Showing papers in "Toxins in 2018"

Aflatoxin B1 and M1: Biological Properties and Their Involvement in Cancer Development.

Abstract: Aflatoxins are fungal metabolites found in feeds and foods. When the ruminants eat feedstuffs containing Aflatoxin B1 (AFB1), this toxin is metabolized and Aflatoxin M1 (AFM1) is excreted in milk. International Agency for Research on Cancer (IARC) classified AFB1 and AFM1 as human carcinogens belonging to Group 1 and Group 2B, respectively, with the formation of DNA adducts. In the last years, some epidemiological studies were conducted on cancer patients aimed to evaluate the effects of AFB1 and AFM1 exposure on cancer cells in order to verify the correlation between toxin exposure and cancer cell proliferation and invasion. In this review, we summarize the activation pathways of AFB1 and AFM1 and the data already reported in literature about their correlation with cancer development and progression. Moreover, considering that few data are still reported about what genes/proteins/miRNAs can be used as damage markers due to AFB1 and AFM1 exposure, we performed a bioinformatic analysis based on interaction network and miRNA predictions to identify a panel of genes/proteins/miRNAs that can be used as targets in further studies for evaluating the effects of the damages induced by AFB1 and AFM1 and their capacity to induce cancer initiation.

Insect Antimicrobial Peptides, a Mini Review.

Abstract: Antimicrobial peptides (AMPs) are crucial effectors of the innate immune system. They provide the first line of defense against a variety of pathogens. AMPs display synergistic effects with conventional antibiotics, and thus present the potential for combined therapies. Insects are extremely resistant to bacterial infections. Insect AMPs are cationic and comprise less than 100 amino acids. These insect peptides exhibit an antimicrobial effect by disrupting the microbial membrane and do not easily allow microbes to develop drug resistance. Currently, membrane mechanisms underlying the antimicrobial effects of AMPs are proposed by different modes: the barrel-stave mode, toroidal-pore, carpet, and disordered toroidal-pore are the typical modes. Positive charge quantity, hydrophobic property and the secondary structure of the peptide are important for the antibacterial activity of AMPs. At present, several structural families of AMPs from insects are known (defensins, cecropins, drosocins, attacins, diptericins, ponericins, metchnikowins, and melittin), but new AMPs are frequently discovered. We reviewed the biological effects of the major insect AMPs. This review will provide further information that facilitates the study of insect AMPs and shed some light on novel microbicides.

Staphylococcus aureus Toxins and Their Molecular Activity in Infectious Diseases.

Abstract: Staphylococcus aureus is a microorganism resident in the skin and nasal membranes with a dreadful pathogenic potential to cause a variety of community and hospital-acquired infections. The frequency of these infections is increasing and their treatment is becoming more difficult. The ability of S. aureus to form biofilms and the emergence of multidrug-resistant strains are the main reasons determining the challenge in dealing with these infections. S. aureus' infectious capacity and its success as a pathogen is related to the expression of virulence factors, among which the production of a wide variety of toxins is highlighted. For this reason, a better understanding of S. aureus toxins is needed to enable the development of new strategies to reduce their production and consequently improve therapeutic approaches. This review focuses on understanding the toxin-based pathogenesis of S. aureus and their role on infectious diseases.

Biochemical and Clinical Impact of Organic Uremic Retention Solutes: A Comprehensive Update

Abstract: In this narrative review, the biological/biochemical impact (toxicity) of a large array of known individual uremic retention solutes and groups of solutes is summarized. We classified these compounds along their physico-chemical characteristics as small water-soluble compounds or groups, protein bound compounds and middle molecules. All but one solute (glomerulopressin) affected at least one mechanism with the potential to contribute to the uremic syndrome. In general, several mechanisms were influenced for each individual solute or group of solutes, with some impacting up to 7 different biological systems of the 11 considered. The inflammatory, cardio-vascular and fibrogenic systems were those most frequently affected and they are one by one major actors in the high morbidity and mortality of CKD but also the mechanisms that have most frequently been studied. A scoring system was built with the intention to classify the reviewed compounds according to the experimental evidence of their toxicity (number of systems affected) and overall experimental and clinical evidence. Among the highest globally scoring solutes were 3 small water-soluble compounds [asymmetric dimethylarginine (ADMA); trimethylamine-N-oxide (TMAO); uric acid], 6 protein bound compounds or groups of protein bound compounds [advanced glycation end products (AGEs); p-cresyl sulfate; indoxyl sulfate; indole acetic acid; the kynurenines; phenyl acetic acid;] and 3 middle molecules [β2-microglobulin; ghrelin; parathyroid hormone). In general, more experimental data were provided for the protein bound molecules but for almost half of them clinical evidence was missing in spite of robust experimental data. The picture emanating is one of a complex disorder, where multiple factors contribute to a multisystem complication profile, so that it seems of not much use to pursue a decrease of concentration of a single compound.

A Review of Current Methods for Analysis of Mycotoxins in Herbal Medicines.

Abstract: The presence of mycotoxins in herbal medicines is an established problem throughout the entire world. The sensitive and accurate analysis of mycotoxin in complicated matrices (e.g., herbs) typically involves challenging sample pretreatment procedures and an efficient detection instrument. However, although numerous reviews have been published regarding the occurrence of mycotoxins in herbal medicines, few of them provided a detailed summary of related analytical methods for mycotoxin determination. This review focuses on analytical techniques including sampling, extraction, cleanup, and detection for mycotoxin determination in herbal medicines established within the past ten years. Dedicated sections of this article address the significant developments in sample preparation, and highlight the importance of this procedure in the analytical technology. This review also summarizes conventional chromatographic techniques for mycotoxin qualification or quantitation, as well as recent studies regarding the development and application of screening assays such as enzyme-linked immunosorbent assays, lateral flow immunoassays, aptamer-based lateral flow assays, and cytometric bead arrays. The present work provides a good insight regarding the advanced research that has been done and closes with an indication of future demand for the emerging technologies.

Colibactin: More Than a New Bacterial Toxin.

Abstract: Cyclomodulins are bacterial toxins that interfere with the eukaryotic cell cycle. A new cyclomodulin called colibactin, which is synthetized by the pks genomic island, was discovered in 2006. Despite many efforts, colibactin has not yet been purified, and its structure remains elusive. Interestingly, the pks island is found in members of the family Enterobacteriaceae (mainly Escherichia coli and Klebsiella pneumoniae) isolated from different origins, including from intestinal microbiota, septicaemia, newborn meningitis, and urinary tract infections. Colibactin-producing bacteria induce chromosomal instability and DNA damage in eukaryotic cells, which leads to senescence of epithelial cells and apoptosis of immune cells. The pks island is mainly observed in B2 phylogroup E. coli strains, which include extra-intestinal pathogenic E. coli strains, and pks E. coli are over-represented in biopsies isolated from colorectal cancer. In addition, pks E. coli bacteria increase the number of tumours in diverse colorectal cancer mouse models. Thus, colibactin could have a major impact on human health. In the present review, we will focus on the biological effects of colibactin, the distribution of the pks island, and summarize what is currently known about its synthesis and its structure.

Temperature Effects Explain Continental Scale Distribution of Cyanobacterial Toxins

Abstract: Insight into how environmental change determines the production and distribution of cyanobacterial toxins is necessary for risk assessment. Management guidelines currently focus on hepatotoxins (microcystins). Increasing attention is given to other classes, such as neurotoxins (e.g., anatoxin-a) and cytotoxins (e.g., cylindrospermopsin) due to their potency. Most studies examine the relationship between individual toxin variants and environmental factors, such as nutrients, temperature and light. In summer 2015, we collected samples across Europe to investigate the effect of nutrient and temperature gradients on the variability of toxin production at a continental scale. Direct and indirect effects of temperature were the main drivers of the spatial distribution in the toxins produced by the cyanobacterial community, the toxin concentrations and toxin quota. Generalized linear models showed that a Toxin Diversity Index (TDI) increased with latitude, while it decreased with water stability. Increases in TDI were explained through a significant increase in toxin variants such as MC-YR, anatoxin and cylindrospermopsin, accompanied by a decreasing presence of MC-LR. While global warming continues, the direct and indirect effects of increased lake temperatures will drive changes in the distribution of cyanobacterial toxins in Europe, potentially promoting selection of a few highly toxic species or strains.

Basics of Antibody Phage Display Technology

Abstract: Antibody discovery has become increasingly important in almost all areas of modern medicine. Different antibody discovery approaches exist, but one that has gained increasing interest in the field of toxinology and antivenom research is phage display technology. In this review, the lifecycle of the M13 phage and the basics of phage display technology are presented together with important factors influencing the success rates of phage display experiments. Moreover, the pros and cons of different antigen display methods and the use of naive versus immunized phage display antibody libraries is discussed, and selected examples from the field of antivenom research are highlighted. This review thus provides in-depth knowledge on the principles and use of phage display technology with a special focus on discovery of antibodies that target animal toxins.

Mitigating Toxic Planktonic Cyanobacterial Blooms in Aquatic Ecosystems Facing Increasing Anthropogenic and Climatic Pressures.

Abstract: Toxic planktonic cyanobacterial blooms are a pressing environmental and human health problem. Blooms are expanding globally and threatening sustainability of our aquatic resources. Anthropogenic nutrient enrichment and hydrological modifications, including water diversions and reservoir construction, are major drivers of bloom expansion. Climatic change, i.e., warming, more extreme rainfall events, and droughts, act synergistically with human drivers to exacerbate the problem. Bloom mitigation steps, which are the focus of this review, must consider these dynamic interactive factors in order to be successful in the short- and long-term. Furthermore, these steps must be applicable along the freshwater to marine continuum connecting streams, lakes, rivers, estuarine, and coastal waters. There is an array of physical, chemical, and biological approaches, including flushing, mixing, dredging, application of algaecides, precipitating phosphorus, and selective grazing, that may arrest and reduce bloom intensities in the short-term. However, to ensure long term, sustainable success, targeting reductions of both nitrogen and phosphorus inputs should accompany these approaches along the continuum. Lastly, these strategies should accommodate climatic variability and change, which will likely modulate and alter nutrient-bloom thresholds.

Multiple Parameters Beyond Lipid Binding Affinity Drive Cytotoxicity of Cholesterol-Dependent Cytolysins.

Abstract: The largest superfamily of bacterial virulence factors is pore-forming toxins (PFTs). PFTs are secreted by both pathogenic and non-pathogenic bacteria. PFTs sometimes kill or induce pro-pathogen signaling in mammalian cells, all primarily through plasma membrane perforation, though the parameters that determine these outcomes are unclear. Membrane binding, calcium influx, pore size, and membrane repair are factors that influence PFT cytotoxicity. To test the contribution of membrane binding to cytotoxicity and repair, we compared the closely related, similarly-sized PFTs Perfringolysin O (PFO) from Clostridium perfringens and Streptolysin O (SLO) from Streptococcus pyogenes. Cell death kinetics for PFO and SLO were different because PFO increased in cytotoxicity over time. We introduced known L3 loop mutations that swap binding affinity between toxins and measured hemolytic activity, nucleated cell death kinetics and membrane repair using viability assays, and live cell imaging. Altered hemolytic activity was directly proportional to toxin binding affinity. In contrast, L3 loop alterations reduced nucleated cell death, and they had limited effects on cytotoxicity kinetics and membrane repair. This suggests other toxin structural features, like oligomerization, drives these parameters. Overall, these findings suggest that repair mechanisms and toxin oligomerization add constraints beyond membrane binding on toxin evolution and activity against nucleated cells.

Epidemiology of Helicobacter pylori and CagA-Positive Infections and Global Variations in Gastric Cancer.

Abstract: Gastric cancer is a major health burden and is the fifth most common malignancy and the third most common cause of death from cancer worldwide. Development of gastric cancer involves several aspects, including host genetics, environmental factors, and Helicobacter pylori infection. There is increasing evidence from epidemiological studies of the association of H. pylori infection and specific virulence factors with gastric cancer. Studies in animal models indicate H. pylori is a primary factor in the development of gastric cancer. One major virulence factor in H. pylori is the cytotoxin-associated gene A (cagA), which encodes the CagA protein in the cag pathogenicity island (cag PAI). Meta-analysis of studies investigating CagA seropositivity irrespective of H. pylori status identified that CagA seropositivity increases the risk of gastric cancer (OR = 2.87, 95% CI: 1.95–4.22) relative to the risk of H. pylori infection alone (OR = 2.31, 95% CI: 1.58–3.39). Eradicating H. pylori is a strategy for reducing gastric cancer incidence. A meta-analysis of six randomised controlled trials (RCTs) suggests that searching for and eradicating H. pylori infection reduces the subsequent incidence of gastric cancer with a pooled relative risk of 0.66 (95% CI: 0.46–0.95). The introduction in regions of high gastric cancer incidence of population-based H. pylori screening and treatment programmes, with a scientifically valid assessment of programme processes, feasibility, effectiveness and possible adverse consequences, would impact the incidence of H. pylori-induced gastric cancer. Given the recent molecular understanding of the oncogenic role of CagA, targeting H. pylori screening and treatment programmes in populations with a high prevalence of H. pylori CagA-positive strains, particularly the more oncogenic East Asian H. pylori CagA strains, may be worth further investigation to optimise the benefits of such strategies.

Fusarium Molds and Mycotoxins: Potential Species-Specific Effects.

Abstract: This review summarizes the information on biochemical and biological activity of the main Fusarium mycotoxins, focusing on toxicological aspects in terms of species-specific effects. Both in vitro and in vivo studies have centered on the peculiarity of the responses to mycotoxins, demonstrating that toxicokinetics, bioavailability and the mechanisms of action of these substances vary depending on the species involved, but additional studies are needed to better understand the specific responses. The aim of this review is to summarize the toxicological responses of the main species affected by Fusarium mycotoxins.

Mechanisms of Action and Cell Death Associated with Clostridium perfringens Toxins.

Abstract: Clostridium perfringens uses its large arsenal of protein toxins to produce histotoxic, neurologic and intestinal infections in humans and animals. The major toxins involved in diseases are alpha (CPA), beta (CPB), epsilon (ETX), iota (ITX), enterotoxin (CPE), and necrotic B-like (NetB) toxins. CPA is the main virulence factor involved in gas gangrene in humans, whereas its role in animal diseases is limited and controversial. CPB is responsible for necrotizing enteritis and enterotoxemia, mostly in neonatal individuals of many animal species, including humans. ETX is the main toxin involved in enterotoxemia of sheep and goats. ITX has been implicated in cases of enteritis in rabbits and other animal species; however, its specific role in causing disease has not been proved. CPE is responsible for human food-poisoning and non-foodborne C. perfringens-mediated diarrhea. NetB is the cause of necrotic enteritis in chickens. In most cases, host–toxin interaction starts on the plasma membrane of target cells via specific receptors, resulting in the activation of intracellular pathways with a variety of effects, commonly including cell death. In general, the molecular mechanisms of cell death associated with C. perfringens toxins involve features of apoptosis, necrosis and/or necroptosis.

Individual and Combined Occurrence of Mycotoxins in Feed Ingredients and Complete Feeds in China.

Abstract: The objective of this study was to investigate the individual and combined contamination of aflatoxin B1 (AFB1), zearalenone (ZEN) and deoxynivalenol (DON) in feedstuffs from different Provinces of China between 2016 and 2017. A total of 1569 samples, including 742 feed ingredients and 827 complete pig feed samples, were collected from various regions of China for mycotoxins analysis. The results showed that individual occurrence rates of AFB1, ZEN, and DON were more than 83.3%, 88%, and 74.5%, respectively, in all the tested samples. DON was the most prevalent contaminant, followed by ZEN and AFB1, with the average concentrations ranging from 450.0–4381.5 μg/kg, 2.3–729.2 μg/kg, and 1.3–10.0 μg/kg, respectively. Notable, 38.2%, 10.8%, and 0.6% of complete pig feeds were contaminated with DON, ZEN, and AFB1 over China’s regulatory limits, respectively. Moreover, over 75.0% analyzed samples were co-contaminated with two or three mycotoxins. In conclusion, the current study revealed that the feedstuffs in China were severely contaminated with DON, followed by ZEN and AFB1 during the past two years. These findings highlight the importance of monitoring mycotoxins in livestock feed and implementing feed management and bioremediation strategies to reduce mycotoxin exposure.

Impacts of Indoxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120.

Abstract: Uremic toxins, such as indoxyl sulfate (IS) and p-cresol, or p-cresyl sulfate (PCS), are markedly accumulated in the organs of chronic kidney disease (CKD) patients These toxins can induce inflammatory reactions and enhance oxidative stress, prompting glomerular sclerosis and interstitial fibrosis, to aggravate the decline of renal function Consequently, uremic toxins play an important role in the worsening of renal and cardiovascular functions Furthermore, they destroy the quantity and quality of bone Oral sorbent AST-120 reduces serum levels of uremic toxins in CKD patients by adsorbing the precursors of IS and PCS generated by amino acid metabolism in the intestine Accordingly, AST-120 decreases the serum IS levels and reduces the production of reactive oxygen species by endothelial cells, to impede the subsequent oxidative stress This slows the progression of cardiovascular and renal diseases and improves bone metabolism in CKD patients Although large-scale studies showed no obvious benefits from adding AST-120 to the standard therapy for CKD patients, subsequent sporadic studies may support its use This article summarizes the mechanisms of the uremic toxins, IS, and PCS, and discusses the multiple effects of AST-120 in CKD patients

Patulin in Apples and Apple-Based Food Products: The Burdens and the Mitigation Strategies.

Abstract: Apples and apple-based products are among the most popular foods around the world for their delightful flavors and health benefits. However, the commonly found mold, Penicillium expansum invades wounded apples, causing the blue mold decay and ensuing the production of patulin, a mycotoxin that negatively affects human health. Patulin contamination in apple products has been a worldwide problem without a satisfactory solution yet. A comprehensive understanding of the factors and challenges associated with patulin accumulation in apples is essential for finding such a solution. This review will discuss the effects of the pathogenicity of Penicillium species, quality traits of apple cultivars, and environmental conditions on the severity of apple blue mold and patulin contamination. Moreover, beyond the complicated interactions of the three aforementioned factors, patulin control is also challenged by the lack of reliable detection methods in food matrices, as well as unclear degradation mechanisms and limited knowledge about the toxicities of the metabolites resulting from the degradations. As apple-based products are mainly produced with stored apples, pre- and post-harvest strategies are equally important for patulin mitigation. Before storage, disease-resistance breeding, orchard-management, and elicitor(s) application help control the patulin level by improving the storage qualities of apples and lowering fruit rot severity. From storage to processing, patulin mitigation strategies could benefit from the optimization of apple storage conditions, the elimination of rotten apples, and the safe and effective detoxification or biodegradation of patulin.

Impact of Altered Intestinal Microbiota on Chronic Kidney Disease Progression

Abstract: In chronic kidney disease (CKD), accumulation of uremic toxins is associated with an increased risk of CKD progression. Some uremic toxins result from nutrient processing by gut microbiota, yielding precursors of uremic toxins or uremic toxins themselves, such as trimethylamine N-Oxide (TMAO), p-cresyl sulphate, indoxyl sulphate and indole-3 acetic acid. Increased intake of some nutrients may modify the gut microbiota, increasing the number of bacteria that process them to yield uremic toxins. Circulating levels of nutrient-derived uremic toxins are associated to increased risk of CKD progression. This offers the opportunity for therapeutic intervention by either modifying the diet, modifying the microbiota, decreasing uremic toxin production by microbiota, increasing toxin excretion or targeting specific uremic toxins. We now review the link between nutrients, microbiota and uremic toxin with CKD progression. Specific focus will be placed on the generation specific uremic toxins with nephrotoxic potential, the decreased availability of bacteria-derived metabolites with nephroprotective potential, such as vitamin K and butyrate and the cellular and molecular mechanisms linking these toxins and protective factors to kidney diseases. This information provides a conceptual framework that allows the development of novel therapeutic approaches.

Human Poisoning from Marine Toxins: Unknowns for Optimal Consumer Protection

Abstract: Marine biotoxins are produced by aquatic microorganisms and accumulate in shellfish or finfish following the food web. These toxins usually reach human consumers by ingestion of contaminated seafood, although other exposure routes like inhalation or contact have also been reported and may cause serious illness. This review shows the current data regarding the symptoms of acute intoxication for several toxin classes, including paralytic toxins, amnesic toxins, ciguatoxins, brevetoxins, tetrodotoxins, diarrheic toxins, azaspiracids and palytoxins. The information available about chronic toxicity and relative potency of different analogs within a toxin class are also reported. The gaps of toxicological knowledge that should be studied to improve human health protection are discussed. In general, gathering of epidemiological data in humans, chronic toxicity studies and exploring relative potency by oral administration are critical to minimize human health risks related to these toxin classes in the near future.

Fungal Cytochrome P450s and the P450 Complement (CYPome) of Fusarium graminearum

Abstract: Cytochrome P450s (CYPs), heme-containing monooxygenases, play important roles in a wide variety of metabolic processes important for development as well as biotic/trophic interactions in most living organisms. Functions of some CYP enzymes are similar across organisms, but some are organism-specific; they are involved in the biosynthesis of structural components, signaling networks, secondary metabolisms, and xenobiotic/drug detoxification. Fungi possess more diverse CYP families than plants, animals, or bacteria. Various fungal CYPs are involved in not only ergosterol synthesis and virulence but also in the production of a wide array of secondary metabolites, which exert toxic effects on humans and other animals. Although few studies have investigated the functions of fungal CYPs, a recent systematic functional analysis of CYP genes in the plant pathogen Fusarium graminearum identified several novel CYPs specifically involved in virulence, asexual and sexual development, and degradation of xenobiotics. This review provides fundamental information on fungal CYPs and a new platform for further metabolomic and biochemical studies of CYPs in toxigenic fungi.

AbobotulinumtoxinA (Dysport®), OnabotulinumtoxinA (Botox®), and IncobotulinumtoxinA (Xeomin®) Neurotoxin Content and Potential Implications for Duration of Response in Patients.

Abstract: Botulinum neurotoxin type-A (BoNT-A) blocks the release of acetylcholine from peripheral cholinergic nerve terminals and is an important option for the treatment of disorders characterised by excessive cholinergic neuronal activity. Several BoNT-A products are currently marketed, each with unique manufacturing processes, excipients, formulation, and non-interchangeable potency units. Nevertheless, the effects of all the products are mediated by the 150 kDa BoNT-A neurotoxin. We assessed the quantity and light chain (LC) activity of BoNT-A in three commercial BoNT-A products (Dysport®; Botox®; Xeomin®). We quantified 150 kDa BoNT-A by sandwich ELISA and assessed LC activity by EndoPep assay. In both assays, we assessed the results for the commercial products against recombinant 150 kDa BoNT-A. The mean 150 kDa BoNT-A content per vial measured by ELISA was 2.69 ng/500 U vial Dysport®, 0.90 ng/100 U vial Botox®, and 0.40 ng/100 U vial Xeomin®. To present clinically relevant results, we calculated the 150 kDa BoNT-A/US Food and Drug Administration (FDA)-approved dose in adult upper limb spasticity: 5.38 ng Dysport® (1000 U; 2 × 500 U vials), 3.60 ng Botox® (400 U; 4 × 100 U vials), and 1.61 ng Xeomin® (400 U; 4 × 100 U vials). EndoPep assay showed similar LC activity among BoNT-A products. Thus, greater amounts of active neurotoxin are injected with Dysport®, at FDA-approved doses, than with other products. This fact might explain the long duration of action reported across multiple indications, which benefits patients, caregivers, clinicians, and healthcare systems.

ROS-Mediated Cell Cycle Arrest and Apoptosis Induced by Zearalenone in Mouse Sertoli Cells via ER Stress and the ATP/AMPK Pathway.

Abstract: Zearalenone (ZEA) can perturb the differentiation of cells, reduce the generation of reproductive cells and induce a death of germ cells, but the molecular mechanism remains unclear. In order to investigate the potential mechanism of ZEA-induced cell cycle arrest and apoptosis, we studied the effects of ZEA on cell proliferation, cell-cycle distribution, cell-cycle-related proteins, cell death, cell apoptosis, ROS generation and the ATP/AMPK pathway in Sertoli cells. The role of ROS, ER stress and the ATP/AMPK pathway in ZEA-induced cell-cycle arrest and cell apoptosis was explored by using the antioxidant NAC, ER stress inhibitor 4-PBA and the AMPK inhibitor dorsomorphin, respectively. The results revealed that ZEA inhibited the cell proliferation, influenced the distribution of the cell cycle and induced cell apoptosis through the ATP/AMPK pathway. The ATP/AMPK pathway was regulated by ER stress that was induced by ROS generation after exposure to ZEA. Taking these together, this study provided evidence that ROS regulated the process of ZEA-induced cell cycle arrest and cell apoptosis through ER stress and the ATP/AMPK signal ways.

Snake Venom Peptides: Tools of Biodiscovery.

Abstract: Nature endowed snakes with a lethal secretion known as venom, which has been fine-tuned over millions of years of evolution. Snakes utilize venom to subdue their prey and to survive in their natural habitat. Venom is known to be a very poisonous mixture, consisting of a variety of molecules, such as carbohydrates, nucleosides, amino acids, lipids, proteins and peptides. Proteins and peptides are the major constituents of the dry weight of snake venoms and are of main interest for scientific investigations as well as for various pharmacological applications. Snake venoms contain enzymatic and non-enzymatic proteins and peptides, which are grouped into different families based on their structure and function. Members of a single family display significant similarities in their primary, secondary and tertiary structures, but in many cases have distinct pharmacological functions and different bioactivities. The functional specificity of peptides belonging to the same family can be attributed to subtle variations in their amino acid sequences. Currently, complementary tools and techniques are utilized to isolate and characterize the peptides, and study their potential applications as molecular probes, and possible templates for drug discovery and design investigations.

Role of Uremic Toxins for Kidney, Cardiovascular, and Bone Dysfunction.

Abstract: With decreasing kidney function, cardiovascular disease (CVD) and mineral bone disorders frequently emerge in patients with chronic kidney disease (CKD). For these patients, in addition to the traditional risk factors, non-traditional CKD-specific risk factors are also associated with such diseases and conditions. One of these non-traditional risk factors is the accumulation of uremic toxins (UTs). In addition, the accumulation of UTs further deteriorates kidney function. Recently, a huge number of UTs have been identified. Although many experimental and clinical studies have reported associations between UTs and the progression of CKD, CVD, and bone disease, these relationships are very complex and have not been fully elucidated. Among the UTs, indoxyl sulfate, asymmetric dimethylarginine, and p-cresylsulfate have been of particular focus, up until now. In this review, we summarize the pathophysiological influences of these UTs on the kidney, cardiovascular system, and bone, and discuss the clinical data regarding the harmful effects of these UTs on diseases and conditions.

Snakebite: When the Human Touch Becomes a Bad Touch

Abstract: Many issues and complications in treating snakebite are a result of poor human social, economic and clinical intervention and management. As such, there is scope for significant improvements for reducing incidence and increasing patient outcomes. Snakes do not target humans as prey, but as our dwellings and farms expand ever farther and climate change increases snake activity periods, accidental encounters with snakes seeking water and prey increase drastically. Despite its long history, the snakebite crisis is neglected, ignored, underestimated and fundamentally misunderstood. Tens of thousands of lives are lost to snakebites each year and hundreds of thousands of people will survive with some form of permanent damage and reduced work capacity. These numbers are well recognized as being gross underestimations due to poor to non-existent record keeping in some of the most affected areas. These underestimations complicate achieving the proper recognition of snakebite’s socioeconomic impact and thus securing foreign aid to help alleviate this global crisis. Antivenoms are expensive and hospitals are few and far between, leaving people to seek help from traditional healers or use other forms of ineffective treatment. In some cases, cheaper, inappropriately manufactured antivenom from other regions is used despite no evidence for their efficacy, with often robust data demonstrating they are woefully ineffective in neutralizing many venoms for which they are marketed for. Inappropriate first-aid and treatments include cutting the wound, tourniquets, electrical shock, immersion in ice water, and use of ineffective herbal remedies by traditional healers. Even in the developed world, there are fundamental controversies including fasciotomy, pressure bandages, antivenom dosage, premedication such as adrenalin, and lack of antivenom for exotic snakebites in the pet trade. This review explores the myriad of human-origin factors that influence the trajectory of global snakebite causes and treatment failures and illustrate that snakebite is as much a sociological and economic problem as it is a medical one. Reducing the incidence and frequency of such controllable factors are therefore realistic targets to help alleviate the global snakebite burden as incremental improvements across several areas will have a strong cumulative effect.

Pharmacokinetics of Snake Venom.

Abstract: Understanding snake venom pharmacokinetics is essential for developing risk assessment strategies and determining the optimal dose and timing of antivenom required to bind all venom in snakebite patients. This review aims to explore the current knowledge of snake venom pharmacokinetics in animals and humans. Literature searches were conducted using EMBASE (1974–present) and Medline (1946–present). For animals, 12 out of 520 initially identified studies met the inclusion criteria. In general, the disposition of snake venom was described by a two-compartment model consisting of a rapid distribution phase and a slow elimination phase, with half-lives of 5 to 48 min and 0.8 to 28 h, respectively, following rapid intravenous injection of the venoms or toxins. When the venoms or toxins were administered intramuscularly or subcutaneously, an initial absorption phase and slow elimination phase were observed. The bioavailability of venoms or toxins ranged from 4 to 81.5% following intramuscular administration and 60% following subcutaneous administration. The volume of distribution and the clearance varied between snake species. For humans, 24 out of 666 initially identified publications contained sufficient information and timed venom concentrations in the absence of antivenom therapy for data extraction. The data were extracted and modelled in NONMEM. A one-compartment model provided the best fit, with an elimination half-life of 9.71 ± 1.29 h. It is intended that the quantitative information provided in this review will provide a useful basis for future studies that address the pharmacokinetics of snakebite in humans.

Intestinal Barrier Function in Chronic Kidney Disease.

Abstract: The kidneys are key contributors to body homeostasis, by virtue of controlled excretion of excessive fluid, electrolytes, and toxic waste products The syndrome of uremia equals the altered physiology due to irreversible loss of kidney function that is left uncorrected for, despite therapeutic intervention(s) The intestines and its microbial content are prime contributors to this syndrome The intestinal barrier separates the self (or the so-called “milieu interior”) from the environment In the large intestine, the intestinal barrier keeps apart human physiology and the microbiota The enterocytes and the extracellular mucin layer functions form a complex multilayered structure, facilitating complex bidirectional metabolic and immunological crosstalk The current review focuses on the intestinal barrier in chronic kidney disease (CKD) Loss of kidney function results in structural and functional alterations of the intestinal barrier, contribution to the syndrome of uremia

Sea Anemones: Quiet Achievers in the Field of Peptide Toxins

Abstract: Sea anemones have been understudied as a source of peptide and protein toxins, with relatively few examined as a source of new pharmacological tools or therapeutic leads. This is surprising given the success of some anemone peptides that have been tested, such as the potassium channel blocker from Stichodactyla helianthus known as ShK. An analogue of this peptide, ShK-186, which is now known as dalazatide, has successfully completed Phase 1 clinical trials and is about to enter Phase 2 trials for the treatment of autoimmune diseases. One of the impediments to the exploitation of sea anemone toxins in the pharmaceutical industry has been the difficulty associated with their high-throughput discovery and isolation. Recent developments in multiple ‘omic’ technologies, including genomics, transcriptomics and proteomics, coupled with advanced bioinformatics, have opened the way for large-scale discovery of novel sea anemone toxins from a range of species. Many of these toxins will be useful pharmacological tools and some will hopefully prove to be valuable therapeutic leads.

The Impact of Uremic Toxins on Vascular Smooth Muscle Cell Function.

Abstract: Chronic kidney disease (CKD) is associated with profound vascular remodeling, which accelerates the progression of cardiovascular disease. This remodeling is characterized by intimal hyperplasia, accelerated atherosclerosis, excessive vascular calcification, and vascular stiffness. Vascular smooth muscle cell (VSMC) dysfunction has a key role in the remodeling process. Under uremic conditions, VSMCs can switch from a contractile phenotype to a synthetic phenotype, and undergo abnormal proliferation, migration, senescence, apoptosis, and calcification. A growing body of data from experiments in vitro and animal models suggests that uremic toxins (such as inorganic phosphate, indoxyl sulfate and advanced-glycation end products) may directly impact the VSMCs’ physiological functions. Chronic, low-grade inflammation and oxidative stress—hallmarks of CKD—are also strong inducers of VSMC dysfunction. Here, we review current knowledge about the impact of uremic toxins on VSMC function in CKD, and the consequences for pathological vascular remodeling.

The Expanding Therapeutic Utility of Botulinum Neurotoxins

Abstract: Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation and delivery, together with highly sensitive analytical tools, will be key for the success of next generation BoNT clinical products.

Protective and detoxifying effects conferred by dietary selenium and curcumin against AFB1-mediated toxicity in livestock: a review.

Abstract: Aflatoxin B1 (AFB1), among other aflatoxins of the aflatoxin family, is the most carcinogenic and hazardous mycotoxin to animals and human beings with very high potency leading to aflatoxicosis. Selenium is an essential trace mineral possessing powerful antioxidant functions. Selenium is widely reported as an effective antioxidant against aflatoxicosis. By preventing oxidative liver damage, suppressing pro-apoptotic proteins and improving immune status in AFB1 affected animals; selenium confers specific protection against AFB1 toxicity. Meticulous supplementation of animal feed by elemental selenium in the organic and inorganic forms has proven to be effective to ameliorate AFB1 toxicity. Curcumin is another dietary agent of importance in tackling aflatoxicosis. Curcumin is one of the major active ingredients in the tubers of a spice Curcuma longa L., a widely reported antioxidant, anticarcinogenic agent with reported protective potential against aflatoxin-mediated liver damage. Curcumin restricts the aflatoxigenic potential of Aspergillusflavus. Curcumin inhibits cytochrome P450 isoenzymes, particularly CYP2A6 isoform; thereby reducing the formation of AFB1-8, 9-epoxide and other toxic metabolites causing aflatoxicosis. In this review, we have briefly reviewed important aflatoxicosis symptoms among animals. With the main focus on curcumin and selenium, we have reviewed their underlying protective mechanisms in different animals along with their extraction and production methods for feed applications.