract The cAMP analogue 8-Br-cAMP-AM (8-Br) confers marked protection against global ischaemia/reperfusion of isolated perfused heart. We tested the hypothesis that 8-Br is also protective under clinically relevant conditions (regional ischaemia) when applied either before ischemia or at the beginning of reperfusion, and this effect is associated with the mitochondrial permeability transition pore (MPTP). 8-Br (10 μM) was administered to Langendorff-perfused rat hearts for 5 min either before or at the end of 30 min regional ischaemia. Ca 2+ -induced mitochondria swelling (a measure of MPTP opening) and binding of hexokinase II (HKII) to mitochondria were assessed following the drug treatment at preischaemia. Haemodynamic function and ventricular arrhythmias were monitored during ischaemia and 2 h reperfusion. Infarct size was evaluated at the end of reperfusion. 8-Br administered before ischaemia attenuated ventricular arrhythmias, improved haemodynamic function, and reduced infarct size during ischaemia/reperfusion. Application of 8-Br at the end of ischaemia protected the heart during reperfusion. 8-Br promoted binding of HKII to the mitochondria and reduced Ca 2+ -induced mitochondria swelling. Thus, 8-Br protects the heart when administered before regional ischaemia or at the beginning of reperfusion. This effect is associated with inhibition of MPTP via binding of HKII to mitochondria, which may underlie the protective mechanism.
    Keywords cyclic AMP ; heart ; regional ischaemia ; cardioprotection ; reperfusion injury ; mitochondria permeability transition pore ; Biology (General) ; QH301-705.5
    Subject code 630
    Language English
    Publishing date 2021-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: Low Doses of Arsenic in a Mouse Model of Human Exposure and in Neuronal Culture Lead to S-Nitrosylation of Synaptic Proteins and Apoptosis via Nitric Oxide

    Haitham Amal / Guanyu Gong / Hongmei Yang / Brian A. Joughin / Xin Wang / Charles G. Knutson / Maryam Kartawy / Igor Khaliulin / John S. Wishnok / Steven R. Tannenbaum

    International Journal of Molecular Sciences, Vol 21, Iss 3948, p

    2020  Volume 3948

    Abstract: Background: Accumulating public health and epidemiological literature support the hypothesis that arsenic in drinking water or food affects the brain adversely. Methods: Experiments on the consequences of nitric oxide (NO) formation in neuronal cell ... ...

    Abstract Background: Accumulating public health and epidemiological literature support the hypothesis that arsenic in drinking water or food affects the brain adversely. Methods: Experiments on the consequences of nitric oxide (NO) formation in neuronal cell culture and mouse brain were conducted to probe the mechanistic pathways of nitrosative damage following arsenic exposure. Results: After exposure of mouse embryonic neuronal cells to low doses of sodium arsenite (SA), we found that Ca 2+ was released leading to the formation of large amounts of NO and apoptosis. Inhibition of NO synthase prevented neuronal apoptosis. Further, SA led to concerted S-nitrosylation of proteins significantly associated with synaptic vesicle recycling and acetyl-CoA homeostasis. Our findings show that low-dose chronic exposure (0.1–1 ppm) to SA in the drinking water of mice led to S-nitrosylation of proteomic cysteines. Subsequent removal of arsenic from the drinking water reversed the biochemical alterations. Conclusions: This work develops a mechanistic understanding of the role of NO in arsenic-mediated toxicity in the brain, incorporating Ca 2+ release and S-nitrosylation as important modifiers of neuronal protein function.
    Keywords arsenic ; nitric oxide ; S-nitrosylation ; brain disorders ; brain cortex ; mouse ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
    Subject code 616
    Language English
    Publishing date 2020-05-01T00:00:00Z
    Publisher MDPI AG
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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