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Hematopoietic Stem Cell Therapy for Patients with Refractory Myasthenia Gravis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Myasthenia gravis (MG), which means severe muscle weakness, is due to antibody mediated loss of motor end plate acetylcholine (ACh) receptors.1,2 In normal muscle, acetylcholine released from a nerve ending binds to the acetylcholine receptor (AChR) on the post synaptic motor end plate of muscle inducing a depolarization potential.2,3 If enough AChR depolarizations occur, the firing threshold is exceeded and an action potential or contraction of the muscle follows. AchR antibody reduce the number of ACh receptors causing loss of synaptic folds on the motor end plate and impaired neuromuscular transmission. Ex vivo transfer of ACh receptor antibody induces disease across a wide range of species.4,5 While in utero, transplacental transfer from mother to fetus causes neonatal MG.6-8 The clinical manifestations are muscular fatigue and weakness.9,10 Treatment of MG includes acetylcholine esterase inhibitors and immune suppressive or immune modulating medications.11-15 For patients with severe disease, HSCT may be considered. In fact, the first animal hematopoietic stem cell transplantation (HSCT) for an autoimmune disease was reported in 1983 for experimental autoimmune myasthenia gravis (EAMG).16 Syngeneic HSCT cured EAMG related muscle weakness.
Application of Data Mining Techniques in Autoimmune Diseases Research and Treatment
Published in Shampa Sen, Leonid Datta, Sayak Mitra, Machine Learning and IoT, 2018
Sweta Bhattacharya, Sombuddha Sengupta
This is a chronic autoimmune disease demarcated by extreme weakness and the degeneration of skeletal muscles.43 The name is derived from the Latin “grave muscle weaknesses.” This disease has no known cure; however, treatment can lead to control of symptoms, thus improving the quality of life for the person afflicted. Nerve cells run through the length of the body and the transmission of impulses through them makes the day-to-day function of our body relatively simpler. In Myasthenia gravis, there is an error in nerve signal transduction via the neurons due to the generation of antibodies against the acetylcholine receptors.44 The generated antibodies bind to the receptor ligand interaction sites and prevent the interaction of the receptors with acetylcholine. This hinders the transmission of the impulse and the polarization cannot cross the synapse, resulting in an interruption in the transmission network. Reports have shown that people with myasthenia gravis can develop thymomas, which may result in cancer.43
Pesticides and Chronic Diseases
Published in William J. Rea, Kalpana D. Patel, Reversibility of Chronic Disease and Hypersensitivity, Volume 4, 2017
William J. Rea, Kalpana D. Patel
According to Abou-Donia et al.,9 organophosphorus compounds cause cholinergic neurotoxicity by disrupting the cholinergic system that includes AChE and its natural substrate, the neurotransmitter acetylcholine.214 Acetylcholine is released in response to nerve stimulation and binds to postsynaptic acetylcholine receptors, resulting in muscle contraction or gland secretions. Its action is rapidly terminated by hydrolysis with AChE via the serine hydroxyl in the catalytic triad of AChE.213 The three-dimensional structure of AChE reveals an active center located at the base of a narrow gorge about 20 μm in depth.215 The active center includes the following sites (Figure 7.17): (1) the catalytic triad; Glu 334, His 447, and Ser 203; (2) an acyl pocket: Phe 295 and Phe 297; (3) a choline subunit: Trp 86, Glu 202, and Tyr 337; and (4) a peripheral site: Trp 286, Tyr 72, Tyr 124, and Asp 74 (Figure 7.19).
Pulmonary effects of e-liquid flavors: a systematic review
Published in Journal of Toxicology and Environmental Health, Part B, 2022
Felix Effah, Benjamin Taiwo, Deborah Baines, Alexis Bailey, Tim Marczylo
Nicotine is a potent stimulator of cell proliferation and may stimulate cancer development and growth (Dasgupta 2006; Khalil et al. 2013; Lee et al. 2005; Mravec et al. 2020). Nicotine is an agonist for the nicotinic acetylcholine receptors (nAChRs) (Dani 2015; Victoria et al. 2022), which are functionally expressed in the non-neuronal tissues of the lung (Chernyavsky et al. 2015; Improgo, Tapper, and Gardner 2011;). There are more than a dozen different nAChR subunit proteins, subdivided into α and β subfamilies, which form pentameric ion channels consisting of either a single type of α subunit (homopentamers) or a combination of α and β subunits (heteropentamers) (Shahsavar et al. 2016). As ligand-gated ion channels, nAChRs undergo complex allosteric changes in response to binding either the endogenous ligand acetylcholine (Ach) or exogenous ligands, including nicotine. nAChRs are classically linked to the plasma membrane depolarization required for neurotransmission; however, non-neuronal nAChRs in the lung act most frequently as calcium channels and were reported to activate numerous cellular pathways upon binding to either adrenergic receptors, nicotinic receptors, or by direct action within the cytoplasm (Wen et al. 2011) which regulate cell proliferation. Nicotine alone is not a carcinogen but is a tumor promoter (Ping Wu 2019). High doses of nicotine induce multi-organ toxicity and perhaps death from paralysis of respiratory muscles via the nAchRs (Mishra et al. 2015).
Experimental and computational analysis of N-methylcytisine alkaloid in solution and prediction of biological activity by docking calculations
Published in Molecular Physics, 2022
Fanny C. Alvarez Escalada, Elida Romano, Silvia Antonia Brandán, Ana E. Ledesma
Nicotinic acetylcholine receptors are ligand-gated ion channels that mediate fast chemical neurotransmission at the neuromuscular junction and have various signalling characters in the central nervous system; human α4β2 is a nicotinic receptor of nicotinic subtype mostly abundant in the brain [41]. Nicotine is a plant alkaloid responsible for the addictive properties of tobacco; it binds with high affinity to the nicotinic acetylcholine receptors α4β2nAChRs and acts as a full agonist. Research works find new use of nAChR partial agonists for the treatment option by smoking cessation, such as cytosine, which diminishes nicotine support and reduces the pleasure from smoking [42]. To evaluate the basis for affinity binding and eventually identify the structural elements, supporting the receptor selectivity of the NMC to nAChRs receptor, we have structurally characterised complexes of that molecule with acetylcholine-binding protein (Ac-AChBP, PDB:4BQT) and human α4β2 nAChR (PDB: 5KXI) receptors. Full details, showing the ligand position in the binding site with NMC docked into each complex, are provided in Figure 6.