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Toxins Jan 2022The concept of "magic bullets", i [...].
The concept of "magic bullets", i [...].
Topics: Humans; Immunotoxins; Toxins, Biological
PubMed: 35051040
DOI: 10.3390/toxins14010063 -
Kidney International May 2003The choice of the correct concentration of potential uremic toxins for in vitro, ex vivo, and in vivo experiments remains a major area of concern; errors at this level... (Review)
Review
BACKGROUND
The choice of the correct concentration of potential uremic toxins for in vitro, ex vivo, and in vivo experiments remains a major area of concern; errors at this level might result in incorrect decisions regarding therpeutic correction of uremia and related clinical complications.
METHODS
An encyclopedic list of uremic retention solutes was composed, containing their mean normal concentration (CN), their highest mean/median uremic concentration (CU), their highest concentration ever reported in uremia (CMAX), and their molecular weight. A literature search of 857 publications on uremic toxicity resulted in the selection of data reported in 55 publications on 90 compounds, published between 1968 and 2002.
RESULTS
For all compounds, CU and/or CMAX exceeded CN. Molecular weight was lower than 500 D for 68 compounds; of the remaining 22 middle molecules, 12 exceeded 12,000 D. CU ranged from 32.0 ng/L (methionine-enkephalin) up to 2.3 g/L (urea). CU in the ng/L range was found especially for the middle molecules (10/22; 45.5%), compared with 2/68 (2.9%) for a molecular weight <500 D (P < 0.002). Twenty-five solutes (27.8%) were protein bound. Most of them had a molecular weight <500 D except for leptin and retinol-binding protein. The ratio CU/CN, an index of the concentration range over which toxicity is exerted, exceeded 15 in the case of 20 compounds. The highest values were registered for several guanidines, protein-bound compounds, and middle molecules, to a large extent compounds with known toxicity. A ratio of CMAX/CU <4, pointing to a Gaussian distribution, was found for the majority of the compounds (74/90; 82%). For some compounds, however, this ratio largely exceeded 4 [e.g., for leptin (6.81) or indole-3-acetic acid (10.37)], pointing to other influencing factors than renal function, such as gender, genetic predisposition, proteolytic breakdown, posttranslation modification, general condition, or nutritional status.
CONCLUSION
Concentrations of retention solutes in uremia vary over a broad range, from nanograms per liter to grams per liter. Low concentrations are found especially for the middle molecules. A substantial number of molecules are protein bound and/or middle molecules, and many of these exert toxicity and are characterized by a high range of toxic over normal concentration (CU/CN ratio). Hence, uremic retention is a complex problem that concerns many more solutes than the current markers of urea and creatinine alone. This list provides a basis for systematic analytic approaches to map the relative importance of the enlisted families of toxins.
Topics: Humans; Renal Insufficiency; Toxins, Biological; Uremia
PubMed: 12675874
DOI: 10.1046/j.1523-1755.2003.00924.x -
Toxins Jul 2019A number of pathogenic bacteria utilize toxins to mediate disease in a susceptible host. The foodborne pathogen is one of the most important and well-studied bacterial... (Review)
Review
A number of pathogenic bacteria utilize toxins to mediate disease in a susceptible host. The foodborne pathogen is one of the most important and well-studied bacterial pathogens. Recently, whole genome sequence characterizations revealed the presence of multiple novel ADP-ribosylating toxins encoded by a variety of serovars. In this review, we discuss both the classical (SpvB) and novel (typhoid toxin, ArtAB, and SboC/SeoC) ADP-ribosylating toxins of , including the structure and function of these toxins and our current understanding of their contributions to virulence.
Topics: ADP Ribose Transferases; Animals; Humans; Salmonella; Toxins, Biological
PubMed: 31315299
DOI: 10.3390/toxins11070416 -
Toxins Nov 2018Toxins and venoms produced by different organisms contain peptides that have evolved to have highly selective and potent pharmacological effects on specific targets for... (Review)
Review
Toxins and venoms produced by different organisms contain peptides that have evolved to have highly selective and potent pharmacological effects on specific targets for protection and predation. Several toxin-derived peptides have become drugs and are used for the management of diabetes, hypertension, chronic pain, and other medical conditions. Despite the similarity in their composition (amino acids as the building blocks), toxin-derived peptide drugs have very profound differences in their structure and conformation, in their physicochemical properties (that affect solubility, stability, etc.), and subsequently in their pharmacokinetics (the processes of absorption, distribution, metabolism, and elimination following their administration to patients). This review summarizes and critically analyzes the pharmacokinetic properties of toxin-derived peptide drugs: (1) the relationship between the chemical structure, physicochemical properties, and the pharmacokinetics of the specific drugs, (2) the major pharmacokinetic properties and parameters of these drugs, and (3) the major pharmacokinetic variability factors of the individual drugs. The structural properties of toxin-derived peptides affect their pharmacokinetics and pose some limitations on their clinical use. These properties should be taken into account during the development of new toxin-derived peptide drugs, and for the efficient and safe use of the clinically approved drugs from this group in the individual patients.
Topics: Humans; Peptides; Toxins, Biological
PubMed: 30463321
DOI: 10.3390/toxins10110483 -
Toxins Jun 2018Uremic solutes contribute to cardiovascular disease in renal insufficiency. In this review we describe the clearance of selected uremic solutes, which have been... (Review)
Review
Uremic solutes contribute to cardiovascular disease in renal insufficiency. In this review we describe the clearance of selected uremic solutes, which have been associated with cardiovascular disease. These solutes-indoxyl sulfate (IS), p-cresol sulfate (PCS), phenylacetylglutamine (PAG), trimethylamine-n-oxide (TMAO), and kynurenine-exemplify different mechanisms of clearance. IS and PCS are protein-bound solutes efficiently cleared by the native kidney through tubular secretion. PAG and TMAO are not protein-bound but are also cleared by the native kidney through tubular secretion, while kynurenine is not normally cleared by the kidney. Increases in the plasma levels of the normally secreted solutes IS, PCS, TMAO, and PAG in chronic kidney disease (CKD) are attributable to a reduction in their renal clearances. Levels of each of these potential toxins are even higher in patients on dialysis than in those with advanced chronic kidney disease, which can be accounted for in part by a low ratio of dialytic to native kidney clearance. The rise in plasma kynurenine in CKD and dialysis patients, by contrast, remains to be explained. Our ability to detect lower levels of the potential uremic cardiovascular toxins with renal replacement therapy may be limited by the intermittency of treatment, by increases in solute production, and by the presence of non-renal clearance. Reduction in the levels of uremic cardiovascular toxins may in the future be achieved more effectively by inhibiting their production.
Topics: Animals; Cardiovascular Diseases; Humans; Renal Dialysis; Toxins, Biological; Uremia
PubMed: 29865226
DOI: 10.3390/toxins10060226 -
Toxins Nov 2010Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through... (Review)
Review
Protein toxins confer a defense against predation/grazing or a superior pathogenic competence upon the producing organism. Such toxins have been perfected through evolution in poisonous animals/plants and pathogenic bacteria. Over the past five decades, a lot of effort has been invested in studying their mechanism of action, the way they contribute to pathogenicity and in the development of antidotes that neutralize their action. In parallel, many research groups turned to explore the pharmaceutical potential of such toxins when they are used to efficiently impair essential cellular processes and/or damage the integrity of their target cells. The following review summarizes major advances in the field of toxin based therapeutics and offers a comprehensive description of the mode of action of each applied toxin.
Topics: Animals; Antineoplastic Agents; Bacterial Toxins; Biological Evolution; Cell Death; Drug Evaluation, Preclinical; Female; Genes, Transgenic, Suicide; Genetic Therapy; Humans; Immunotoxins; Male; Pharmaceutical Preparations; Plant Extracts; Plants, Toxic; Toxins, Biological
PubMed: 22069564
DOI: 10.3390/toxins2112519 -
Dong Wu Xue Yan Jiu = Zoological... Jul 2015Venom (toxins) is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance... (Review)
Review
Venom (toxins) is an important trait evolved along the evolutionary tree of animals. Our knowledges on venoms, such as their origins and loss, the biological relevance and the coevolutionary patterns with other organisms are greatly helpful in understanding many fundamental biological questions, i.e., the environmental adaptation and survival competition, the evolution shaped development and balance of venoms, and the sophisticated correlations among venom, immunity, body power, intelligence, their genetic basis, inherent association, as well as the cost-benefit and trade-offs of biological economy. Lethal animal envenomation can be found worldwide. However, from foe to friend, toxin studies have led lots of important discoveries and exciting avenues in deciphering and fighting human diseases, including the works awarded the Nobel Prize and lots of key clinic therapeutics. According to our survey, so far, only less than 0.1% of the toxins of the venomous animals in China have been explored. We emphasize on the similarities shared by venom and immune systems, as well as the studies of toxin knowledge-based physiological toxin-like proteins/peptides (TLPs). We propose the natural pairing hypothesis. Evolution links toxins with humans. Our mission is to find out the right natural pairings and interactions of our body elements with toxins, and with endogenous toxin-like molecules. Although, in nature, toxins may endanger human lives, but from a philosophical point of view, knowing them well is an effective way to better understand ourselves. So, this is why we study toxins.
Topics: Animal Communication; Animals; Blood Coagulation; Evolution, Molecular; Humans; Immunity; Toxins, Biological; Venoms; beta-Defensins
PubMed: 26228472
DOI: 10.13918/j.issn.2095-8137.2015.4.183 -
Toxins Mar 2018Venoms from marine and terrestrial animals (cone snails, scorpions, spiders, snakes, centipedes, cnidarian, etc.) can be seen as an untapped cocktail of biologically...
Venoms from marine and terrestrial animals (cone snails, scorpions, spiders, snakes, centipedes, cnidarian, etc.) can be seen as an untapped cocktail of biologically active compounds, being increasingly recognized as a new emerging source of peptide-based therapeutics.
Topics: Animals; Drug Discovery; Humans; Toxins, Biological
PubMed: 29547537
DOI: 10.3390/toxins10030126 -
Toxins Mar 2021The evolutionary arms race between plants and herbivores has led, over millions of years, to the production of many substances that prevent plants from being over-eaten...
The evolutionary arms race between plants and herbivores has led, over millions of years, to the production of many substances that prevent plants from being over-eaten by plant-feeding animals [...].
Topics: Animals; Humans; Plant Extracts; Plants, Toxic; Toxins, Biological
PubMed: 33809838
DOI: 10.3390/toxins13030228 -
Toxicon : Official Journal of the... Dec 2014Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However,... (Review)
Review
Components from venoms have stimulated many drug discovery projects, with some notable successes. These are briefly reviewed, from captopril to ziconotide. However, there have been many more disappointments on the road from toxin discovery to approval of a new medicine. Drug discovery and development is an inherently risky business, and the main causes of failure during development programmes are outlined in order to highlight steps that might be taken to increase the chances of success with toxin-based drug discovery. These include having a clear focus on unmet therapeutic needs, concentrating on targets that are well-validated in terms of their relevance to the disease in question, making use of phenotypic screening rather than molecular-based assays, and working with development partners with the resources required for the long and expensive development process.
Topics: Animals; Drug Discovery; Toxins, Biological
PubMed: 25448391
DOI: 10.1016/j.toxicon.2014.10.020