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1.
Role of ferroptosis in neurological diseases.
Yao, MY, Liu, T, Zhang, L, Wang, MJ, Yang, Y, Gao, J
Neuroscience letters. 2021;:135614
Abstract
Ferroptosis is a newly identified form of nonapoptotic regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides which leads to oxidative stress and cell death. Recent studies have indicated that ferroptosis plays an essential role in the pathology of neurological diseases, such as intracerebral hemorrhage, ischemic stroke, epilepsy, neurodegenerative diseases, traumatic brain injury and brain cancer. This review focuses on the latest researches on the relationship of ferroptosis with nervous system diseases, highlighting the ferroptosis-based mechanisms, and elaborating the new perspective therapeutic targets of neurological disorders.
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2.
Role of Hydrogen Sulfide and Polysulfides in Neurological Diseases: Focus on Protein S-Persulfidation.
Sun, HJ, Wu, ZY, Nie, XW, Bian, JS
Current neuropharmacology. 2021;(6):868-884
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Abstract
Hydrogen sulfide (H2S) and hydrogen polysulfides are recognized as important signaling molecules that are generated physiologically in the body, including the central nervous system (CNS). Studies have shown that these two molecules are involved in cytoprotection against oxidative stress and inflammatory response. In the brain system, H2S and polysulfides exert multiple functions in both health and diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), memory decline, and glioma. Mechanistically, S-Persulfidation (also known as S-sulfuration or S-sulfhydration) of target proteins is believed to be a fundamental mechanism that underlies H2S-regulated signaling pathways. Cysteine S-Persulfidation is an important paradigm of post translational protein modification in the process of H2S signaling. This model is established as a critical redox mechanism to regulate numerous biological functions, especially in H2S-mediated neuroprotection and neurogenesis. Although the current research of S-Persulfidation is still in its infancy, accumulative evidence suggests that protein S-Persulfidation may share similar characteristics with protein S-nitrosylation. In this review, we will provide a comprehensive insight into the S-Persulfidation biology of H2S and polysulfides in neurological ailments and presume potential avenues for therapeutic development in these disorders based on S-Persulfidation of target proteins.
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3.
A SARS-CoV-2 -human metalloproteome interaction map.
Chasapis, CT, Georgiopoulou, AK, Perlepes, SP, Bjørklund, G, Peana, M
Journal of inorganic biochemistry. 2021;:111423
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Abstract
The recent pandemic caused by the novel coronavirus resulted in the greatest global health crisis since the Spanish flu pandemic of 1918. There is limited knowledge of whether SARS-CoV-2 is physically associated with human metalloproteins. Recently, high-confidence, experimentally supported protein-protein interactions between SARS-CoV-2 and human proteins were reported. In this work, 58 metalloproteins among these human targets have been identified by a structure-based approach. This study reveals that most human metalloproteins interact with the recently discovered SARS-CoV-2 orf8 protein, whose antibodies are one of the principal markers of SARS-CoV-2 infections. Furthermore, this work provides sufficient evidence to conclude that Zn2+ plays an important role in the interplay between the novel coronavirus and humans. First, the content of Zn-binding proteins in the involved human metalloproteome is significantly higher than that of the other metal ions. Second, a molecular linkage between the identified human Zn-binding proteome with underlying medical conditions, that might increase the risk of severe illness from the SARS-CoV-2 virus, has been found. Likely perturbations of host cellular metal homeostasis by SARS-CoV-2 infection are highlighted.
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Clinical Role of Smartphone Fundus Imaging in Diabetic Retinopathy and Other Neuro-retinal Diseases.
Pujari, A, Saluja, G, Agarwal, D, Sinha, A, P R, A, Kumar, A, Sharma, N
Current eye research. 2021;(11):1605-1613
Abstract
Purpose: In today's life, many electronic gadgets have the potential to become invaluable health care devices in future. The gadgets in this category include smartphones, smartwatches, and others. Till now, smartphone role has been highlighted on many occasions in different areas, and they continue to possess immense role in clinical documentation, clinical consultation, and digitalization of ocular care. In last one decade, many treatable conditions including diabetic retinopathy, glaucoma, and other pediatric retinal diseases are being imaged using smartphones.Methods: To comprehend this cumulative knowledge, a detailed medical literature search was conducted on PubMed/Medline, Scopus, and Web of Science till February 2021.Results: The included literature revealed a definitive progress in posterior segment imaging. From simple torch light with smartphone examination to present day compact handy devices with artificial intelligence integrated software's have changed the very perspectives of ocular imaging in ophthalmology. The consistently reproducible results, constantly improving imaging techniques, and most importantly their affordable costs have renegotiated their role as effective screening devices in ophthalmology. Moreover, the obtained field of view, ocular safety, and their key utility in non-ophthalmic specialties are also growing.Conclusions: To conclude, smartphone imaging can now be considered as a quick, cost-effective, and digitalized tool for posterior segment screenings, however, their definite role in routine ophthalmic clinics is yet to be established.
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Expanding the molecular spectrum and the neurological phenotype related to CAMTA1 variants.
Jacobs, EZ, Brown, K, Byler, MC, D'haenens, E, Dheedene, A, Henderson, LB, Humberson, JB, van Jaarsveld, RH, Kanani, F, Lebel, RR, et al
Clinical genetics. 2021;(2):259-268
Abstract
The CAMTA1-associated phenotype was initially defined in patients with intragenic deletions and duplications who showed nonprogressive congenital ataxia, with or without intellectual disability. Here, we describe 10 individuals with CAMTA1 variants: nine previously unreported (likely) pathogenic variants comprising one missense, four frameshift and four nonsense variants, and one missense variant of unknown significance. Six patients were diagnosed following whole exome sequencing and four individuals with exome-based targeted panel analysis. Most of them present with developmental delay, manifesting in speech and motor delay. Other frequent findings are hypotonia, cognitive impairment, cerebellar dysfunction, oculomotor abnormalities, and behavioral problems. Feeding problems occur more frequently than previously observed. In addition, we present a systematic review of 19 previously published individuals with causal variants, including copy number, truncating, and missense variants. We note a tendency of more severe cognitive impairment and recurrent dysmorphic features in individuals with a copy number variant. Pathogenic variants are predominantly observed in and near the N- and C- terminal functional domains. Clinical heterogeneity is observed, but 3'-terminal variants seem to associate with less pronounced cerebellar dysfunction.
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Withania somnifera in Neurological Disorders: Ethnopharmacological Evidence, Mechanism of Action and its Progress in Delivery Systems.
Syed, AA, Reza, MI, Singh, P, Thombre, GK, Gayen, JR
Current drug metabolism. 2021;(7):561-571
Abstract
BACKGROUND The underlying cause of major neurodegenerative disorders remains a healthcare mystery. The thoroughly investigated causes include oxidative stress, inflammation, environmental factor, mitochondrial dysfunction, and irregular neuronal protein aggregation. Withania somnifera has been used for more than 2500 years as a useful medicinal plant to improve disease defense, prevent aging, rejuvenate the body in a vulnerable situation, and generate a feeling of mental well-being. However, a persuasive paper emphasizing its neuroprotective nature is missing. OBJECTIVE In the current review, we have delineated the protective role of W. somnifera against various neurological disorders and its progress in delivery systems. METHODS The database used in the retrieval of data were PubMed, Scopus, Science direct, and SciFinder. The keywords used were W. somnifera, Ashwagandha, neuroprotective activities, etc. The principal source of the data retrieval includes research articles, review papers, and short communications from reputed publishers, including the New England Journal of Medicine, Elsevier, Nature, Springer, and Taylor & Francis. RESULTS After an extensive literature review, we found that W. somnifera mitigates various neurological disorders, including Parkinson's disease, Alzheimer's disease, Huntington disease, tardive dyskinesia, stroke, and anxiety. Furthermore, natural compounds in nano sizes range possess better neuroprotective activity. Consequently, polymeric nanomicelles, nanoparticles, and nanofibers of natural products are used in the treatment of neurodegenerative diseases. CONCLUSION The current review substantially deciphered the protective role of W. somnifera against various neurological disorders. However, future studies are further required better to understand the molecular mechanisms behind their neuroprotective nature.
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Active site variants in STT3A cause a dominant type I congenital disorder of glycosylation with neuromusculoskeletal findings.
Wilson, MP, Garanto, A, Pinto E Vairo, F, Ng, BG, Ranatunga, WK, Ventouratou, M, Baerenfaenger, M, Huijben, K, Thiel, C, Ashikov, A, et al
American journal of human genetics. 2021;(11):2130-2144
Abstract
Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs.
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Frequency and Clinical Aspects of Neurological and Psychiatric Symptoms in Patients with Non-Celiac Wheat Sensitivity.
Carroccio, A, Soresi, M, Chiavetta, M, La Blasca, F, Compagnoni, S, Giuliano, A, Fayer, F, Mandreucci, F, Castellucci, D, Seidita, A, et al
Nutrients. 2021;(6)
Abstract
BACKGROUND Non-Celiac Wheat Sensitivity (NCWS) is characterized by both intestinal and extra-intestinal symptoms. The study aims to investigate the frequency of neuropsychiatric manifestations in NCWS patients and identify their clinical and demographic characteristics. METHODS 278 clinical records of NCWS patients, diagnosed by a double-blind placebo-controlled wheat challenge between 2006 and 2020, were retrospectively revised. Fifty-two patients with Celiac Disease (CD) and 54 patients with Irritable Bowel Syndrome (IBS) served as controls. RESULTS 87% of the NCWS patients had an IBS-like clinical presentation. The NCWS group showed a longer duration of symptoms, a higher frequency of positive serum anti-nuclear antibodies than CD and IBS patients, and a higher frequency of DQ2/DQ8 haplotypes and duodenal mucosa lymphocytosis than IBS controls. In addition, 50% of NCWS patients showed neuropsychiatric manifestations, while lower percentages were observed in CD (25%) and IBS (28%) controls. Neuropsychiatric symptoms in NCWS were more frequently associated with the male sex, longer duration of symptoms, and IBS-diarrhea-like clinical presentation. CONCLUSIONS Our data suggest that in patients with IBS-like symptoms and neuropsychiatric manifestations of unknown cause, it could be useful to investigate a correlation of these symptoms with wheat ingestion to identify NCWS patients with this 'atypical' manifestation.
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[Ketogenic diet – mechanism of action and perspectives for the use in the therapy: data from clinical studies].
Pondel, N, Liśkiewicz, D, Liśkiewicz, A
Postepy biochemii. 2020;(3):270-286
Abstract
Ketogenic diet is a high fat and very low-carbohydrate nutritional approach that induces increased production of ketone bodies, which serve as an alternative to glucose energetic substrates. Since almost a century ketogenic diet has been used in the therapy of refractory epilepsy, especially in children. Because of the pleiotropic effect of ketogenic diet on physiology, including inflammation, oxidative stress, energy balance and signaling pathways, in recent years scientists have been intensively exploring the use of it in the treatment of other diseases. In the present article current clinical studies regarding the possibility of using the ketogenic diet in the treatment of obesity, diabetes, neurological disorders and cancer has been reviewed alongside with potential mechanisms responsible for the therapeutic effect of ketogenic diet in these diseases. The metabolic processes engaged in nutritional ketosis and practicals aspects of ketogenic dieting have been also discussed.
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Allicin pharmacology: Common molecular mechanisms against neuroinflammation and cardiovascular diseases.
Mocayar Marón, FJ, Camargo, AB, Manucha, W
Life sciences. 2020;:117513
Abstract
According to investigations in phytomedicine and ethnopharmacology, the therapeutic properties of garlic (Allium sativum) have been described by ancestral cultures. Notwithstanding, it is of particular concern to elucidate the molecular mechanisms underlying this millenary empirical knowledge. Allicin (S-allyl prop-2-ene-1-sulfinothioate), a thioester of sulfenic acid, is one of the main bioactive compounds present in garlic, and it is responsible for the particular aroma of the spice. The pharmacological attributes of allicin integrate a broad spectrum of properties (e.g., anti-inflammatory, immunomodulatory, antibiotic, antifungal, antiparasitic, antioxidant, nephroprotective, neuroprotective, cardioprotective, and anti-tumoral activities, among others). The primary goal of the present article is to review and clarify the common molecular mechanisms by which allicin and its derivates molecules may perform its therapeutic effects on cardiovascular diseases and neuroinflammatory processes. The intricate interface connecting the cardiovascular and nervous systems suggests that the impairment of one organ could contribute to the dysfunction of the other. Allicin might target the cornerstone of the pathological processes underlying cardiovascular and neuroinflammatory disorders, like inflammation, renin-angiotensin-aldosterone system (RAAS) hyperactivation, oxidative stress, and mitochondrial dysfunction. Indeed, the current evidence suggests that allicin improves mitochondrial function by enhancing the expression of HSP70 and NRF2, decreasing RAAS activation, and promoting mitochondrial fusion processes. Finally, allicin represents an attractive therapeutic alternative targeting the complex interaction between cardiovascular and neuroinflammatory disorders.