Gotfredsenodgaard9287

Snake venom three-finger α-neurotoxins (α-3FNTx) act on postsynaptic nicotinic acetylcholine receptors (nAChRs) at the neuromuscular junction (NMJ) to produce skeletal muscle paralysis. The discovery of the archetypal α-bungarotoxin (α-BgTx), almost six decades ago, exponentially expanded our knowledge of membrane receptors and ion channels. This included the localisation, isolation and characterization of the first receptor (nAChR); and by extension, the pathophysiology and pharmacology of neuromuscular transmission and associated pathologies such as myasthenia gravis, as well as our understanding of the role of α-3FNTxs in snakebite envenomation leading to novel concepts of targeted treatment. Subsequent studies on a variety of animal venoms have yielded a plethora of novel toxins that have revolutionized molecular biomedicine and advanced drug discovery from bench to bedside. This review provides an overview of nAChRs and their subtypes, classification of α-3FNTxs and the challenges of typifying an increasing arsenal of structurally and functionally unique toxins, and the three-finger protein (3FP) fold in the context of the uPAR/Ly6/CD59/snake toxin superfamily. The pharmacology of snake α-3FNTxs including their mechanisms of neuromuscular blockade, variations in reversibility of nAChR interactions, specificity for nAChR subtypes or for distinct ligand-binding interfaces within a subtype and the role of α-3FNTxs in neurotoxic envenomation are also detailed. Lastly, a reconciliation of structure-function relationships between α-3FNTx and nAChRs, derived from historical mutational and biochemical studies and emerging atomic level structures of nAChR models in complex with α-3FNTxs is discussed.On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) a global pandemic. As of July 2020, SARS-CoV-2 has infected more than 14 million people and provoked more than 590,000 deaths, worldwide. From the beginning, a variety of pharmacological treatments has been empirically used to cope with the life-threatening complications associated with Corona Virus Disease 2019 (COVID-19). Thus far, only a couple of them and not consistently across reports have been shown to further decrease mortality, respect to what can be achieved with supportive care. In most cases, and due to the urgency imposed by the number and severity of the patients' clinical conditions, the choice of treatment has been limited to repurposed drugs, approved for other indications, or investigational agents used for other viral infections often rendered available on a compassionate-use basis. The rationale for drug selection was mainly, though not exclusively, based either i) on the activity against other coronaviruses or RNA viruses in order to potentially hamper viral entry and replication in the epithelial cells of the airways, and/or ii) on the ability to modulate the excessive inflammatory reaction deriving from dysregulated host immune responses against the SARS-CoV-2. In several months, an exceptionally large number of clinical trials have been designed to evaluate the safety and efficacy of anti-COVID-19 therapies in different clinical settings (treatment or pre- and post-exposure prophylaxis) and levels of disease severity, but only few of them have been completed so far. This review focuses on the molecular mechanisms of action that have provided the scientific rationale for the empirical use and evaluation in clinical trials of structurally different and often functionally unrelated drugs during the SARS-CoV-2 pandemic.The human population is burdened by morbidity and mortality from liver diseases that largely arise due to hepatitis virus infection, alcohol abuse, obesity, and diabetes. Despite 2 million global deaths per annum from liver disease, the number of drugs approved by the U.S. Food and Drug Administration (FDA) for the treatment of these disorders is sparse. Eastern medicine embodies a millennia long tradition in the use of natural product remedies for liver disease, which has attracted the interest of western medical practitioners and patients alike. selleck compound Questions remain regarding the safety, efficacy, and quality of such natural products in a western medical context. Of particular concern is whether or not the mechanism of action of the product is known and, if the remedy has multiple natural constituents, how these interact at a biochemical, physiological, and clinical level. In this Commentary, we have examined the potential of metabolomics to help answer these queries, illustrated by investigations of yin chen hao tang, silymarin, and xiaozhang tie. In all cases, unique understandings of the mechanism of action of these natural products was obtained through metabolomic investigations in animal models, cell culture systems, and in clinical studies. Such mechanistic insights help assure the safety and efficacy of these natural product therapies.This study evaluated the effect of amylases on the formation, and characteristics of retrograded starches using sweet potato (SPS), cassava (CAS) and high amylose maize (HAS) starches. The starches were gelatinized, hydrolyzed with fungal or maltogenic α-amylase, de-branched and retrograded. The modified starches were then analyzed for digestibility, chain size distribution, relative crystallinity and crystallite size, thermal properties and the proportion of double helices. CAS was the most susceptible and HAS the most resistant to the action of both enzymes. Amylolysis was efficient in forming resistant starch type 3 (RS3) and high levels (> 60%) were found for all starches. RS3 content was highly correlated with the proportion of chains with degrees of polymerization between 13 and 30 for all starches, especially for the root starches, while for HAS, the high amylose content and reduction in the size of amylose chains and very long amylopectin chains also deeply contributed for the RS3 formation. These sizes (DP 13-30) are best suited for the formation of a more crystalline, more perfect, and more strongly bonded structure, composed of larger crystallites, and with a higher concentration of double helices. High correlation coefficients were found between RS3, relative crystallinity, crystallites size, and enthalpy change.