ABSTRACT
BACKGROUND: Cancer stem cells (CSCs) in triple-negative breast cancer (TNBC) are recognized as a highly challenging subset of cells, renowned for their heightened propensity for relapse and unfavorable prognosis. Monensin, an ionophoric antibiotic, has been reported to exhibit significant therapeutic efficacy against various cancers, especially CSCs. Erlotinib is classified as one of the EGFR-TKIs and has been previously identified as a promising therapeutic target for TNBC. Our research aims to assess the effectiveness of combination of monensin and erlotinib as a potential treatment strategy for TNBC. METHODS: The combination of monensin and erlotinib was assessed for its potential anticancer activity through various in vitro assays, including cytotoxicity assay, colony formation assay, wound healing assay, transwell assay, mammosphere formation assay, and proportion of CSCs assay. Additionally, an in vivo study using tumor-bearing nude mice was conducted to evaluate the inhibitory effect of the monensin and erlotinib combination on tumor growth. RESULTS: The results indicated that combination of monensin with erlotinib synergistically inhibited cell proliferation, the migration rate, the invasion ability and decreased the CSCs proportion, and CSC markers SOX2 and CD133 in vivo and in vitro. Furthermore, the primary proteins involved in the signaling pathways of the EGFR/ERK and PI3K/AKT are simultaneously inhibited by the combination treatment of monensin and erlotinib in vivo and in vitro. CONCLUSIONS: The simultaneous inhibition of the EGFR/ERK and PI3K/AKT/mTOR signaling pathways by the combination of monensin and erlotinib exhibited a synergistic effect on suppressing tumor proliferation and cancer cell stemness in TNBC.
Subject(s)
Cell Proliferation , Drug Synergism , ErbB Receptors , Erlotinib Hydrochloride , Monensin , Neoplastic Stem Cells , Signal Transduction , Triple Negative Breast Neoplasms , Xenograft Model Antitumor Assays , Erlotinib Hydrochloride/pharmacology , Erlotinib Hydrochloride/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Humans , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Animals , ErbB Receptors/metabolism , ErbB Receptors/antagonists & inhibitors , Female , Mice , Signal Transduction/drug effects , Monensin/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Phosphatidylinositol 3-Kinases/metabolism , Cell Movement/drug effects , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Mice, NudeABSTRACT
This study investigated the effects of the early administration of enrofloxacin (E) or doxycycline (D) for the first 5 consecutive days of life, or the continuous administration of the coccidiostat monensin (M) throughout the rearing period on gastrointestinal function in turkeys infected with avian pathogenic Escherichia coli (APEC) in an early or later stage of rearing. Experiment 1 lasted 21 d, and turkeys in groups E, D, and M were infected with APEC on d 15. Experiment 2 lasted 56 d, and it had a factorial arrangement of treatments where birds in groups E, D, and M were infected with APEC on d 15 or d 50. In both experiments, control groups (C) consisted of infected and uninfected birds without antibiotic or coccidiostat administration. On d 21 (Experiment 1) and d 56 (Experiment 2), 8 birds from each subgroup were killed, and the ileal and cecal digesta were sampled to analyze the activity of bacterial enzymes and the concentrations of short-chain fatty acids (SCFA). The experimental treatments did not affect the final body weight or body weight gain of birds. Both experiments demonstrated that APEC contributed to an increase in ammonia levels of the cecal digesta (means from 2 experiments: 0.311 vs. 0.225 mg/g in uninfected birds) and ileal pH (6.79 vs. 6.00) and viscosity (2.43 vs. 1.83 mPaâ s). Moreover, the E. coli challenge enhanced the extracellular activity of several cecal bacterial enzymes, especially in older turkeys infected with APEC in a later stage of life. The continuous administration of monensin throughout the rearing period resulted in a weaker gastrointestinal response in older birds, compared with the other 2 antibiotics administered for the first 5 d of life. The results of the study are inconclusive as both desirable and undesirable effects of preventive early short-term antibiotic therapy were observed in turkeys, including normalization of ileal viscosity and cecal ammonia concentration (positive effect), and disruption in cecal SCFA production (negative effect).
Subject(s)
Anti-Bacterial Agents , Escherichia coli Infections , Escherichia coli , Poultry Diseases , Turkeys , Animals , Escherichia coli Infections/veterinary , Escherichia coli Infections/drug therapy , Escherichia coli Infections/microbiology , Poultry Diseases/microbiology , Poultry Diseases/drug therapy , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/pharmacology , Escherichia coli/drug effects , Enrofloxacin/administration & dosage , Monensin/administration & dosage , Monensin/pharmacology , Male , Gastrointestinal Tract/microbiology , Gastrointestinal Tract/drug effects , Random AllocationABSTRACT
The objective of the current study was to evaluate the effects of tannin and monensin supplementation in feedlot diets and breed (Holstein vs. Angusâ ×â Holstein) on growth performance, energetic efficiency, and carcass characteristics. Eighty purebred Holstein calves (HOL; initial body weight (BW)â =â 130â ±â 5 kg) and 80 Angusâ ×â Holstein calves (AXH; initial BWâ =â 129â ±â 6 kg) were blocked by initial BW and randomly assigned to 40 pens. Dietary treatments consisted of a steam-flaked corn-based diet supplemented with (1) no feed additive (CON); (2) 30 mg of monensin/kg of dry matter (DM; MON; Rumensin 90, Elanco, Greenfield, IN); (3) 1.5 g tannin)/kg of DM (TAN; ByPro, 70% condensed tannin, SilvaFeed, Indunor, S.A., Buenos Aires, Argentina); (4) Mâ +â T, the combination of MON plus TAN dietary treatments. Data were analyzed as a randomized complete block in a 2â ×â 4 factorial arrangement of treatments, using pens as experimental units. There were no interactions (Pâ >â 0.05) between feed additives and breed. Supplemental MON increased (Pâ ≤â 0.04) initial 112-d BW and gain efficiency. However, there were no dietary treatment effects (Pâ >â 0.10) on overall growth performance. Monensin supplementation decreased (Pâ =â 0.04) minimum daily ruminal temperature compared with other dietary treatments during July, but TAN did not affect ruminal temperature. Holstein steers had greater (Pâ =â 0.04) overall DM intake compared with AXH, with no difference (Pâ =â 0.19) in overall ADG, leading to increased (Pâ <â 0.01) gain efficiency for AXH compared with HOL. Dietary net energy for maintenance and gain, based on growth performance, were greater (Pâ ≤â 0.01) for AXH vs HOL. Compared with HOL, AXH steers had greater (Pâ ≤â 0.01) carcass weight, dressing percentage, kidney, pelvic, and heart fat, 12th rib fat thickness, longissimus area, and preliminary yield grade. Holstein steers had lower (Pâ ≤â 0.04) minimum average ruminal temperature during June compared with AXH, with no differences (Pâ ≥â 0.14) between breeds during July or August. Results indicate that feed additives did not appreciably affect steer growth performance and carcass characteristics, but crossbred AXH steers had greater growth performance, efficiency of dietary energy utilization, and carcass quality measures compared with HOL. This study observed a reduction (4.7%) in maintenance energy expenditure in AXH compared with HOL, implying in maintenance energy coefficient of 0.086 vs 0.082 for HOL and AXH, respectively.
Effects of tannin and monensin supplementation on growth performance, energetic efficiency, and carcass characteristics were evaluated in Holstein and Angusâ ×â Holstein steers. The investigation used a factorial design to access the impacts of both feed additives and breed on the study's parameters. Tannin supplementation did not affect growth performance. There were no dietary treatment effects on overall steer growth performance. Calf Holstein steers were fed with grain diet based. Holstein steers had greater overall DM intake than Angusâ ×â Holstein steers, but breed did not affect average daily gain. Thus, gain efficiency was greater for Angusâ ×â Holstein vs Holstein steers. There was no effect of dietary treatment on carcass measures. Compared with Holsteins, Angusâ ×â Holstein steers had greater carcass weight, dressing percentage, internal and external fat, longissimus area, and marbling score than Holstein steers. The current study suggests that monensin and tannin supplementation did not affect overall steer growth performance and carcass characteristics. Compared with Holsteins, crossbred Angusâ ×â Holstein steers had increased growth performance and carcass quality measures.
Subject(s)
Monensin , Tannins , Animals , Cattle , Animal Feed/analysis , Diet/veterinary , Dietary Supplements , Monensin/pharmacology , Plant Breeding , Tannins/pharmacologyABSTRACT
Allicin is a sulfur-containing compound extracted from raw garlic (Allium sativum L.). We compared the effect of allicin addition on growth performance, serum biochemical parameters, and rumen microbiota of goats compared to monensin. Twenty-four Anhui white goats were assigned randomly to one of three dietary treatments: 1) a basal diet (CON); 2) the basal diet with allicin addition at 750 mg per head per day (AC); 3) the basal diet with monensin addition at 30 mg per kg of diet (MS). Animals were fed for 8 weeks. Results showed the average daily gain, and feed efficiency was increased with allicin and monensin addition. Serum levels of IgG, total superoxide dismutase, and glutathione peroxidase were higher in the AC group than those in the CON and MS groups. The microbiota analysis revealed that monensin addition mainly affected genera related to carbohydrate and protein metabolism, and allicin mainly affected genera related to energy metabolism and intestinal health. In conclusion, allicin could improve growth performance and have advantages over monensin in improving the antioxidant capacity and immune function of goats. Allicin may be a potential alternative to monensin.
Subject(s)
Disulfides , Garlic , Microbiota , Sulfinic Acids , Animals , Animal Feed/analysis , Antioxidants/metabolism , Diet/veterinary , Dietary Supplements/analysis , Goats/metabolism , Monensin/pharmacology , Rumen/metabolismABSTRACT
The objective of this study was to evaluate the effects of supplementing monensin (19.8 g/Mg DM TMR; MON) and Saccharomyces cerevisiae CNCM I-1077 live-cell yeasts (Saccharomyces cerevisiae CNCM I-1077; 1 × 1010 cfu/head per day; LCY) on lactation performance, feeding behavior, and total-tract nutrient digestibility of high-producing dairy cows. Sixty-four multiparous Holstein cows (3.2 ± 1.5 lactations; 97 ± 16 DIM, and 724 ± 68 kg of BW at covariate period initiation) and 32 gate feeders were enrolled in a study with a completely randomized design and a 2 × 2 factorial arrangement. Cows and gate feeders were randomly assigned to treatments (16 cows and 8 gate feeders per treatment). Cows were allowed 2 wk to acclimate to feeding gates followed by a 2-wk covariate period. During the acclimation and covariate periods, all cows were fed a diet containing MON and LCY. Following the covariate period, cows were enrolled in a 10-wk treatment period during which cows were randomly assigned to 1 of 4 treatments: (1) a combination of MON and LCY (MON-LCY), (2) MON-CON, (3) CON-LCY, or (4) neither MON nor LCY (CON-CON). Data were analyzed using a mixed model with week as a repeated measure and fixed effects of MON, LCY, week, and all their interactions. Cow (treatment) was included as a random effect. The average covariate period value of each variable was used as a covariate. Three-way interactions were observed for DMI and feed efficiency. Dry matter intake decreased from wk 4 to 5 and wk 8 to 10 in MON-LCY cows compared with CON-CON. No treatment differences were observed for actual or component-corrected milk yield or milk components, except for a tendency for LCY to decrease milk fat yield. Feed efficiency was greater for MON-LCY relative to CON-CON in 4 of 10 wk. Interactions between MON and LCY were observed for dry matter and organic matter digestibility, where both were lower for CON-CON than other treatments. Under the conditions of the present study, feeding dairy cows in a high feed bunk density a combination of MON and LCY can decrease intake and improve feed efficiency without affecting milk production or components. Additionally, monensin and live-cell yeasts may each improve total-tract digestibility based on improvements in DM and OM digestibility.
Subject(s)
Animal Feed , Diet , Dietary Supplements , Digestion , Feeding Behavior , Lactation , Milk , Monensin , Animals , Cattle , Female , Monensin/pharmacology , Digestion/drug effects , Diet/veterinary , Milk/metabolism , Milk/chemistry , Saccharomyces cerevisiaeABSTRACT
Ionophores are antibacterial compounds that affect bacterial growth by changing intracellular concentrations of the essential cations, sodium and potassium. They are extensively used in animal husbandry to increase productivity and reduce infectious diseases, but our understanding of the potential for and effects of resistance development to ionophores is poorly known. Thus, given their widespread global usage, it is important to determine the potential negative consequences of ionophore use on human and animal health. In this study, we demonstrate that exposure to the ionophore monensin can select for resistant mutants in the human and animal pathogen Staphylococcus aureus, with a majority of the resistant mutants showing increased growth rates in vitro and/or in mice. Whole-genome sequencing and proteomic analysis of the resistant mutants show that the resistance phenotype is associated with de-repression of de novo purine synthesis, which could be achieved through mutations in different transcriptional regulators including mutations in the gene purR, the repressor of the purine de novo synthesis pathway. This study shows that mutants with reduced susceptibility to the ionophore monensin can be readily selected and highlights an unexplored link between ionophore resistance, purine metabolism, and fitness in pathogenic bacteria.IMPORTANCEThis study demonstrates a novel link between ionophore resistance, purine metabolism, and virulence/fitness in the key human and animal pathogen Staphylococcus aureus. The results show that mutants with reduced susceptibility to the commonly used ionophore monensin can be readily selected and that the reduced susceptibility observed is associated with an increased expression of the de novo purine synthesis pathway. This study increases our understanding of the impact of the use of animal feed additives on both human and veterinary medicine.
Subject(s)
Monensin , Staphylococcal Infections , Humans , Animals , Mice , Monensin/pharmacology , Virulence , Staphylococcus aureus , Proteomics , Staphylococcal Infections/veterinary , Staphylococcal Infections/microbiology , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/metabolism , Ionophores/pharmacology , Ionophores/metabolism , PurinesABSTRACT
Since the US Food and Drug Administration's approval of monensin in 2004, significant nutritional advances have been made to increase feed efficiency and milk fat production. Recent evidence suggests monensin's adverse effect on milk fat percentage may be absent when diets are formulated to address known diet-induced milk fat depression risk factors. Thus, study objectives were to evaluate effects of monensin level on dry matter intake (DMI), milk production and composition, and efficiency of high-producing cows fed diets formulated to optimize milk fat. Ninety-six lactating Holstein cows (36 primiparous, 60 multiparous; 106 ± 17 d in milk [DIM]) were balanced by parity, DIM, and milk production and were randomly assigned to 1 of 12 pens with 8 cows per pen. All cows received 11 g/t monensin for 5 wk after which pens received 1 of 4 dietary treatments (n = 3) formulated to provide 0 (CON), 11 (R11), 14.5 (R14.5), or 18 (R18) g/t monensin for 9 wk. The basal diet was 54% forage, 27% NDF, 29% starch, and 2.3% rumen unsaturated fatty acid load. Pen was the experimental unit and data were analyzed using the Fit Model Procedure of JMP. Effects of treatment, time, and treatment × time interaction were included as fixed effects and pen as a random effect. Least squares means were determined and linear and quadratic contrasts were tested. Dry matter intake tended to decrease linearly with increasing monensin dose. Milk yield, fat percentage, and protein percentage and yield were unaffected by treatment while fat yield was quadratically increased. Milk de novo and mixed fatty acid (FA) yields (g/d) increased quadratically with monensin whereas preformed FA linearly decreased during the experimental period. Energy-corrected milk (ECM) was quadratically increased by monensin. Milk urea nitrogen concentrations increased linearly with increasing monensin dose. Monensin linearly increased feed efficiency (ECM/DMI, 3.5% fat-corrected milk/DMI, and solids-corrected milk/DMI). Body weight gain did not differ between treatments. Estimated dietary energy tended to increase linearly with increasing monensin level. These data suggest monensin improves component-corrected milk production efficiency, estimated dietary energy, and does not negatively affect milk fat percentage or FA profile.
Subject(s)
Milk , Monensin , Female , Pregnancy , Cattle , Animals , Monensin/pharmacology , Lactation , Diet/veterinary , Energy Intake , Fatty Acids , Rumen , Animal Feed , Dietary Supplements , DigestionABSTRACT
The objective of this study was to evaluate the effects of cashew nut shell extract (CNSE) and monensin on ruminal in vitro fermentation, CH4 production, and ruminal bacterial community structure. Treatments were as follows: control (CON, basal diet without additives); 2.5 µM monensin (MON); 0.1 mg CNSE granule/g DM (CNSE100); and 0.2 mg CNSE granule/g DM (CNSE200). Each treatment was incubated with 52 mL of buffered ruminal content and 500 mg of total mixed ration for 24 h using serum vials. The experiment was performed as a complete randomized block design with 3 runs. Run was used as a blocking factor. Each treatment had 5 replicates, in which 2 were used to determine nutrient degradability, and 3 were used to determine pH, NH3-N, volatile fatty acids, lactate, total gas, CH4 production, and bacterial community composition. Treatment responses for all data, excluding bacterial abundance, were analyzed with the GLIMMIX procedure of SAS v9.4. Treatment responses for bacterial community structure were analyzed with a PERMANOVA test run with the R package vegan. Orthogonal contrasts were used to test the effects of (1) additive inclusion (ADD: CON vs. MON, CNSE100, and CNSE200); (2) additive type (MCN: MON vs. CNSE100 and CNSE200); and (3) CNSE dose (DOS: CNSE100 vs. CNSE200). We observed that pH, acetate, and acetate:propionate ratio in the CNSE100 treatment were lower compared with CNSE200, and propionate in the CNSE100 treatment was greater compared with CNSE200. Compared with MON, CNSE treatments tended to decrease total lactate concentration. Total gas production of CON was greater by 2.63% compared with all treatments, and total CH4 production was reduced by 10.64% in both CNSE treatments compared with MON. Also, compared with MON, in vitro dry matter degradabilities in CNSE treatments were lower. No effects were observed for NH3-N or in vitro neutral detergent fiber degradability. Finally, the relative abundances of Prevotella, Treponema, and Schwartzia were lower, whereas the relative abundances of Butyrivibrio and Succinivibrio were greater in all treatments compared with CON. Overall, the inclusion of CNSE decreased CH4 production compared with MON, making CNSE a possible CH4 mitigation additive in dairy cattle diets.
Subject(s)
Anacardium , Monensin , Cattle , Female , Animals , Monensin/pharmacology , Monensin/metabolism , Lactation , Propionates/metabolism , Fermentation , Nuts , Digestion , Diet/veterinary , Bacteria , Acetates/pharmacology , Methane/metabolism , Lactates/metabolism , Plant Extracts/pharmacology , Rumen/metabolism , Animal Feed/analysisABSTRACT
1. The following study was conducted to evaluate the influence of coccidiosis vaccine-induced metabolic stress on the utilisation of minerals in broilers. The starter, grower and finisher phase diets, including macro- and micro minerals at the recommended levels for the breed standards, were fed to chickens between 1 and 39 d of age.2. A total of 486, one-d-old male broilers were randomly distributed into three coccidiosis management programs (CMP) with six replications each. The CMP comprised: monensin sodium (MON), coccidiosis vaccine (VAC), not treated with MON or VAC (CNT).3. No significant differences between CMP were observed for body weight and weight gain among treatments. When compared to the CNT, the VAC program increased feed intake (P < 0.05) between d 1 to 13 and 14 to 26, while FCR worsened in the latter (P < 0.05) and the former (P = 0.05) periods.4. For birds in the MON and VAC programs, tibia bone length at d 13 and bone diameter at d 39 were both enhanced (P < 0.05). Meat yield characteristics were comparable among the CMP.5. Faeces of VAC birds had a lower (P < 0.05) dry matter and ash content than those in CNT program. CMP had no effect on serum or bone mineral concentrations at any point in time. For minerals, Mg, Na, and K faecal excretion was reduced (P < 0.01) as a result of the VAC program at d 13 with a trend at d 26.6. Compared to the CNT, the VAC program decreased the percentage ratio of drip loss (P = 0.08), water holding capacity (P < 0.01) and cooking loss (P < 0.01) in breast meat.7. Overall, the results showed that current broiler industry practices are capable of meeting the mineral needs of broilers vaccinated against coccidiosis.
Subject(s)
Coccidiosis , Poultry Diseases , Male , Animals , Chickens , Vaccines, Attenuated , Monensin/pharmacology , Minerals , Coccidiosis/prevention & control , Coccidiosis/veterinary , Diet/veterinary , Animal Feed , Dietary Supplements , Poultry Diseases/prevention & controlABSTRACT
A small molecule screen identified several cardiotonic steroids (digitoxin and ouabain) and the ionophore monensin as potent inhibitors of HCoV-229E, HCoV-OC43, and SARS-CoV-2 replication with EC50s in the low nM range. Subsequent tests confirmed antiviral activity in primary cell models including human nasal epithelial cells and lung organoids. Addition of digitoxin, ouabain, or monensin strongly reduced viral gene expression as measured by both viral protein and RNA accumulation. Furthermore, the compounds acted post virus entry. While the antiviral activity of digitoxin was dependent upon activation of the MEK and JNK signaling pathways but not signaling through GPCRs, the antiviral effect of monensin was reversed upon inhibition of several signaling pathways. Together, the data demonstrates the potent anti-coronavirus properties of two classes of FDA approved drugs that function by altering the properties of the infected cell, rendering it unable to support virus replication.
Subject(s)
Cardiac Glycosides , Coronavirus 229E, Human , Humans , Cardiac Glycosides/pharmacology , Monensin/pharmacology , Ouabain/pharmacology , Digitoxin/pharmacology , Antiviral Agents/pharmacologyABSTRACT
The effects of a novel direct-fed microbial (DFM) on feedlot performance, carcass characteristics, digestibility, ruminal morphology, and volatile fatty acid (VFA) profile of finishing steers were evaluated. Single-source Angus-crossbred yearling steers (nâ =â 144; initial body weight (BW)â =â 371â ±â 19 kg) were used in a randomized complete block design. Steers were blocked by initial BW and randomly assigned to treatments (12 pens/treatment; 4 steers/pen). Treatments included (A) CONTROL (no DFM, tylosin, or monensin, (B) MONTY (monensin sodium [330 mg/animal-daily] and tylosin phosphate [90 mg/animal-daily]), and (C) MONPRO (monensin sodium [same as previous] and Lactobacillus salivarius L28 [1â ×â 106 CFU/animal-daily]). Treatments were included in a steam-flaked corn-based finisher diet offered once daily using a clean-bunk management for ~149 d. The digestibility assessment was performed from days 70 to 74. Ruminal fluid and rumen tissue samples were collected at the slaughter for VFA profile and papillae morphology analyses, respectively. Data were analyzed using the GLIMMIX procedure of SAS with pen serving as the experimental unit, treatment as fixed effect, and BW block as random effect. Steers offered MONPRO had on average 5.3% less (Pâ <â 0.01) dry matter intake (9.56 kg/d) compared with either CONTROL (10.16 kg/d) or MONTY (9.96 kg/d). The carcass-adjusted final BW (613 kg; Pâ =â 0.23), overall average daily gain (1.64 kg/d; Pâ =â 0.23), and gain-efficiency (0.165; Pâ =â 0.61) were not affected by treatments. Steers offered CONTROL had greater (Pâ <â 0.01) marbling score and tended (Pâ =â 0.06) to have less carcasses grading Select and tended (Pâ =â 0.10) to have more carcasses grading Upper-Choice, while other carcass characteristics and liver-abscesses were not affected (Pâ ≥â 0.23) by treatments. The digestibility of nutrients (Pâ ≥â 0.13) and the ruminal VFA profile (Pâ ≥â 0.12) were not affected by treatments. Steers offered MONPRO tended (Pâ =â 0.09) to have 16% greater average papillae number compared to other treatments. Yearlings offered finishing diets containing L. salivarius L28 plus monensin did not affect growth performance, digestibility, or ruminal VFA, but reduced feed intake. Carcass quality was negatively affected by treatments, while animals consuming L. salivarius L28 and monensin tended to improve ruminal morphology. Current findings in ruminal morphology and feed intake may warrant further assessment of diets containing L. salivarius L28 on beef cattle food safety aspects.
Antimicrobial resistance is a growing concern to public health and medically important antibiotics have been listed in the Veterinary Feed Directive. Nutritional technologies, such as direct-fed microbials, are being increasingly studied for the development of an effective use on beef cattle production systems. The newly isolated strain of Lactobacillus salivarius L28 has demonstrated pathogenic inhibition of Escherichia coli, Salmonella, and Listeria monocytogenes on in vitro assessments. The potential benefits have warranted the exploration of L. salivarius L28 in a feedlot setting. Single-source Angus-crossbred yearling steers were offered steam-flaked corn-based finishing diets containing no feed additive, or either a combination of tylosin plus monensin or L. salivarius L28 plus monensin. Steers offered L. salivarius L28 plus monensin consumed 5.3% less feed compared with other treatments, while other growth performance variables and the digestibility of nutrients were not affected. Carcasses from cattle supplemented with monensin had slightly lower carcass quality grades than those not supplemented with monensin. Lactobacillus salivarius L28 plus monensin tended to improve steers ruminal morphology. Current findings may warrant further food safety assessments when cattle are offered diets containing L. salivarius L28.
Subject(s)
Monensin , Tylosin , Cattle , Animals , Monensin/pharmacology , Tylosin/pharmacology , Diet/veterinary , Eating , Body Weight , Nutrients , Animal Feed/analysis , DigestionABSTRACT
The emerging viruses SARS-CoV-2 and arenaviruses cause severe respiratory and hemorrhagic diseases, respectively. The production of infectious particles of both viruses and virus spread in tissues requires cleavage of surface glycoproteins (GPs) by host proprotein convertases (PCs). SARS-CoV-2 and arenaviruses rely on GP cleavage by PCs furin and subtilisin kexin isozyme-1/site-1 protease (SKI-1/S1P), respectively. We report improved luciferase-based reporter cell lines, named luminescent inducible proprotein convertase reporter cells that we employ to monitor PC activity in its authentic subcellular compartment. Using these sensor lines we screened a small compound library in high-throughput manner. We identified 23 FDA-approved small molecules, among them monensin which displayed broad activity against furin and SKI-1/S1P. Monensin inhibited arenaviruses and SARS-CoV-2 in a dose-dependent manner. We observed a strong reduction in infectious particle release upon monensin treatment with little effect on released genome copies. This was reflected by inhibition of SARS-CoV-2 spike processing suggesting the release of immature particles. In a proof of concept experiment using human precision cut lung slices, monensin potently inhibited SARS-CoV-2 infection, evidenced by reduced infectious particle release. We propose that our PC sensor pipeline is a suitable tool to identify broad-spectrum antivirals with therapeutic potential to combat current and future emerging viruses.
Subject(s)
Arenavirus , Furin , Humans , Furin/metabolism , Viral Envelope Proteins/genetics , Monensin/metabolism , Monensin/pharmacology , Arenavirus/genetics , Arenavirus/metabolism , Antiviral Agents/therapeutic useABSTRACT
Sodium monensin is the most frequently used ionophore as a growth promoter in ruminant diets. It has numerous benefits; however its toxic effects have also been observed in several animal species. Naturally occurring cases have not yet been reported in goats. This study describes an outbreak of accidental poisoning, characterizing its clinical, laboratory and pathological findings. Thirty-seven of 40 Anglo Nubian goat kids became intoxicated after receiving a diet that was erroneously supplemented with sodium monensin. They ingested an estimated toxic dose between 25 and 39 mg/kg BW. Clinical evolution was monitored (n = 27), followed by serum creatine kinase (CK) and aspartate aminotransferase (AST) activities measurements, and blood gas analysis. Postmortem examinations were performed between 1 and 8 days of evolution (n = 14). Clinical signs began 5 h after ingestion and included reticuloruminal hypomotility, lethargy, anorexia, tachycardia, cardiac arrhythmia, wet cough, pulmonary and tracheal crackles, and serous nasal discharge. The morbidity and lethality rates were 92.5 and 62.1%, respectively. CK and AST activities increased, reaching median values of 10,860 and 1596 U/L, respectively; the hyperchloremic metabolic acidosis was mild. The lesions were characterized by degeneration and necrosis of the cardiac and skeletal muscles, pulmonary congestion and edema, and passive liver congestion. The kids essentially developed cardiomyopathy with left and right congestive heart failures. Unlike in other ruminant species, skeletal muscle functional disability was infrequent. It can be concluded that monensin is toxic to goats and should be used with caution in their diet.
Subject(s)
Goats , Monensin , Animals , Monensin/pharmacology , Heart , Muscle, Skeletal/pathology , Sodium/pharmacologyABSTRACT
The objective of this study was to compare cashew nutshell extract (CNSE) to monensin and evaluate changes in in vitro mixed ruminal microorganism fermentation, nutrient digestibility, and microbial nitrogen outflow. Treatments were randomly assigned to 8 fermenters in a replicated 4 × 4 Latin square design with 4 experimental periods of 10 d (7 d for diet adaptation and 3 d for sample collection). Basal diets contained 43.5:56.5 forage: concentrate ratio and each fermenter was fed 106 g of DM/d divided equally between 2 feeding times. Treatments were control (CON, basal diet without additives), 2.5 µM monensin (MON), 0.1 mg CNSE granule/g DM (CNSE100), and 0.2 mg CNSE granule/g DM (CNSE200). On d 8 to10, samples were collected for pH, lactate, NH3-N, volatile fatty acids (VFA), mixed protozoa counts, organic matter (OM), and neutral detergent fiber (NDF) digestibility. Data were analyzed with the GLIMMIX procedure of SAS. Orthogonal contrasts were used to test the effects of (1) ADD (CON vs. MON, CNSE100, and CNSE200); (2) MCN (MON vs. CNSE100 and CNSE200); and (3) DOSE (CNSE100 vs. CNSE200). We observed that butyrate concentration in all treatments was lower compared with CON and the concentration for MON was lower compared with CNSE treatments. Protozoal population in all treatments was lower compared with CON. No effects were observed for pH, lactate, NH3-N, total VFA, OM, or N utilization. Within the 24-h pool, protozoal generation time, tended to be lower, while NDF digestibility tended to be greater in response to all additives. Furthermore, the microbial N flow, and the efficiency of N use tended to be lower for the monensin treatment compared with CNSE treatments. Overall, our results showed that both monensin and CNSE decreased butyrate synthesis and protozoal populations, while not affecting OM digestibility and tended to increase NDF digestibility; however, such effects are greater with monensin than CNSE nutshell.
Subject(s)
Anacardium , Monensin , Animals , Monensin/pharmacology , Monensin/metabolism , Fermentation , Rumen/metabolism , Digestion , Diet , Fatty Acids, Volatile/metabolism , Butyrates/metabolism , Lactates/metabolism , Animal Feed/analysisABSTRACT
BACKGROUND: Grazing in arid and semi-arid regions faces pregnant ewes with feed restrictions and hence affects the offspring muscle fibre characteristics. Using feed additives that enhance nutrient availability during foetal muscle development is expected to alter offspring skeletal muscle characteristics. OBJECTIVES: This study evaluated the effect of maternal restricted nutrition and supplementation of propylene glycol, monensin sodium and rumen-protected choline chloride on lamb's muscle fibre characteristics. METHODS: Forty-eight Ghezel ewes were randomly allocated to one of six diets (N = 8) during the last 6 weeks of gestation: ad libitum feed intake (AL); restricted feeding (RF); restricted feeding containing propylene glycol (PG); restricted feeding containing propylene glycol and monensin sodium (MS); restricted feeding containing propylene glycol and rumen-protected choline chloride (RPC); restricted feeding containing propylene glycol, monensin sodium and rumen-protected choline chloride (PMC). The muscle samples were obtained from the semitendinosus muscle of 2-week-old male lambs (n = 5/treatment) via biopsy and were stained and classified as fibre types I, IIA and IIB. RESULTS: Pre-parturient maternal feed restriction and administration of propylene glycol, monensin sodium and rumen-protected choline chloride had no significant effect on fibre-type composition, fibre density of muscle, muscle cross-sectional area and volume density of fibres (p > 0.05). CONCLUSIONS: Either maternal dietary restriction or supplementation of nutrient flux-involved additives during late pregnancy did not alter muscle fibre development and had no short-term effects on muscle properties of the resulting offspring as myogenesis occurs in early and mid-gestation, not late gestation. Therefore, maternal nutrition may not be a problematic issue in sheep production in arid and semi-arid areas.
Subject(s)
Choline , Monensin , Pregnancy , Animals , Sheep , Female , Male , Monensin/pharmacology , Choline/pharmacology , Rumen , Propylene Glycol , Muscle Fibers, Skeletal , Dietary SupplementsABSTRACT
BACKGROUND: Eosinophils contribute to the pathology of several types of disorders, in particular of allergic nature, and strategies to limit their actions are therefore warranted. OBJECTIVE: We sought to evaluate the possibility of targeting the acidic, lysosome-like eosinophil granules as a potential means of inducing eosinophil cell death. METHODS: To this end, we used monensin, an ionophoric drug that has previously been shown to permeabilize the secretory granules of mast cells, thereby inducing cell death. RESULTS: Our findings reveal that monensin induces cell death in human eosinophils, whereas neutrophils were less affected. Blockade of granule acidification reduced the effect of monensin on the eosinophils, demonstrating that granule acidity is an important factor in the mechanism of cell death. Furthermore, monensin caused an elevation of the granule pH, which was accompanied by a decrease of the cytosolic pH, hence indicating that monensin caused leakage of acidic contents from the granules into the cytosol. In agreement with a granule-targeting mechanism, transmission electron microscopy analysis revealed that monensin caused extensive morphological alterations of the eosinophil granules, as manifested by a marked loss of electron density. Eosinophil cell death in response to monensin was caspase-independent, but dependent on granzyme B, a pro-apoptotic serine protease known to be expressed by eosinophils. CONCLUSIONS: We conclude that monensin causes cell death of human eosinophils through a granule-mediated mechanism dependent on granzyme B.
Subject(s)
Eosinophils , Monensin , Humans , Monensin/pharmacology , Monensin/metabolism , Granzymes/metabolism , Granzymes/pharmacology , Secretory Vesicles/metabolism , Cytoplasmic GranulesABSTRACT
AIM: The aim of this study was to investigate the in vitro dose-dependent effects of sigla storax (Styrax liquidus) on rumen microbiota and rumen microbial fermentation in comparison to monensin as a positive control. METHODS AND RESULTS: This study was carried out using a rumen simulation model (Rusitec). Treatments consisted of no additive (control), 10 mg l-1 of monensin sodium salt, 100 mg l-1 (Low-Sigla), and 500 mg l-1 (High-Sigla) of sigla storax (n = 6/treatment). In addition to rumen fermentation characteristics, rumen microbial composition was investigated using 16S rRNA sequencing. The methane variables and the acetate to propionate ratio decreased in the both High-Sigla and monensin groups (P < 0.05). High-Sigla had no effect on ammonia, total SCFA and nutrition degradation, while monensin decreased these parameters (P < 0.05). Unlike monensin, the sigla storax treatments did not affect the alpha or beta diversity indexes of the microbiota. The relative abundance of Methanomethylophilaceae and Ruminococcaceae decreased with High-Sigla and monensin (P < 0.05), and Atopobiaceae and Eggerthellaceae decreased with the both doses of sigla storax as well as monensin treatments (P < 0.05). Syntrophococcus, DNF00809, and Kandleria were among the genera that most decreased with High-Sigla and monensin (Q < 0.07) and were strongly positively correlated with methane production (r = 0.52-0.56). CONCLUSIONS: The high dose of sigla storax (500 mg l-1) decreased methane in the rumen ecosystem without adverse effects on nutrient degradation and SCFA production, and without dramatically impacting the microbial composition. Sigla storax might be a novel feed additive to mitigate methane in cattle.
Subject(s)
Liquidambar , Microbiota , Animals , Cattle , Monensin/pharmacology , Monensin/metabolism , Fermentation , Liquidambar/metabolism , Rumen/metabolism , RNA, Ribosomal, 16S/genetics , RNA, Ribosomal, 16S/metabolism , Styrax/metabolism , Methane/metabolism , Nutrients , Diet/veterinary , Animal FeedABSTRACT
Monensin is an ionophore antibiotic that inhibits the growth of cancer cells. The aim of this study was to investigate the apoptosis-mediated anticarcinogenic effects of monensin in SH-SY5Y neuroblastoma cells. The effects of monensin on cell viability, invasion, migration, and colony formation were determined by XTT, matrigel-chamber, wound healing, and colony formation tests, respectively. The effects of monensin on apoptosis were determined by real-time polymerase chain reaction, TUNEL, Western blot, and Annexin V assay. We have shown that monensin suppresses neuroblastoma cell viability, invasion, migration, and colony formation. Moreover, we reported that monensin inhibits cell viability by triggering apoptosis of neuroblastoma cells. Monensin caused apoptosis by increasing caspase-3, 7, 8, and 9 expressions and decreasing Bax and Bcl-2 expressions in neuroblastoma cells. In Annexin V results, the rates of apoptotic cells were found to be 9.66 ± 0.01% (p < 0.001), 29.28 ± 0.88% (p < 0.01), and 62.55 ± 2.36% (p < 0.01) in the 8, 16, and 32 µM monensin groups, respectively. In TUNEL results, these values were, respectively; 35 ± 2% (p < 0.001), 34 ± 0.57% (p < 0.001), and 75 ± 2.51% (p < 0.001). Our results suggest that monensin may be a safe and effective therapeutic candidate for treating pediatric neuroblastoma.
Subject(s)
Neuroblastoma , Humans , Child , Neuroblastoma/drug therapy , Monensin/pharmacology , Monensin/therapeutic use , Annexin A5/pharmacology , Annexin A5/therapeutic use , Apoptosis , Cell Line, Tumor , Cell ProliferationABSTRACT
The aim of the present experiment was to evaluate the effect of feeding a newly produced bacteriocin-like substance (BLS) as a replacement for monensin in the diets of lactating ewes. In Experiment 1, the effects of BLS or monensin at 0.5, 1, 1.5, and 2 g/kg diet on in vitro ruminal fermentation were compared. In Experiment 2, 30 multiparous Barki ewes were divided into three treatments in a complete randomized design for 90 days. The ewes were fed a basal diet without supplementation or supplemented with monensin or BLS at 0.5 g/kg DM diet. In Experiment 1, the highest levels of BLS and monensin decreased gas production, while all levels of additives linearly decreased methane production. In Experiment 2, BLS increased nutrient digestibility. Additives increased ruminal total and individual volatile fatty acids and decreased ruminal ammonia-N. The BLS increased serum albumin and decreased the concentrations of serum liver enzymes, while both additives increased serum glucose and decreased urea-N. Additives increased daily production of milk, while the BLS treatment increased the feed efficiency. It is concluded that dietary inclusion of BLS at 0.5 g/kg DM for lactating ewes is recommended to replace monensin.
Subject(s)
Lactation , Monensin , Animals , Female , Sheep , Monensin/pharmacology , Digestion , Rumen/metabolism , Diet/veterinary , Milk , Fermentation , Animal Feed/analysisABSTRACT
The emergence of SARS-CoV-2 and its variants have posed a significant threat to humankind in tackling the viral spread. Furthermore, currently repurposed drugs and frontline antiviral agents have failed to cure severe ongoing infections effectively. This insufficiency has fuelled research for potent and safe therapeutic agents to treat COVID-19. Nonetheless, various vaccine candidates have displayed a differential efficacy and need for repetitive dosing. The FDA-approved polyether ionophore veterinary antibiotic for treating coccidiosis has been repurposed for treating SARS-CoV-2 infection (as shown by both in vitro and in vivo studies) and other deadly human viruses. Based on selectivity index values, ionophores display therapeutic effects at sub-nanomolar concentrations and exhibit selective killing ability. They act on different viral targets (structural and non-structural proteins), host-cell components leading to SARS-CoV-2 inhibition, and their activity is further enhanced by Zn2+ supplementation. This review summarizes the anti-SARS-CoV-2 potential and molecular viral targets of selective ionophores like monensin, salinomycin, maduramicin, CP-80,219, nanchangmycin, narasin, X-206 and valinomycin. Ionophore combinations with Zn2+ are a new therapeutic strategy that warrants further investigation for possible human benefits.