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Haematologica Jun 2022Sickle cell disease (SCD) is characterized by sickle hemoglobin (HbS) which polymerizes under deoxygenated conditions to form a stiff, sickled erythrocyte. The...
Sickle cell disease (SCD) is characterized by sickle hemoglobin (HbS) which polymerizes under deoxygenated conditions to form a stiff, sickled erythrocyte. The dehydration of sickle erythrocytes increases intracellular HbS concentration and the propensity of erythrocyte sickling. Prevention of this mechanism may provide a target for potential SCD therapy investigation. Ionophores such as monensin can increase erythrocyte sodium permeability by facilitating its transmembrane transport, leading to osmotic swelling of the erythrocyte and decreased hemoglobin concentration. In this study, we treated 13 blood samples from patients with SCD with 10 nM of monensin ex vivo. We measured changes in cell volume and hemoglobin concentration in response to monensin treatment, and we perfused treated blood samples through a microfluidic device that permits quantification of blood flow under controlled hypoxia. Monensin treatment led to increases in cell volume and reductions in hemoglobin concentration in most blood samples, though the degree of response varied across samples. Monensin-treated samples also demonstrated reduced blood flow impairment under hypoxic conditions relative to untreated controls. Moreover, there was a significant correlation between the improvement in blood flow and the decrease in hemoglobin concentration. Thus, our results demonstrate that a reduction in intracellular HbS concentration by osmotic swelling improves blood flow under hypoxic conditions. Although the toxicity of monensin will likely prevent it from being a viable clinical treatment, these results suggest that osmotic swelling should be investigated further as a potential mechanism for SCD therapy.
Topics: Anemia, Sickle Cell; Erythrocytes; Hemoglobin, Sickle; Humans; Hypoxia; Ionophores; Monensin
PubMed: 34706495
DOI: 10.3324/haematol.2021.278666 -
Journal of Dairy Science Sep 2021This work examined the effects of precalving administration of continuous-release monensin capsule on postcalving milk fatty acid (FA) profile and on the accuracy of FA...
Effect of monensin on milk fatty acid profile in dairy cows and on the use of fatty acids for early diagnosis of elevated blood plasma concentrations of nonesterified fatty acids and hyperketonemia.
This work examined the effects of precalving administration of continuous-release monensin capsule on postcalving milk fatty acid (FA) profile and on the accuracy of FA as a biomarker in the early identification of cows with elevated blood plasma nonesterified fatty acids (NEFA) and β-hydroxybutyrate (BHB) concentrations. Approximately 3 wk before expected calving, 203 multiparous Estonian Holstein cows were randomly divided into control (CO; n = 116) and experimental (MO; n = 87) groups, and a continuous-release capsule of monensin was administered to the MO cows. Blood samples were taken daily in the first 4 d postpartum, then on the sixth or seventh day in milk, twice in the second week, and thenceforth once per week until the end of the sixth week. Milk samples were taken once from 4 to 7 d in milk, twice in the second week, and thenceforth once per week. Blood samples were analyzed for NEFA and BHB, and milk was analyzed for FA concentrations. Cows with postpartum BHB concentrations ≥1.2 mmol/L at least once during the 6 wk were classified as hyperketonemic (HYK), and cows with NEFA concentrations ≥1.0 mmol/L as having elevated concentration of NEFA (NEFA). The ability of FA to predict NEFA and HYK cows was studied with logistic regression and receiver operating characteristic curve analysis and the identification accuracy was estimated by area under the receiver operating characteristic curve. For these analyses, we used FA measured on the ninth day after calving. Monensin administration affected FA mobilization and metabolism of the animals as blood NEFA were lower in the MO group on wk 1 and wk 3, and BHB values were considerably lower from wk 1 to wk 4 compared with the CO group. The FA dynamics were generally similar for MO and CO groups. Monensin administration resulted in higher concentrations of C15:0, C16:0, iso C17:0, anteiso C15:0, anteiso C17:0, total trans monounsaturated FA, and C18:2 cis-9,trans-11, and lower proportions of C18:0, C18:1 cis-9, and most of the iso FA. The identification accuracy of NEFA and HYK cows was higher in the CO compared with the MO group and for the identification of HYK compared with NEFA cows (0.75-0.77 vs. 0.78-0.80 in the CO group, and 0.61-0.66 vs. 0.68-0.75 in the MO group for NEFA vs. HYK, respectively). For all FA, the threshold values to identify NEFA and HYK cows were different in the CO and MO groups. Results suggest that specific threshold values for the identification of NEFA and HYK cows could be applicable only within similar feeding conditions and rumen environment.
Topics: 3-Hydroxybutyric Acid; Animals; Cattle; Early Diagnosis; Fatty Acids; Fatty Acids, Nonesterified; Female; Lactation; Milk; Monensin; Plasma; Postpartum Period
PubMed: 34147218
DOI: 10.3168/jds.2020-20041 -
Journal of Dairy Science Feb 2024The objective of this study was to evaluate the effects of cashew nut shell extract (CNSE) and monensin on ruminal in vitro fermentation, CH production, and ruminal...
The objective of this study was to evaluate the effects of cashew nut shell extract (CNSE) and monensin on ruminal in vitro fermentation, CH 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, NH-N, volatile fatty acids, lactate, total gas, CH 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 CH 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 NH-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 CH production compared with MON, making CNSE a possible CH mitigation additive in dairy cattle diets.
Topics: Cattle; Female; Animals; Monensin; Anacardium; Lactation; Propionates; Fermentation; Nuts; Digestion; Diet; Bacteria; Acetates; Methane; Lactates; Plant Extracts; Rumen; Animal Feed
PubMed: 37730175
DOI: 10.3168/jds.2023-23669 -
Journal of Dairy Science Mar 2021Our objectives were to evaluate the effects of prepartum monensin supplementation and dry-period nutritional strategy on the postpartum productive performance of cows...
Our objectives were to evaluate the effects of prepartum monensin supplementation and dry-period nutritional strategy on the postpartum productive performance of cows fed monensin during lactation. A total of 102 Holstein cows were enrolled in the experiment (32 primiparous and 70 multiparous). The study was a completely randomized design, with randomization restricted to balance for parity, body condition score, and expected calving date. A 2 × 2 factorial arrangement of prepartum treatments was used; the variables of interest were prepartum feeding strategy [controlled-energy diet throughout the dry period (CE) vs. controlled-energy diet from dry-off to 22 d before expected parturition, followed by a moderate-energy close-up diet from d 21 before expected parturition through parturition (CU)] and prepartum monensin supplementation [0 g/t (control, CON) or 24.2 g/t (MON); Rumensin; Elanco Animal Health, Greenfield, IN]. Lactation diets before and after the dry period contained monensin at 15.4 g/t. During the close-up period, cows fed CU had greater DM and NE intakes than cows fed CE. Calf BW at birth tended to be greater for cows fed CU than for those fed CE but was not affected by MON supplementation. Diet did not affect calving difficulty score, but cows supplemented with MON had an increased calving difficulty score. We found a tendency for a MON × parity interaction for colostral IgG concentration, such that multiparous MON cows tended to have lower IgG concentration than CON cows, but colostral IgG concentration for primiparous MON and CON cows did not differ. Postpartum milk yield did not differ between diets but tended to be greater for cows supplemented with MON. Milk fat and lactose content were greater for cows fed CU than for those fed CE, and lactose content and yield were increased for cows supplemented with MON. Solids-corrected and fat-corrected milk yields were increased by MON supplementation, but were not affected by diet. Overall means for postpartum DMI did not differ by diet or MON supplementation. The CU diet decreased the concentration of nonesterified fatty acids during the close-up period but increased it postpartum. Neither diet nor monensin affected β-hydroxybutyrate or liver composition. Overall, postpartum productive performance differed little between prepartum dietary strategies, but cows fed MON had greater energy-corrected milk production. In herds fed monensin during lactation, monensin should also be fed during the dry period.
Topics: Animals; Cattle; Diet; Dietary Supplements; Energy Metabolism; Female; Lactation; Milk; Monensin; Postpartum Period; Pregnancy
PubMed: 33358806
DOI: 10.3168/jds.2020-19414 -
The Journal of Allergy and Clinical... Nov 2023Eosinophils contribute to the pathology of several types of disorders, in particular of allergic nature, and strategies to limit their actions are therefore warranted.
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.
Topics: Humans; Eosinophils; Monensin; Granzymes; Secretory Vesicles; Cytoplasmic Granules
PubMed: 37536509
DOI: 10.1016/j.jaci.2023.07.012 -
Animal : An International Journal of... Apr 2023Feedlot diets are often enriched with additives to mitigate health disorders and promote cattle performance, including the feed-grade antimicrobials monensin and...
Feedlot diets are often enriched with additives to mitigate health disorders and promote cattle performance, including the feed-grade antimicrobials monensin and tylosin. However, alternative feeding strategies are warranted given the increasing regulations regarding the use of antimicrobials in feedlot diets. This study evaluated the performance, physiological, and health responses of feedlot cattle offered a synbiotic supplement (yeast-derived prebiotic + Bacillus subtilis probiotic), which replaced or was fed in conjunction with monensin and tylosin. Angus-influenced steers (n = 192) from four different cowherds were weaned on day -1 and transported (800 km) to the feedlot. Steers were allocated to 1 of 24 pens (eight steers/pen) upon arrival on day 0. Pens were assigned to receive (n = 8/treatment) a total-mixed ration (TMR) containing: (1) monensin and tylosin (RT; 360 mg/steer daily from Rumensin and 90 mg/steer daily from Tylan; Elanco Animal Health, Greenfield, IN, USA), (2) yeast-derived ingredient and B. subtilis probiotic (CC; 18 g/steer daily of Celmanax and 28 g/steer daily of Certillus; Church and Dwight Co., Inc., Princeton, NJ, USA), or (3) a combination of RT and CC (RTCC). Steers were slaughtered according to BW in four groups balanced by treatment and pens and received treatments for 252 ± 4 days. No treatment effects were detected (P ≥ 0.17) for steer BW gain and morbidity responses. Mean TMR intake was greater and gain:feed ratio was less (P ≤ 0.01) in CC compared with RT and RTCC steers. Mean plasma leptin concentration was greater (P ≤ 0.05) in CC compared with RT and RTCC steers. Steers receiving CC had greater (P ≤ 0.04) concentrations of plasma cortisol, haptoglobin, glucose, and beta-hydroxybutyrate, and less (P ≤ 0.05) concentration of non-esterified fatty acids compared with RT and RTCC steers on day 14 of the experiment. Carcass marbling was greater (P = 0.01) in CC compared with RT steers and tended to be greater (P = 0.07) in RTCC compared with RT steers. Proportion of carcasses that graded Choice or better and Longissimus muscle area were greater (P ≤ 0.05) in CC and RTCC compared with RT steers. Incidence of liver abscesses was less (P = 0.01) in RTCC compared with CC steers and tended to be less (P = 0.09) in RT compared with CC steers. Results from this experiment indicate that the synbiotic supplement may replace monensin and tylosin without reducing steer BW gain, with potential improvements to carcass quality traits.
Topics: Cattle; Animals; Tylosin; Monensin; Saccharomyces cerevisiae; Animal Feed; Diet; Probiotics; Anti-Infective Agents
PubMed: 37031589
DOI: 10.1016/j.animal.2023.100770 -
Journal of Dairy Science Apr 2017In response to oral application, monensin alters the rumen microbiota, increasing ruminal propionate production and energy availability in the animal. Data from...
In response to oral application, monensin alters the rumen microbiota, increasing ruminal propionate production and energy availability in the animal. Data from different studies indicate that the susceptibility of rumen bacteria to monensin is mainly cell-wall dependent but tracing its activity to specific microbial groups has been challenging. Several studies have shown a similar effect for essential oils but results are inconsistent. To investigate the influence of monensin and a blend of essential oils (BEO, containing thymol, guaiacol, eugenol, vanillin, salicylaldehyde, and limonene) on the rumen microbiome, rumen liquid samples were collected orally on d 56 postpartum from cows that had either received a monensin controlled-release capsule 3 wk antepartum, a diet containing a BEO from 3 wk antepartum onward, or a control diet (n = 12). The samples were analyzed for pH, volatile fatty acid, ammonia, and lipopolysaccharide concentrations and protozoal counts. A 16S rRNA gene fingerprinting analysis (PCR-single-strand conformation polymorphism) and sequencing revealed that the BEO treatment had no effect on the rumen microbiota, whereas monensin decreased bacterial diversity. Twenty-three bacterial species-level operational taxonomic units were identified for which monensin caused a significant decrease in their relative abundance, all belonging to the phyla Bacteroidetes (uncultured BS11 gut group and BS9 gut group) and Firmicutes (Lachnospiraceae, Ruminococcaceae, and Erysipelotrichaceae). Ten bacterial operational taxonomic units belonging to the phyla Actinobacteria (Coriobacteriaceae), Bacteroidetes (Prevotella), Cyanobacteria (SHA-109), and Firmicutes (Lachnospiraceae and Ruminococcaceae) increased in relative abundance due to the monensin treatment. These results confirm the hypothesis that varying effects depending on cell-wall constitution and thickness might apply for monensin sensitivity rather than a clear-cut difference between gram-negative and gram-positive bacteria. No effect of monensin on the archaea population was observed, confirming the assumption that reported inhibition of methanogenesis is most likely caused through a decrease in substrate availability, rather than by a direct effect on the methanogens. The data support the hypothesis that the observed increase in ruminal molar propionate proportions due to monensin may be caused by a decrease in abundance of non-producers and moderate producers of propionate and an increase in abundance of succinate and propionate producers.
Topics: Animals; Cattle; Diet; Female; Fermentation; Microbiota; Monensin; Oils, Volatile; RNA, Ribosomal, 16S; Rumen
PubMed: 28161182
DOI: 10.3168/jds.2016-11994 -
Parasites & Vectors Jul 2016African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the...
BACKGROUND
African trypanosomes are the causative agents of sleeping sickness in humans and nagana disease in livestock animals. As the few drugs available for treatment of the diseases have limited efficacy and produce adverse reactions, new and better tolerated therapies are required. Polyether ionophores have been shown to display anti-cancer, anti-microbial and anti-parasitic activity. In this study, derivatives of the polyether ionophores, salinomycin and monensin were tested for their in vitro activity against bloodstream forms of Trypanosoma brucei and human HL-60 cells.
RESULTS
Most polyether ionophore derivatives were less trypanocidal than their corresponding parent compounds. However, two salinomycin derivatives (salinomycin n-butyl amide and salinomycin 2,2,2-trifluoroethyl ester) were identified that showed increased anti-trypanosomal activity with 50 % growth inhibition values in the mid nanomolar range and minimum inhibitory concentrations of below 1 μM similar to suramin, a drug used in the treatment of sleeping sickness. In contrast, human HL-60 cells were considerably less sensitive towards all polyether ionophore derivatives. The cytotoxic to trypanocidal activity ratio (selectivity) of the two promising compounds was greater than 250.
CONCLUSIONS
The data indicate that polyether ionophore derivatives are interesting lead compounds for rational anti-trypanosomal drug development.
Topics: HL-60 Cells; Humans; Monensin; Parasitic Sensitivity Tests; Pyrans; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African
PubMed: 27457761
DOI: 10.1186/s13071-016-1698-8 -
Poultry Science Jun 1992Freshly excysted sporozoites (SZ) of the turkey coccidia Eimeria meleagrimitis and Eimeria adenoeides were incubated at 41 C in concentrations of monensin from .01 to...
Freshly excysted sporozoites (SZ) of the turkey coccidia Eimeria meleagrimitis and Eimeria adenoeides were incubated at 41 C in concentrations of monensin from .01 to 1.0 microgram/mL, washed free of the drug, and either processed for phase, fluorescence, and transmission electron microscopy or inoculated into cultures of turkey kidney cells. Phase microscopy indicated that after 1.5 h incubation in 1.0 micrograms/mL monensin, about 60% of the SZ of E. meleagrimitis had become notably rounded or displayed localized protrusions. These alterations were accompanied by ultrastructural abnormalities (in 90% of the SZ) including vacuoles in the cytoplasm, bulging and separation of plasma membrane layers, and dense bands in the refractile bodies that extended toward the periphery of the refractile body. Similar morphological and ultrastructural changes were observed in over half of the E. adenoeides SZ after 2 h incubation in 1.0 micrograms/mL monensin. Additionally, some specimens contained a pycnotic nucleus that was usually surrounded by a large vacuole. After 4 h incubation, almost all of the SZ displayed some degree of ultrastructural damage. Indirect fluorescent antibody labeling with parasite-specific monoclonal antibodies demonstrated clouds of antigen surrounding the monensin-treated but not the untreated SZ, suggesting an increase in permeability with incubation in monensin. With both E. meleagrimitis and E. adenoeides, the structural changes were reflected in a significant inhibition of cellular invasion. The inhibitory activity of monensin was concentration- and time-dependent in that the greatest inhibition of invasion was observed in SZ incubated for 4 h in 1.0 micrograms/mL of monensin; shorter incubation times or lower concentrations of monensin having less effect.
Topics: Animals; Cells, Cultured; Eimeria; Fluorescent Antibody Technique; Microscopy, Electron; Monensin; Turkeys
PubMed: 1614953
DOI: 10.3382/ps.0710970 -
Anais Da Academia Brasileira de Ciencias 2022This study assessed the association between encapsulated nitrate product (ENP) and monensin (MON) to mitigate enteric methane (CH4) in vitro and possible effects on...
This study assessed the association between encapsulated nitrate product (ENP) and monensin (MON) to mitigate enteric methane (CH4) in vitro and possible effects on ruminal degradability, enteric fermentation characteristics, and microbial populations. Six treatments were used in randomized complete design in a 2×3 factorial arrangement with two levels of MON (0 and 2.08 mg/mL of buffered rumen fluid) and three levels of ENP (0, 1.5 and 3.0%). The substrate consisted of 50% Tifton-85 hay and 50% concentrate mixture (ground corn and soybean meal). ENP replaced soybean meal to achieve isonitrogenous diets (15% CP). No ENP×MON interaction was observed for any measured variable (P > 0.05) except for the relative abundance of F. succinogenes (P = 0.02) that linearly increased in diets with MON when ENP was added. The ENP addition decreased CH4 production (P < 0.01) without affecting (P > 0.05) truly degraded organic matter nor the relative abundance of methanogens. Hydrogen production was reduced with MON (P = 0.04) and linearly decreased with ENP inclusion (P = 0.02). We concluded that use of nitrate is a viable strategy for CH4 reduction, however, no additive effect of ENP and MON was observed for mitigating CH4 production.
Topics: Animals; Diet; Fermentation; Monensin; Nitrates; Rumen; Glycine max
PubMed: 36102387
DOI: 10.1590/0001-3765202220200213