Phytogenic Bioactive Compounds Shape Fish Mucosal Immunity

Aquaculture growth will unavoidably involve the implementation of innovative and sustainable production strategies, being functional feeds among the most promising ones. A wide spectrum of phytogenics, particularly those containing terpenes and organosulfur compounds, are increasingly studied in aquafeeds, due to their growth promoting, antimicrobial, immunostimulant, antioxidant, anti-inflammatory and sedative properties. This trend relies on the importance of the mucosal barrier in the fish defense. Establishing the phytogenics’ mode of action in mucosal tissues is of importance for further use and safe administration. Although the impact of phytogenics upon fish mucosal immunity has been extensively approached, most of the studies fail in addressing the mechanisms underlying their pharmacological effects. Unstandardized testing as an extended practice also questions the reproducibility and safety of such studies, limiting the use of phytogenics at commercial scale. The information presented herein provides insight on the fish mucosal immune responses to phytogenics, suggesting their mode of action, and ultimately encouraging the practice of reliable and reproducible research for novel feed additives for aquafeeds. For proper screening, characterization and optimization of their mode of action, we encourage the evaluation of purified compounds using in vitro systems before moving forward to in vivo trials. The formulation of additives with combinations of compounds previously characterized is recommended to avoid bacterial resistance. To improve the delivery of phytogenics and overcome limitations associated to compounds volatility and susceptibility to degradation, the use of encapsulation is advisable. Besides, newer approaches and dedicated methodologies are needed to elucidate the phytogenics pharmacokinetics and mode of action in depth.

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In Vitro Characterization of the Antibacterial Spectrum of Novel Bacterial Type II Topoisomerase Inhibitors of the Aminobenzimidazole Class

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.50.4.1228-1237.2006 ◽

2006 ◽

Vol 50 (4) ◽

pp. 1228-1237 ◽

Cited By ~ 56

Author(s):

Nagraj Mani ◽

Christian H. Gross ◽

Jonathan D. Parsons ◽

Brian Hanzelka ◽

Ute Müh ◽

...

Keyword(s):

Bacterial Resistance ◽

Wide Spectrum ◽

Dna Gyrase ◽

Antibacterial Activities ◽

Mechanisms Of Action ◽

Fluoroquinolone Resistance ◽

Topoisomerase Iv ◽

Low Frequencies

ABSTRACT Antibiotics with novel mechanisms of action are becoming increasingly important in the battle against bacterial resistance to all currently used classes of antibiotics. Bacterial DNA gyrase and topoisomerase IV (topoIV) are the familiar targets of fluoroquinolone and coumarin antibiotics. Here we present the characterization of two members of a new class of synthetic bacterial topoII ATPase inhibitors: VRT-125853 and VRT-752586. These aminobenzimidazole compounds were potent inhibitors of both DNA gyrase and topoIV and had excellent antibacterial activities against a wide spectrum of problematic pathogens responsible for both nosocomial and community-acquired infections, including staphylococci, streptococci, enterococci, and mycobacteria. Consistent with the novelty of their structures and mechanisms of action, antibacterial potency was unaffected by commonly encountered resistance phenotypes, including fluoroquinolone resistance. In time-kill assays, VRT-125853 and VRT-752586 were bactericidal against Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis, and Haemophilus influenzae, causing 3-log reductions in viable cells within 24 h. Finally, similar to the fluoroquinolones, relatively low frequencies of spontaneous resistance to VRT-125853 and VRT-752586 were found, a property consistent with their in vitro dual-targeting activities.

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The nutritional applications of garlic (Allium sativum) as natural feed additives in animals

PeerJ ◽

10.7717/peerj.11934 ◽

2021 ◽

Vol 9 ◽

pp. e11934

Author(s):

Jiashun Chen ◽

Fang Wang ◽

Yexin Yin ◽

Xiaokang Ma

Keyword(s):

Allium Sativum ◽

Animal Feed ◽

Animal Husbandry ◽

Feed Additives ◽

Bioactive Molecules ◽

Herbal Remedies ◽

Organosulfur Compounds ◽

Beneficial Effects ◽

Stress Markers

Garlic (Allium sativum) is an essential vegetable that has been widely utilized as seasoning, flavoring, culinary and in herbal remedies. Garlic contains several characteristic organosulfur compounds, such as diallyl sulfide, allicin (diallyl thiosulphate), γ-glutamylcysteine, and S-allyl cysteine (alliin) and ajoene, which garlic has beneficial effects on inflammation, oxidative stress markers, hypertension, hyperlipidaemia and endothelial function in vitro or in animal model. These bioactive molecules are also playing pivotal role in livestock and fisheries production apart from its application in humans. Supplementation of animal feed with garlic and its related products is consistent with the modern agricultural concept of organic animal husbandry. This review compiles the information describing the effects of feeding garlic and its extracts on selected performance parameters in animals (chicken, rabbits, ruminants, pigs and fish). This review may provide reference for scientists and entrepreneurs to investigate the applications of feeds added with garlic and allicin by-products for the improvement of animal husbandry and aquatic production.

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Evaluation of Curcumin and Copper Acetate Against Salmonella Typhimurium Infection, Intestinal Permeability, and Cecal Microbiota Composition in Broiler Chickens

10.21203/rs.3.rs-42229/v1 ◽

2020 ◽

Author(s):

Anaisa A. Leyva-Diaz ◽

Daniel Hernandez-Patlan ◽

Bruno Solis-Cruz ◽

Bishnu Adhikari ◽

Young Min Kwon ◽

...

Keyword(s):

Intestinal Permeability ◽

Broiler Chickens ◽

Bacterial Resistance ◽

Copper Acetate ◽

Fluorescein Isothiocyanate ◽

Feed Additives ◽

Microbiota Composition ◽

Linear Discriminant ◽

Cecal Microbiota ◽

The Impact

Abstract Background: Interest in the use of natural feed additives as an alternative to antimicrobials in the poultry industry has increased in recent years because of the risk of bacterial resistance. One of the most studied groups are polyphenolic compounds, given their advantages over other types of additives and their easy potentiation of effects when complexes are formed with metal ions. Therefore, the objective of the present study was to evaluate the impact of dietary supplementation of Copper Acetate (CA), Curcumin (CR), and their combination (CA-CR) against Salmonella Typhimurium colonization, intestinal permeability, and cecal microbiota composition in broiler chickens.Results: The obtained results showed that in two independent studies, all experimental treatments were able to significantly reduce the S. Typhimurium colonization in cecal tonsils (CT, p < 0.05) compared to the positive control (PC) group. However, CR and CA-CR were the best treatments reducing S. Typhimurium counts. Furthermore, the serum fluorescein isothiocyanate dextran (FITC-d) concentration in chickens treated with CR was significantly lower when compared to PC (p < 0.05). The effect of dietary treatments in reducing S. Typhimurium colonization was further supported by the Linear discriminant analysis effect size (LEfSe) analysis of microbiome data, where Salmonella was significantly enriched in PC group (LDA score > 2.0 and p<0.05). In addition, Coprobacillus, Eubacterium, and Clostridium were significantly higher in the PC group compared to other treatment groups. On the contrary, Fecalibacterium and Enterococcus at CR, unknown genus of Erysipelotrichaceae at CA-CR, and unknown genus of Lachnospiraceae at CA were significantly abundant respectively.Conclusions: CR treatment was the most effective treatment to reduce S. Typhimurium intestinal colonization and intestinal permeability associated with variations in the cecae microbiota structure in broiler chickens.

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The Puzzling Potential of Carbon Nanomaterials: General Properties, Application, and Toxicity

Nanomaterials ◽

10.3390/nano10081508 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1508

Author(s):

Danica Jović ◽

Vesna Jaćević ◽

Kamil Kuča ◽

Ivana Borišev ◽

Jasminka Mrdjanovic ◽

...

Keyword(s):

Carbon Nanomaterials ◽

Wide Spectrum ◽

Chemical Properties ◽

Carbon Nanomaterial ◽

In Vivo Models ◽

Physico Chemical ◽

The Impact ◽

Cell Signaling Pathways

Being a member of the nanofamily, carbon nanomaterials exhibit specific properties that mostly arise from their small size. They have proved to be very promising for application in the technical and biomedical field. A wide spectrum of use implies the inevitable presence of carbon nanomaterials in the environment, thus potentially endangering their whole nature. Although scientists worldwide have conducted research investigating the impact of these materials, it is evident that there are still significant gaps concerning the knowledge of their mechanisms, as well as the prolonged and chronic exposure and effects. This manuscript summarizes the most prominent representatives of carbon nanomaterial groups, giving a brief review of their general physico-chemical properties, the most common use, and toxicity profiles. Toxicity was presented through genotoxicity and the activation of the cell signaling pathways, both including in vitro and in vivo models, mechanisms, and the consequential outcomes. Moreover, the acute toxicity of fullerenol, as one of the most commonly investigated members, was briefly presented in the final part of this review. Thinking small can greatly help us improve our lives, but also obliges us to deeply and comprehensively investigate all the possible consequences that could arise from our pure-hearted scientific ambitions and work.

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The future of animal production: improving productivity and sustainability

The Journal of Agricultural Science ◽

10.1017/s0021859610001188 ◽

2011 ◽

Vol 149 (S1) ◽

pp. 9-16 ◽

Cited By ~ 26

Author(s):

D. A. HUME ◽

C. B. A. WHITELAW ◽

A. L. ARCHIBALD

Keyword(s):

Agricultural Research ◽

Wide Spectrum ◽

Genetic Selection ◽

Reproductive Technologies ◽

Breeding Value ◽

Food Needs ◽

Analytical Tools ◽

The Impact

SUMMARYThe challenge for the next 50 years is to increase the productivity of major livestock species to address the food needs of the world, while at the same time minimizing the environmental impact. The present review presents an optimistic view of this challenge. The completion of genome sequences, and high-density analytical tools to map genetic markers, allows for whole-genome selection programmes based on linkage disequilibrium for a wide spectrum of traits, simultaneously. In turn, it will be possible to redefine genetic prediction based on allele sharing, rather than pedigree relationships and to make breeding value predictions early in the life of the peak sire. Selection will be applied to a much wider range of traits, including those that are directed towards environmental or adaptive outcomes. In parallel, reproductive technologies will continue to advance to allow acceleration of genetic selection, probably including recombination in vitro. Transgenesis and/or mutagenesis will be applied to introduce new genetic variation or desired phenotypes. Traditional livestock systems will continue to evolve towards more intensive integrated farming modes that control inputs and outputs to minimize the impact and improve efficiency. The challenges of the next 50 years can certainly be met, but only if governments reverse the long-term disinvestment in agricultural research.

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Frequency of Impaired Fibroblast Growth Factor Receptor 1 Signaling as a Cause of Normosmic Idiopathic Hypogonadotropic Hypogonadism

Molecular Endocrinology ◽

10.1210/mend.23.12.9994 ◽

2009 ◽

Vol 23 (12) ◽

pp. 2120-2121

Author(s):

Taneli Raivio ◽

Yisrael Sidis ◽

Lacey Plummer ◽

Huaibin Chen ◽

Jinghong Ma ◽

...

Keyword(s):

Wide Spectrum ◽

Pubertal Development ◽

Hypogonadotropic Hypogonadism ◽

Growth Factor Receptor ◽

Cell Surface Expression ◽

Heterozygous Mutation ◽

Loss Of Function ◽

Idiopathic Hypogonadotropic Hypogonadism ◽

The Impact

ABSTRACT Context FGFR1 mutations have been identified in about 10% of patients with Kallmann syndrome. Recently cases of idiopathic hypogonadotropic hypogonadism (IHH) with a normal sense of smell (nIHH) have been reported. Aims The objective of the study was to define the frequency of FGFR1 mutations in a large cohort of nIHH, delineate the spectrum of reproductive phenotypes, assess functionality of the FGFR1 mutant alleles in vitro, and investigate genotype-phenotype relationships. Design FGFR1 sequencing of 134 well-characterized nIHH patients (112 men and 22 women) and 270 healthy controls was performed. The impact of the identified mutations on FGFR1 function was assessed using structural prediction and in vitro studies. Results Nine nIHH subjects (five males and four females; 7%) harbor a heterozygous mutation in FGFR1 and exhibit a wide spectrum of pubertal development, ranging from absent puberty to reversal of IHH in both sexes. All mutations impair receptor function. The Y99C, Y228D, and I239T mutants impair the tertiary folding, resulting in incomplete glycosylation and reduced cell surface expression. The R250Q mutant reduces receptor affinity for FGF. The K618N, A671P, and Q680X mutants impair tyrosine kinase activity. However, the degree of functional impairment of the mutant receptors did not always correlate with the reproductive phenotype, and variable expressivity of the disease was noted within family members carrying the same FGFR1 mutation. These discrepancies were partially explained by additional mutations in known IHH loci. Conclusions Loss-of-function mutations in FGFR1 underlie 7% of nIHH with different degrees of impairment in vitro. These mutations act in concert with other gene defects in several cases, consistent with oligogenicity.

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The impact of duration of antibiotic exposure on bacterial resistance predictions using in vitro dynamic models

Journal of Antimicrobial Chemotherapy ◽

10.1093/jac/dkp287 ◽

2009 ◽

Vol 64 (4) ◽

pp. 815-820 ◽

Cited By ~ 10

Author(s):

M. V. Smirnova ◽

S. N. Vostrov ◽

E. V. Strukova ◽

S. A. Dovzhenko ◽

M. B. Kobrin ◽

...

Keyword(s):

Bacterial Resistance ◽

Dynamic Models ◽

Antibiotic Exposure ◽

The Impact

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Beta-Lactam Antibiotics: Is Continuous Infusion The Preferred Method of Administration?

Annals of Pharmacotherapy ◽

10.1177/106002809502900413 ◽

1995 ◽

Vol 29 (4) ◽

pp. 415-424 ◽

Cited By ~ 34

Author(s):

Thomas G Vondracek

Keyword(s):

Clinical Trials ◽

Continuous Infusion ◽

Bacterial Resistance ◽

In Vitro Studies ◽

Antibiotic Administration ◽

Beta Lactam ◽

Optimal Method ◽

Beta Lactam Antibiotics ◽

The Impact

Objective: To examine the pharmacodynamic properties of the beta-lactam class of antibiotics and the rationale for their continuous infusion (CI), and to explore reasons that this mode of administration has not replaced intermittent infusion as the standard of practice. Data Sources: A MEDLINE search of the English-language literature evaluating CI administration of beta-lactam antibiotics was conducted. Bibliographic searches of these articles also were performed. Study Selection: Because there were few human trials, all available trials were considered for review. A cross section of clinical trials, animal studies, and in vitro studies examining the impact of the route of antibiotic administration was selected for each pharmacodynamic variable addressed. Data Synthesis: The support for CI as the preferred method of beta-lactam administration comes primarily from in vitro and animal data. Most beta-lactam antibiotics do not demonstrate concentration-dependent killing and have an appreciable postantibiotic effect only against gram-positive cocci. Their efficacy appears to be optimized by maintaining suprainhibitory concentrations throughout the dosing interval. Therefore, CI of beta-lactams could potentially enhance the efficacy of treatment or allow less drug to be used on a daily basis. This has yet to be demonstrated convincingly in human clinical trials. Comparative trials need to continue to explore die impact of the method of administration on patient outcomes such as duration and cost of therapy, as well as morbidity and mortality. Conclusions: Results of many animal and in vitro studies suggest that CI may be the optimal method of beta-lactam administration. Clinical trials need to further document the impact of the method of beta-lactam administration on the incidence of adverse effects, emergence of bacterial resistance, and patient outcome. Pharmacodynamic studies defining target beta-lactam concentrations, the practicality of CI in patients requiring multiple intravenous fluids and medications, and the pertinence of this issue when beta-lactam antibiotics are used as sole agents or in combination with other antimicrobials require further exploration.

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Multi-omic Characterization of the Mode of Action of a Potent New Antimalarial Compound, JPC-3210, Against Plasmodium falciparum

Molecular & Cellular Proteomics ◽

10.1074/mcp.ra119.001797 ◽

2019 ◽

Vol 19 (2) ◽

pp. 308-325 ◽

Cited By ~ 1

Author(s):

Geoffrey W. Birrell ◽

Matthew P. Challis ◽

Amanda De Paoli ◽

Dovile Anderson ◽

Shane M. Devine ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Mode Of Action ◽

Antimalarial Activity ◽

Protein Translation ◽

Multidrug Resistant ◽

Metabolomics Data ◽

The Impact ◽

Hemoglobin Metabolism

The increasing incidence of antimalarial drug resistance to the first-line artemisinin combination therapies underpins an urgent need for new antimalarial drugs, ideally with a novel mode of action. The recently developed 2-aminomethylphenol, JPC-3210, (MMV 892646) is an erythrocytic schizonticide with potent in vitro antimalarial activity against multidrug-resistant Plasmodium falciparum lines, low cytotoxicity, potent in vivo efficacy against murine malaria, and favorable preclinical pharmacokinetics including a lengthy plasma elimination half-life. To investigate the impact of JPC-3210 on biochemical pathways within P. falciparum-infected red blood cells, we have applied a “multi-omics” workflow based on high resolution orbitrap mass spectrometry combined with biochemical approaches. Metabolomics, peptidomics and hemoglobin fractionation analyses revealed a perturbation in hemoglobin metabolism following JPC-3210 exposure. The metabolomics data demonstrated a specific depletion of short hemoglobin-derived peptides, peptidomics analysis revealed a depletion of longer hemoglobin-derived peptides, and the hemoglobin fractionation assay demonstrated decreases in hemoglobin, heme and hemozoin levels. To further elucidate the mechanism responsible for inhibition of hemoglobin metabolism, we used in vitro β-hematin polymerization assays and showed JPC-3210 to be an intermediate inhibitor of β-hematin polymerization, about 10-fold less potent then the quinoline antimalarials, such as chloroquine and mefloquine. Further, quantitative proteomics analysis showed that JPC-3210 treatment results in a distinct proteomic signature compared with other known antimalarials. While JPC-3210 clustered closely with mefloquine in the metabolomics and proteomics analyses, a key differentiating signature for JPC-3210 was the significant enrichment of parasite proteins involved in regulation of translation. These studies revealed that the mode of action for JPC-3210 involves inhibition of the hemoglobin digestion pathway and elevation of regulators of protein translation. Importantly, JPC-3210 demonstrated rapid parasite killing kinetics compared with other quinolones, suggesting that JPC-3210 warrants further investigation as a potentially long acting partner drug for malaria treatment.

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Synthesis, Antibacterial Activities, Mode of Action and Acute Toxicity Studies of New Oxazolidinone-Fluoroquinolone Hybrids

Molecules ◽

10.3390/molecules24081641 ◽

2019 ◽

Vol 24 (8) ◽

pp. 1641 ◽

Cited By ~ 2

Author(s):

Liu ◽

Shao ◽

Li ◽

Cui ◽

Li ◽

...

Keyword(s):

Acute Toxicity ◽

Mode Of Action ◽

Bacterial Resistance ◽

Antibacterial Activities ◽

Oral Toxicity ◽

Gram Positive ◽

Gram Positive Bacteria ◽

Synthetic Hybrids ◽

Drug Resistant Strains

To combat bacterial resistance, a series of new oxazolidinone-fluoroquinolone hybrids have been synthesized and characterized. All synthetic hybrids were preliminarily evaluated for their in vitro antibacterial activities against 6 standard strains and 3 clinical isolates. The majority of hybrids displayed excellent activities against Gram-positive bacteria, but limited activities against Gram-negative bacteria. Hybrids OBP-4 and OBP-5 were found to be the most promising compounds. Further, in vitro antibacterial activities, mode of action and acute toxicity in mice of hybrids OBP-4 and OBP-5 were investigated. Hybrids OBP-4 and OBP-5 exhibited potent activities against Gram-positive bacteria, including drug-resistant strains. Correspondingly, studies on the mode of action of hybrids OBP-4 and OBP-5 indicated a strong inhibitory activity on protein synthesis by binding the active site of 50S subunit, but a weak inhibitory action on DNA synthesis. In addition, LD50 values of hybrids OBP-4 and OBP-5 in the acute oral toxicity were larger than 2000 mg/kg, suggesting a good safety profile.

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