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Nanostructured Drug Carriers for Nose-to-Brain Drug Delivery
Published in Yasser Shahzad, Syed A.A. Rizvi, Abid Mehmood Yousaf, Talib Hussain, Drug Delivery Using Nanomaterials, 2022
Talita Nascimento da Silva, Emanuelle Vasconcellos de Lima, Anna Lecticia Martinez Martinez Toledo, Julia H. Clarke, Thaís Nogueira Barradas
PD is a neurodegenerative disease that leads to the death of dopaminergic neurons in the substantia nigra pars compacta. Following dopamine deficiency in the basal, patients can develop a set of movement disorders. Classical motor symptoms include rigidity, resting tremor, and bradykinesia. Its ethiopathogenesis is currently unknown and PD has been linked to genetic, environmental, and immunological factors. Currently available treatments involve the delivery of dopamine precursors (levodopa, l-DOPA, l-3,4 dihidroxifenilalanina), and other symptomatic treatments including dopamine agonists (amantadine, apomorphine, bromocriptine, cabergoline, lisuride, pergolide, pramipexole, ropinirole, rotigotine), monoamine oxidase (MAO) inhibitors (selegiline, rasagiline), and catechol-O-methyltransferase (COMT) inhibitors (entacapone, tolcapone) (Cacabelos, 2017; De Virgilio et al., 2016). The conventional treatments for PD show very small drug bioavailability in the SNC, since only >1% of the drug can overcome the BBB. Clinical trials using intranasal approaches such as intranasal insulin (NCT04251585; NCT04687878), intranasal glutathione (NCT01398748), and intranasal levodopa (NCT03541356) have tried to enhance the drug delivery method, but none so far have reached phase 3.
Toxic Metal Removal Using Microbial Nanotechnology
Published in Mahendra Rai, Patrycja Golińska, Microbial Nanotechnology, 2020
Platinum (Pt) drugs are effective chemotherapeutic agents used widely against cancer. The most severe side effect related to Pt is ototoxicity. Activated monoaqua-platin is reported to bind with DNA, forming intra- and inter-strand complexes that inhibit DNA synthesis, suppress RNA transcription, arrest cell cycle, and induce apoptosis. Cisplatin alkylation in mitochondria results in release of pro-apoptotic factors and generation of ROS, which together eventually trigger caspase activation‒mediated cell death. ROS-mediated proteins and lipid damage in addition to depletion of cellular intrinsic antioxidant molecules cause further cytotoxicity. They may also lead to genetic variations in two specific genes, thiopurine S-methyltransferase (TPMT) and catechol-O-methyltransferase (COMT), which are identified as key targets of cisplatin-induced ototoxicity (Brock et al. 2012).
Applications of imaging genomics beyond oncology
Published in Ruijiang Li, Lei Xing, Sandy Napel, Daniel L. Rubin, Radiomics and Radiogenomics, 2019
Xiaohui Yao, Jingwen Yan, Li Shen
Genetic factors were found to play a major role in the etiology of schizophrenia. A meta-analysis using pooled data from 12 twin studies estimated the heritability of schizophrenia to be approximately 80% [107]. To date, around 30 schizophrenia-associated loci have been identified through GWAS to play a role in conferring the risk of schizophrenia, such as catechol-O-methyltransferase (COMT), Disrupted In Schizophrenia 1 (DISC1), regulator of G protein signaling 4 (RGS4), neuregulin 1 (NRG1), dystrobrevin binding protein 1 (DTNBP1), D-amino acid oxidase activator (DAOA), phosphodiesterase 4B (PDE4B), Dopamine- and cAMP-regulated phosphoprotein, Mr 32 kDa (DARPP-32) protein phosphatase 1 regulatory subunit 3B and glutamate metabotropic receptor 3 (GRM3) [108]. There are also growing evidences from exome sequencing studies indicating that some risk genes and pathways are affected by both common and rare variants [109], which implies large effects of rare variants on individual risk. This can be best exemplified by 11 large, rare recurrent CNVs and loss-of-function variants in set domain containing 1A, histone lysine methyltransferase (SETD1A) [109,110]. Evidences from other exome sequencing studies imply more other rare variants conferring substantial individual risk [111,112]. Despite the remarkable progress in the search for risk genes associated with schizophrenia, translation of genetic associations into targetable mechanisms related to disease pathogenesis remains poorly understood.
Transhumanist Genetic Enhancement: Creation of a ‘New Man’ Through Technological Innovation
Published in The New Bioethics, 2021
The contribution of genetic factors to the regulation of brain dopaminergic activity is widely acknowledged, but the genetic basis of the resultant cognitive phenotypes of executive function of the frontal lobe have yet to be identified. The gene COMT encodes the enzyme catechol-O-methyltransferase involved in the degradation of several catecholamines, and is especially relevant in the metabolism of the neurotransmitter dopamine engaged in several brain and cognitive functions; in particular, COMT is implicated in information processing in prefrontal-related working memory tasks (Mier et al.2010). An SNP in an allele allows COMT to have three type variants: AA, GG and AG. The A allele can increase dopamine levels by four-fold in the prefrontal cortex and affects executive functions such as cognitive flexibility, impulse control, abstract thought, and ability to follow rules or task structure (Bruder et al.2005). The AA variants result in the highest dopamine levels, the GG variants in the lowest levels, and the AG variants are somewhere in the middle. Dopamine levels increase under stress, and individuals with the AA variant (5% of humans) will have too much dopamine, consequently they will be jittery and perform worse under difficult conditions (Blasi et al.2005). Moreover, the dopamine D4 receptor encoded by the gene DRD4 has been implicated in prefrontal functions and an SNP in DRD4 has been found to affect the transcriptional efficiency of the receptor it encodes (Okuyama et al.1999). Statistical analyses employed to detect the genetic contribution of multiple genes to executive function demonstrated gene-gene interactions between SNP in COMT and DRD4 that influence significantly this function making their collective editing a highly problematic (Mitaki et al.2013).