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Feed additives are used in animal husbandry to prevent diseases and enhance growth rates. Salinomycin sodium (SAL) is an approved feed additive for rabbit fattening diets, typically administered at a dosage of 20–25 mg/kg feed with a 5-day withdrawal period. However, the misuse or abuse of SAL can result in toxicity in rabbits. This study aimed to evaluate the adverse effects of SAL administration in different organs for the first time and the protective role of silymarin in rabbits. Seven groups of rabbits were randomly allocated. The control group received no additives. The second and third groups received rations with 20 mg SAL/kg and 40 mg SAL/kg, respectively. The fourth and fifth groups received the same SAL doses with silymarin at 6.5 mg/kg body weight (bw) and 13 mg/kg bw, respectively. The sixth and seventh groups were administered silymarin alone at 6.5 mg/kg bw and 13 mg/kg bw, respectively. Rabbits were euthanized and slaughtered on day 29 following the Halal method. SAL at 20 mg/kg ration caused mild to moderate pathological changes compared to the control group, while 40 mg SAL/kg ration induced severe pathological changes. However, silymarin supplementation, alone or with SAL, improved organs histology. Both silymarin doses (6.5 mg/kg bw and 13 mg/kg bw) mitigated SAL's harmful effects. In conclusion, this study highlights the potential detrimental effects of SAL toxicity on different organs in rabbits. The supplementation of silymarin reduced and prevented these hazardous effects. These findings emphasize the promising role of silymarin as a protective agent against SAL-induced toxicity in rabbits. Article Highlights: This study highlighted the risk of using salinomycin in rabbits' feed Histological examination revealed mild to severe SAL-induced pathological alterations in different organs The continued use of silymarin prevented and cured SAL-induced histopathological alterations in rabbits [ABSTRACT FROM AUTHOR]

Pirarubicin attracted considerable attention in clinical studies because of its high therapeutic efficacy and reduced toxicity in comparison with other anthracyclines. Nevertheless, ~ 30% patients undergoing PIRA treatment still experience relapse and metastasis. Clinical advancements unveiled that cancer stem cells (CSCs) residing in the tumor constitutes a major factor for such limitations and subsequently are the reason for treatment failure. Consequently, eradicating CSCs alongside bulk tumor is a crucial undertaking to attain utmost therapeutic efficacy of the treatment. Nevertheless, majority of the CSCs inhibitors currently under examination lack specificity, show unsynchronized bioavailability with other primary treatments and exhibit notable toxicity in their therapeutic applications, which is primarily attributable to their inadequate tumor-targeting capabilities. Therefore, we have developed a biodegradable polylactic acid based blend block copolymeric NPs for concomitant delivery of CSCs inhibitor Salinomycin (SAL) & chemotherapeutic drug Pirarubicin (PIRA) with an aim to improve the efficacy of treatment and prevent cancer relapse. Prepared NPs showed < 100 nm size and excellent loading with sustained release for both the drugs. Also, PIRA:SAL co-loaded NPs exhibits synergistically enhanced cytotoxicity against cancer cell as well as CSCs. Most importantly, NPs mediated co-delivery of the drugs showed complete tumor eradication, without any reoccurrence throughout the surveillance period. Additionally, NPs treatment didn't show any histopathological alteration in vital organs confirming their non-toxic nature. Altogether, present study concludes that the developed PIRA:SAL NPs have excellent efficacy for tumor regression as well as prevention of cancer relapse, hence can be used as a potential combination therapy for cancer treatment. [ABSTRACT FROM AUTHOR]

Abstract Feed additives are used in animal husbandry to prevent diseases and enhance growth rates. Salinomycin sodium (SAL) is an approved feed additive for rabbit fattening diets, typically administered at a dosage of 20–25 mg/kg feed with a 5-day withdrawal period. However, the misuse or abuse of SAL can result in toxicity in rabbits. This study aimed to evaluate the adverse effects of SAL administration in different organs for the first time and the protective role of silymarin in rabbits. Seven groups of rabbits were randomly allocated. The control group received no additives. The second and third groups received rations with 20 mg SAL/kg and 40 mg SAL/kg, respectively. The fourth and fifth groups received the same SAL doses with silymarin at 6.5 mg/kg body weight (bw) and 13 mg/kg bw, respectively. The sixth and seventh groups were administered silymarin alone at 6.5 mg/kg bw and 13 mg/kg bw, respectively. Rabbits were euthanized and slaughtered on day 29 following the Halal method. SAL at 20 mg/kg ration caused mild to moderate pathological changes compared to the control group, while 40 mg SAL/kg ration induced severe pathological changes. However, silymarin supplementation, alone or with SAL, improved organs histology. Both silymarin doses (6.5 mg/kg bw and 13 mg/kg bw) mitigated SAL's harmful effects. In conclusion, this study highlights the potential detrimental effects of SAL toxicity on different organs in rabbits. The supplementation of silymarin reduced and prevented these hazardous effects. These findings emphasize the promising role of silymarin as a protective agent against SAL-induced toxicity in rabbits.

Salinomycin, a naturally occurring polyether ionophore antibiotic isolated from Streptomyces albus, has been demonstrated potent cytotoxic activity against a variety of cancer cell lines. In particular, it exhibits selective targeting of cancer stem cells. However, systemic toxicity, drug resistance and low bioavailability of the drug significantly limit its potential applications. In this study, the C20‐epi‐isothiocyanate of salinomycin was designed and synthesized, and then reacted with amines as a versatile synthon to assemble a series of salinomycin thiourea derivatives, which improved the druggability of salinomycin. The antiproliferative activities of the compounds were evaluated in vitro against A549, HepG2, HeLa, 4T1, and MCF‐7 cancer cell lines using the CCK‐8 assay. The pharmacological results showed that some salinomycin thiourea derivatives exhibited excellent inhibitory activity against at least one of the tested tumor cells and high selectivity. Further mechanistic studies showed that compound 9 f, containing a 3,5‐difluorobenzyl moiety, could directly induce apoptosis, probably by increasing caspase‐9 protein expression and cell cycle arrest in G1 phase in a concentration dependent manner. [ABSTRACT FROM AUTHOR]

Simple Summary: There has been an exponential increase in demand for poultry meat and eggs worldwide. Therefore, it is essential to keep coccidiosis under control in broilers to fulfill the increase in demand for protein. The objective of this study was to assess the efficacy of two ionophore coccidiostats against coccidiosis and their impact on broiler gut health and performance. Both the ionophores were effective in treatment against coccidiosis, and out of the two, narasin demonstrated superiority in terms of improved performance parameters compared with salinomycin. This finding is highly important as it significantly focuses on sustainable poultry and, in turn, can help prevent economic losses and maintain broiler health. The objective of this study was primarily to assess the different performance impacts of two ionophore coccidiostats (narasin and salinomycin) used to manage coccidiosis. While both products may be efficacious in controlling disease challenges, previous literature has suggested that some ionophores are less well tolerated by the broiler chickens. In this study, we were particularly interested to know how the use of different coccidiostat programs translates into broiler health and performance, as measured by zootechnical parameters such as the feed conversion ratio, average daily gain, and final body weight. A total of 352 male Ross 308 one-day-old broilers were randomly divided into two treatment groups (T1 and T2). Treatment 1 included a basal diet (BD) + nicarbazin/narasin (Maxiban®, Elanco) at 100 ppm 0–24 days, narasin at 70 ppm 25–42 days, and (2) Treatment 2 included basal diet + nicarbazin/narasin at 100 ppm 0–24 days, salinomycin (Sacox®, Huvepharma) at 70 ppm 25–42 days. Efficacy and performance parameters, slaughter analysis, dry matter (DM) in litter, and intestinal integrity (I2) were measured for the broilers from both treatment groups. The findings demonstrated more favorable results for broilers reared in the group diet fed with narasin (in the finisher phase), including higher daily body weight gain, higher final body weight, lower feed conversion ratio value (improved feed efficiency), and higher European Production Efficiency Factor value, compared with the salinomycin-supplemented group. [ABSTRACT FROM AUTHOR]

In this study we demonstrated for the first time synthetic procedures for composites of salinomycin (SalH) and two-line ferrihydrite. The products were characterized by various methods such as elemental analysis, attenuated total reflectance–Fourier-transform spectroscopy (ATR-FTIR), electron paramagnetic resonance spectroscopy (EPR), powder X-ray diffraction analysis (XRD), electrospray-ionization mass spectrometry (ESI-MS), thermogravimetric analysis with differential thermal analysis (DTA) and mass spectrometry (TG-DTA/MS). The EPR spectra of the isolated compounds consisted of signals associated with both isolated Fe3+ ions and magnetically coupled Fe3+ ions. Powder XRD analyses of the isolated products showed two intense and broad peaks at 9° and 15° 2Θ, corresponding to salinomycinic acid. Broad peaks with very low intensity around 35°, assigned to two-line ferrihydrite, were also registered. Based on the experimental results, we concluded that salinomycin sodium reacted with Fe(III) chloride to form composites consisting of two-line ferrihydrite and salinomycinic acid. One of the composites exerted pronounced antitumor activity in the sub-micromolar concentration range against human cervical cancer (HeLa), non-small-cell lung cancer (A549), colon cancer (SW480), and ovarian teratocarcinoma (CH1/PA1) cells. [ABSTRACT FROM AUTHOR]

Background: Acute Myeloid Leukemia (AML) is a fast-developing invading cancer that impacts the blood and bone marrow, marked by the rapid proliferation of abnormal white blood cells. Chemotherapeutic agents, a primary treatment for AML, encounter clinical limitations such as poor solubility and low bioavailability. Previous studies have highlighted antibiotics as effective in inducing cancer cell death and potentially preventing metastasis. Besides, insulin is known to activate the PI3K/Akt pathway, often disrupted in cancers, leading to enhanced cell survival and resistance to apoptosis. In light of the above-mentioned points, we examined the anti-cancer impact of antibiotics Ciprofloxacin (CP) and Salinomycin (SAL) and their combination on KG1-a cells in the presence and absence of insulin. Methods: This was accomplished by exposing KG1-a cells to different doses of CP and SAL alone, in combination, and with or without insulin for 24–72 h. Cell viability was evaluated using the MTT assay. Besides, apoptotic effects were examined using Hoechst staining and Annexin-V/PI flow cytometry. The expression levels of Bax, p53, BIRC5, Akt, PTEN, and FOXO1 were analyzed through Real-Time PCR. Results: CP and SAL demonstrated cytotoxic and notable pro-apoptotic impact on KG1-a cells by upregulating Bax and p53 and downregulating BIRC5, leading to G0/G1 cell cycle arrest and prevention of the PI3K-Akt signaling pathway. Our findings demonstrated that combination of CP and SAL promote apoptosis in the KG1-a cell line by down-regulating BIRC5 and Akt, as well as up-regulating Bax, p53, PTEN, and FOXO1. Additionally, the findings strongly indicated that insulin effectively mitigates apoptosis by enhancing Akt expression and reducing FOXO1 and PTEN gene expression in the cells treated with CP and SAL. Conclusion: Our findings showed that the combined treatment of CP and SAL exhibit a strong anti-cancer effect on leukemia KG1-a cells. Moreover, it was discovered that the PI3K-Akt signaling can be a promising target in leukemia treatment particularly in hyperinsulinemia condition. [ABSTRACT FROM AUTHOR]

Salinomycin is a coccidiostat approved as a feed additive for the prevention of coccidiosis in poultry. Official control of its residues is set by the Commission Delegated Regulation (EU) 2022/1644. The aim of our study was to assess the suitability of three microbial inhibition tests (MITs), Premi®Test, Explorer 2.0, and the Screening Test for Antibiotic Residues (STAR) linked to the enzyme-linked immunosorbent assay (ELISA), for the screening of salinomycin residues in the tissues of broiler chickens (breast and thigh muscle, heart, liver, gizzard, kidneys, lungs, spleen, skin, and fat) fed commercially produced feed containing 70 mg.kg−1 of salinomycin in the complete feed. The first residue screening (Sampling A) was performed on the last day of administration of the salinomycin-medicated feed (day 30), and the second screening (Sampling B) was performed on the day of slaughter (day 37) after the expiry of the withdrawal period with the feeding of non-medicated feed. Based on the quantitative confirmation of salinomycin residues in the examined chicken tissues by the ELISA method (Sampling A from 0.025 to 0.241 mg.kg−1; Sampling B from 0.003 to 0.076 mg.kg−1), all the MITs with the preference of the bacterial strain Bacillus stearothermophilus var. calidolactis ATCC 10149 demonstrated the ability to detect the residues of salinomycin in the examined tissues of broiler chickens at the level of the maximum residue limits set from 0.015 to 0.150 mg.kg−1 by Commission Implementing Regulation (EU) 2017/1914 and confirmed the relevance of their sensitivity to the coccidiostat salinomycin. [ABSTRACT FROM AUTHOR]

Following a request from the European Commission, EFSA was asked to deliver a scientific opinion on the safety and efficacy of the coccidiostat salinomycin sodium (Sacox®) for rabbits for fattening. The EFSA Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) concluded that the use of salinomycin sodium (SAL‐Na) from Sacox® does not raise safety concerns for the target species, consumers, users and the environment with regard to the production strain. In the absence of adequate tolerance studies, the FEEDAP Panel could not conclude on the safety of SAL‐Na from Sacox® for rabbits for fattening. The FEEDAP Panel concluded that the additive is safe for the consumer when it is used at the proposed maximum level of 25 mg SAL‐Na/kg complete feed for rabbits and a withdrawal period of 1 day is respected. The following maximum residue limits (MRL) are proposed for the marker residue compound salinomycin (SAL): 0.2 and 0.03 mg SAL/kg for liver and kidney, respectively. The additive is not irritant to skin and eyes but should be considered a potential dermal and respiratory sensitiser. A risk for inhalation toxicity could not be excluded. The use of the SAL‐Na from Sacox® in feed for rabbits for fattening up to the highest proposed level will not pose a risk for the terrestrial and aquatic compartment and ground water. The risk of secondary poisoning can be excluded for worm‐eating birds and mammals, while it cannot be excluded for fish‐eating birds and mammals. The FEEDAP Panel concludes that SAL‐Na from Sacox® at the minimum concentration of 20 mg SAL‐Na/kg complete feed has the potential to control coccidiosis in rabbits for fattening. Development of resistance to SAL‐Na of field Eimeria spp. strains isolated from rabbits for fattening should be monitored. [ABSTRACT FROM AUTHOR]

Abstract Background Salinomycin, an antibiotic, have potential as a veterinary drug for fish due to its anti-parasitic activity against several fish parasites. Thus the residual levels of salinomycin in muscles of two significant aquaculture species in Korea, olive flounder and black rockfish, were analyzed using HPLC-MS-MS. Results The proper method to analyze the residual salinomycin in fish muscles using LC-MS-MS was settled and the method was validated according to CODEX guidelines. The residues in three distinct groups for two fish species were analyzed using the matrix match calibration curves at points of five different times following oral administration. After oral administration, salinomycin rapidly breaks down in both olive flounder and black rockfish. After 7th days, the average residue in all groups of two fish spp. decreased below limit of quantitation (LOQ). Conclusion Due to low residue levels in fish muscles, salinomycin may therefore be a treatment that is safe for both fish and humans. This result could contribute to establishment of MRL (minimal residual limit) for approval of salinomycin for use in aquaculture.

This study aimed to investigate the nutritional effects of phytosomal green tea on growth performance, lipid parameters, immune responses, antioxidant status, ileum bacterial population, and gamma interferon gene expression in compared to green tea extract. 375 male broiler chickens (ROSS 308)were randomly assigned to 5 treatments, with 5 replications and 15 chickens per cage. Treatments included 1- basal diet (negative control), 2- basal diet + 0.10 g/kg avilamycin, 3- basal diet + 0.60 g/kg salinomycin, 4- basal diet + 400 ml/kg green tea extract and 5-basal diet + 300 ml/kg green tea phytosome. Experimental treatments did not affect growth and carcass performance (P>0.05). Malondialdehyde, triglycerides, low density lipoprotein cholesterol in plasma affected by phytosomal extract decreased compared to control (P<0.05). Antibody levels against red blood cells, immunoglobulin G and immunoglobulin M increased in chickens fed phytosome supplement in comparison to the form of green tea extract at 28 days (P<0.05). The use of green tea extract reduced the population of Escherichia coli in comparison to avilamycin and increased the population of lactobacilli cmpared to salinomycin (P<0.05). The expression of interferon gamma gene in the spleen of chickens that received the phytosomal green tea extract was higher compared to the consumption of green tea extract (P<0.05). Conclusion is that, green tea extract -phospholipid complexes showed the same efficiency compared to green tea extract on the evaluated parameters and can be considered as an alternative in order to reduce the consumption of plant extracts in poultry nutrition. [ABSTRACT FROM AUTHOR]

The combination of ionophoric coccidiostats and amino acids (AAs) is important in poultry feeding to enhance immunity and improve the growth and feed efficiency of birds suffering from coccidiosis. A simple, rapid, and economical high‐performance liquid chromatography‐ultraviolet detection (HPLC‐UV) method for the simultaneous determination of three ionophoric coccidiostats, namely salinomycin (SAL), maduramicin (MAD), and monensin (MON) in addition to three AAs; L‐tryptophan (L‐TRP), alpha‐ketoleucin (KLEU), and L‐valine (L‐VAL) in feed premixes was developed and validated. Chromatographic separation was achieved in less than 12 min using a phenyl hexyl column with a mobile phase consisting of acetonitrile/methanol/water (25:20:55, v/v/v) adjusted to pH 3 using phosphoric acid. Isocratic elution was performed at a flow rate of 1 mL/min with UV detection at 210 nm. The method showed good linearity in the ranges 0.50–5.0 mg/mL for MON, 0.20–2.0 mg/mL for MAD and SAL, 10.0–100.0 μg/mL for L‐TRP and KLEU, and 50.0–500.0 μg/mL for VAL. The developed method was successfully applied to determine the studied analytes in feed premixes with good recoveries and precision. The good validation criteria of the proposed method allow its utilization in quality control laboratories. [ABSTRACT FROM AUTHOR]

Salinomycin, belonging to ionophore antibiotics, has been used as a feed additive for poultry for its coccidiostatic effect. Poisoning by ionophore antibiotics has been reported in cattle and other sensitive animals due to the replacement of medicated feed and/or accidental overdoses. The aim of this paper is to report the toxicity of salinomycin for fallow deer and to describe the different levels of sensitivity of cervids to this substance. In the presented case study, a medicated feed containing ivermectin used for deworming red deer and fallow deer was accidentally contaminated with sodium salinomycinate in a concentration of 252.6 mg/kg. The contaminated feed was consumed by the animals over a period of four days. The mortality of fallow deer within 12 days was 58%. No mortality was recorded in the red deer. In the affected animals, clinical signs associated with acute and congestive heart failure were observed. The biochemical examination indicated prerenal azotaemia caused by circulatory insufficiency and ion imbalance. The histological examination revealed pronounced focal acute cardiomyopathy and massive subacute myopathy in the skeletal muscles. [ABSTRACT FROM AUTHOR]

The presence of antimicrobial residues in products of animal origin is a constant problem for consumer health. The aim of this study was to observe the effect of the addition of humic substances (H), fermented products (F) and a mixture of both (FH) to feed supplemented with the coccidiostat salinomycin, compared with a control group (C), on the content of salinomycin residues in the edible tissues of broiler chickens using two microbial inhibition screening methods, Explorer 2.0 test and the Screening Test for Antibiotic Residues (STAR), and a confirmatory competitive enzyme immunoassay analysis (Salinomycin ELISA Kit). The results of the microbial inhibition tests showed a gradual decline in the positive results in the tissue samples from the last day of salinomycin administration (30th day) tothe last day of fattening (37th day, day of slaughter) in group C and no positive results in the tissue samples from experimental groups H, F and FH slaughtered on the last day of fattening. Using the Salinomycin ELISA Kit, salinomycin was detected in the chicken muscle tissues of all the control and experimental groups. However, no sample from any group contained salinomycin at a concentration exceeding the maximum residue limits set by European law. The high level of significance (p < 0.001) confirmed the positive influence of the administration of humic substances and fermented products on the content of salinomycin residues in chicken tissues. [ABSTRACT FROM AUTHOR]

Besides the fission–fusion dynamics, the cellular distribution of mitochondria has recently emerged as a critical biological parameter in regulating mitochondrial function and cell survival. We previously found that mitochondrial clustering on the nuclear periphery, or monopolar perinuclear mitochondrial clustering (MPMC), accompanies the anticancer activity of air plasma-activated medium (APAM) against glioblastoma and human squamous cell carcinoma, which is closely associated with oxidant-dependent tubulin remodeling and mitochondrial fragmentation. Accordingly, this study investigated the regulatory roles of nitric oxide (NO) in the anticancer activity of APAM. Time-lapse analysis revealed a time-dependent increase in NO accompanied by MPMC. In contrast, APAM caused minimal increases in MPMC and NO levels in nontransformed cells. NO, hydroxyl radicals, and lipid peroxide levels increased near the damaged nuclear periphery, possibly within mitochondria. NO scavenging prevented tubulin remodeling, MPMC, perinuclear oxidant production, nuclear damage, and cell death. Conversely, synthetic NO donors augmented all the prodeath events and acted synergistically with APAM. Salinomycin, an emerging drug against multidrug-resistant cancers, had similar NO-dependent effects. These results suggest that APAM and salinomycin induce NO-dependent cell death, where MPMC and oxidative mitochondria play critical roles. Our findings encourage further investigations on MPMC as a potential target for NO-driven anticancer agents against drug-resistant cancers.

In this study we demonstrated for the first time synthetic procedures for composites of salinomycin (SalH) and two-line ferrihydrite. The products were characterized by various methods such as elemental analysis, attenuated total reflectance–Fourier-transform spectroscopy (ATR-FTIR), electron paramagnetic resonance spectroscopy (EPR), powder X-ray diffraction analysis (XRD), electrospray-ionization mass spectrometry (ESI-MS), thermogravimetric analysis with differential thermal analysis (DTA) and mass spectrometry (TG-DTA/MS). The EPR spectra of the isolated compounds consisted of signals associated with both isolated Fe3+ ions and magnetically coupled Fe3+ ions. Powder XRD analyses of the isolated products showed two intense and broad peaks at 9° and 15° 2Θ, corresponding to salinomycinic acid. Broad peaks with very low intensity around 35°, assigned to two-line ferrihydrite, were also registered. Based on the experimental results, we concluded that salinomycin sodium reacted with Fe(III) chloride to form composites consisting of two-line ferrihydrite and salinomycinic acid. One of the composites exerted pronounced antitumor activity in the sub-micromolar concentration range against human cervical cancer (HeLa), non-small-cell lung cancer (A549), colon cancer (SW480), and ovarian teratocarcinoma (CH1/PA1) cells.

Context: Salinomycin (SAL) is a chemotherapeutic drug with anti-osteosarcoma efficacy, but its hydrophobic properties have hindered its application. Nanoparticles have been widely used as drug carriers to improve the solubility of hydrophobic drugs. The dodecapeptide GE11 has been shown to have great binding affinity to the epidermal growth factor receptor (EGFR), which is highly overexpressed in osteosarcoma. Materials and Methods: We designed novel SAL-loaded GE11-conjugated polymer–lipid hybrid nanoparticles (GE11-NPs-SAL) to target osteosarcoma. The characterization and antitumor activity of GE11-NPs-SAL were evaluated both in vitro and in vivo. Results: The results showed that GE11-NPs-SAL had a size of ~100 nm with a high encapsulation efficacy of ~80%. Compared with the non-targeted nanoparticles, GE11-NPs-SAL showed increased internalization in osteosarcoma cells and improved therapeutic efficacy in osteosarcoma both in vitro and in vivo. Conclusions: GE11-NPs-SAL is a promising treatment for osteosarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Aquaculture is vital for global food production, but parasites like Microcotyle sebastis pose challenges to Korean rockfish, leading to economic concerns. As there is a growing worry about drug resistance, we explored salinomycin, previously recognized for treating other parasites, to combat this issue. Our experiments revealed that salinomycin effectively lessens these parasites in Korean rockfish without significant side effects. Importantly, the treatment appeared potentially more stable when administered at a water temperature of 13 °C. This study suggests that salinomycin could be a promising alternative, especially if resistance against current treatments like praziquantel emerges. Aquaculture, a crucial sector of the global food industry, faces a myriad of issues due to parasitic invasions. One such parasite, Microcotyle sebastis, which afflicts Korean rockfish in South Korea, has a significant economic impact. The impending danger of resistance to traditional anthelmintics necessitates the exploration of new antiparasitic candidates. Although the efficacy of salinomycin against aquatic parasites such as ciliates and sporozoans is known, its influence on monogeneans has yet to be studied. Therefore, this study investigated the efficacy and safety of salinomycin for the treatment of M. sebastis infections, presenting the first exploration of salinomycin's therapeutic potential against monogeneans. In vitro examinations revealed a minimum effective concentration of salinomycin of 5 mg/kg, which led to necrosis of the haptor upon dislodging from the gill filaments. The one-time oral administration of the drug at concentrations of 5 mg/kg and 10 mg/kg showed a significant dose-dependent reduction in parasite counts, with no apparent behavioral side effects in Korean rockfish. Biochemical analyses monitored the liver, heart, and kidney enzymes, specifically aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and creatine kinase–myocardial band (CK-MB). At both 20 °C and 13 °C, no significant differences were observed in the levels of AST and ALT. However, at 20 °C, alterations in BUN levels were evident on Day 14, a deviation not observed at 13 °C. The CK-MB analysis revealed elevated enzyme levels at both temperatures when compared to the control group, reflecting the similar changes observed in terrestrial animals administered salinomycin. The biochemical data suggest that the oral administration of salinomycin is potentially more favorable at 13 °C than at 20 °C. Although our findings warrant further comprehensive studies, including on the long-term and potential effects on nontarget species and water quality, they also suggest that salinomycin could be considered as an alternative or adjunctive treatment if resistance to the currently used praziquantel against M. sebastis is confirmed. [ABSTRACT FROM AUTHOR]

Background: Autophagy and the unfolded protein response (UPR) are important pathways in colorectal tumorigenesis and drug resistance, rendering them as potential therapeutic targets for treating this cancer. As an ionophoric polyether antibiotic, salinomycin has anti-cancer effects and overcomes drug resistance in cancer cells. Considering the minimal information on the molecular action mechanism of salinomycin in colorectal cancer (CRC), this study was designed to investigate the effect of this compound on autophagy and UPR pathways in CRC cells. Methods: The in vitro cytotoxicity of salinomycin on CRC cell line HCT116 was determined using the MTT assay by treating the cells with different concentrations of salinomycin for 24 and 48 h. The gene expression analysis of three main autophagy biomarkers (Beclin1, LC3, and P62) and two UPR biomarkers (XBP-1s and CHOP) was performed using quantitative real-time polymerase chain reaction (RT-PCR). Data were analyzed with GraphPad Prism 8 software. Results: Salinomycin had cytotoxic effects on HCT116 cells in a time- and dose-dependent manner. The expression analysis of the UPR and autophagy-related genes showed UPR activation at both 24 h and 48 h (increase of XBP-1s and CHOP), autophagy activation at 24 h (increase of Beclin 1, LC3II, and decrease of P62), and autophagy flux inhibition at 48 h (increase of Beclin 1, LC3II and P62). Conclusion: The anti-cancer activity of salinomycin against the HCT116 cell line seems to be through triggering cell death by targeting UPR and autophagy pathways. Further studies are required to confirm our results.

Cancer stem cells (CSCs) are the cells in a primary tumor that have the opportunity to self-renew as well as differentiate into certain cell types, thus forming a mixed tumor. CSCs have been shown to be involved in every aspect of cancer development, including tumor initiation, proliferation, and metastatic activity; they are also involved in chemotherapeutic drug resistance and the recurrence of certain cancers. Based on these capabilities, CSCs have been explored as the next target for the treatment and management of cancer. Salinomycin (SAL), a polyether ionophore antibiotic being used in the poultry industry, was identified as a powerful anti-cancer compound that possesses broad-spectrum activities, especially against CSCs. Here we point out the noteworthy work reported on SAL’s mechanism of action, anticancer activities, toxicity, and clinic applications. In addition, SAL derivatives synthesized by different research groups and their biological activity will also be highlighted.

Salinomycin is a coccidiostat approved as a feed additive for the prevention of coccidiosis in poultry. Official control of its residues is set by the Commission Delegated Regulation (EU) 2022/1644. The aim of our study was to assess the suitability of three microbial inhibition tests (MITs), Premi®Test, Explorer 2.0, and the Screening Test for Antibiotic Residues (STAR) linked to the enzyme-linked immunosorbent assay (ELISA), for the screening of salinomycin residues in the tissues of broiler chickens (breast and thigh muscle, heart, liver, gizzard, kidneys, lungs, spleen, skin, and fat) fed commercially produced feed containing 70 mg.kg−1 of salinomycin in the complete feed. The first residue screening (Sampling A) was performed on the last day of administration of the salinomycin-medicated feed (day 30), and the second screening (Sampling B) was performed on the day of slaughter (day 37) after the expiry of the withdrawal period with the feeding of non-medicated feed. Based on the quantitative confirmation of salinomycin residues in the examined chicken tissues by the ELISA method (Sampling A from 0.025 to 0.241 mg.kg−1; Sampling B from 0.003 to 0.076 mg.kg−1), all the MITs with the preference of the bacterial strain Bacillus stearothermophilus var. calidolactis ATCC 10149 demonstrated the ability to detect the residues of salinomycin in the examined tissues of broiler chickens at the level of the maximum residue limits set from 0.015 to 0.150 mg.kg−1 by Commission Implementing Regulation (EU) 2017/1914 and confirmed the relevance of their sensitivity to the coccidiostat salinomycin.

ABSTRACT: Ionophores are antibiotics frequently used in animals of production. The most common are monensin, salinomycin, narasin, and lasalocid. The equine species is highly susceptible to ionophores poisoning. The present study aimed to analyze the serum use of cardiac troponin I (cTnI) and the anti-troponin C immunohistochemistry (IHC) technique (anti-cTnC) as a diagnostic tool for cardiac injuries in horses spontaneously poisoned by salinomycin. Seven horses were affected by a disease lasting for 6-72 hours. Three horses recovered. The primary morphological lesions reported in the four necropsied horses that died spontaneously were necrosis of the myocardium and skeletal muscle. Immunohistochemistry for anti-cTnC was performed in selected sections of the cardiac muscle from the equine submitted for necropsy. A decrease in cTnC expression in the cytoplasm of cardiomyocytes was noticed in all four necropsied horses. Samples of serum from six horses tested for cardiac troponin I levels; the most expressive values were mainly in horses with more severe cardiac histological lesions. The serum detection of cTnI can be considered a good marker to determine cardiac damage in horses intoxicated with salinomycin with a clinical evolution of 48 hours or more. The anti-cTnC IHC aided in the detection of cardiac injury in horses independent of clinical evolution.

Epithelial-to-mesenchymal transition (EMT) gives rise to cells with properties similar to cancer stem cells (CSCs). Targeting the EMT program to selectively eliminate CSCs is a promising way to improve cancer therapy. Salinomycin (Sal), a K+/H+ ionophore, was identified as highly selective towards CSC-like cells, but its mechanism of action and selectivity remains elusive. Here, we show that Sal, similar to monensin and nigericin, disturbs the function of the Golgi. Sal alters the expression of Golgi-related genes and leads to marked changes in Golgi morphology, particularly in cells that have undergone EMT. Moreover, Golgi-disturbing agents severely affect post-translational modifications of proteins, including protein processing, glycosylation and secretion. We discover that the alterations induced by Golgidisturbing agents specifically affect the viability of EMT cells. Collectively, our work reveals a novel vulnerability related to the EMT, suggesting an important role for the Golgi in the EMT and that targeting the Golgi could represent a novel therapeutic approach against CSCs. [ABSTRACT FROM AUTHOR]

Colorectal cancer remains one of the major causes of morbidity and mortality in both developed and emerging countries. Cancer stem cells (CSCs) are a subpopulation of cells within the tumor mass harboring stem cell characteristics, considered responsible for tumor initiation, growth, relapse, and treatment failure. Lately, it has become clear that both CSCs and non-CSCs have to be eliminated for the successful eradication of cancer. Drug delivery systems have been extensively employed to enhance drug efficacy. In this study, salinomycin (SAL), a selective anti-CSC drug, and gemcitabine (GEM), a conventional anticancer drug, were co-loaded in liposomes and tested for optimal therapeutic efficacy. We employed the Design of Experiments approach to develop and optimize a liposomal delivery system for GEM and SAL. The antiproliferative effect of the liposomes was evaluated in SW-620 human colorectal cancer cells. The GEM and SAL-loaded liposomes exhibited adequate size, polydispersity, zeta potential, and drug content. The in vitro release study showed a sustained release of GEM and SAL from the liposomes over 72 h. Moreover, no sign of liposome aggregation was seen over 1 month and in a biological medium (FBS). The in vitro cytotoxic effects of the co-loaded liposomes were superior to that of single GEM either in free or liposomal form. The combination therapy using GEM and SAL co-loaded in liposomes could be a promising strategy for tackling colorectal cancer. [ABSTRACT FROM AUTHOR]

Coccidiosis is a protozoal disease caused by Eimeria that significantly impacts the global poultry industry. In this study, in vitro and in vivo experiments were conducted to evaluate the anticoccidial effect of Juglans mandshurica epicarp aqueous extract as an alternative treatment against coccidiosis in broiler chickens. In the in vitro experiment, unsporulated Eimeria tenella oocysts were exposed to various concentrations of the aqueous extract. After 48 hours of incubation, the degree of inhibition of sporulation and morphed oocysts were examined. For the in vivo experiment, seven groups of two-week-old broiler chickens were divided into A1-A5, positive control (PC), and negative control (NC) groups. The A1-A4 groups received different doses of the aqueous extract calculated based on toxicity tests, while group A5 was fed diets mixed with salinomycin. Groups A1-A5 were infected with E. tenella, while PC was infected but unmedicated, and NC was uninfected and unmedicated. Results showed that the aqueous extract inhibited the sporulation of E. tenella oocysts in vitro in a concentration-dependent manner. All experimental groups fed with the extract exhibited significantly higher weight gain, particularly those receiving 5 mL/kg BW. Moreover, the groups receiving doses of 5 and 7 mL/kg BW showed significant differences in bloody Diarrhea and cecal lesion scores compared to the PC group. The anticoccidial index (ACI) value for these groups was above 160, indicating high efficacy similar to the group fed with mixed salinomycin. In conclusion, the study suggests that J. mandshurica epicarp aqueous extract could be a safe and effective alternative treatment for coccidiosis in broilers. This could provide a new approach to control coccidiosis in the global poultry industry. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are associated with metastasis and recurrence in prostate cancer as well as other cancers. We aimed to enhance the sensitivity of cabazitaxel in prostate cancer cell therapy by targeting CSCs with a Wnt inhibitor and salinomycin pretreatment. PC3, DU-145, and LNCaP human prostate cancer cells were exposed to Wnt/β-catenin pathway inhibitor CCT036477 (iWnt) with salinomycin for 48 h, followed by cabazitaxel treatment for 48 h. Cell viability, mRNA, and protein expression changes were evaluated by MTT, RT-qPCR, and Western blot assays, respectively. Apoptosis was determined by image-based cytometry, and cell migration was assessed by wound healing assay. Three-dimensional culture was established to assess the malignant phenotype and stemness potential of transformed or cancer cells. CD44 + CSCs were isolated using magnetic-activated cell sorting system. Pretreatment of PC3, DU-145, and LNCaP cells with salinomycin iWnt significantly sensitized the cells to cabazitaxel therapy. Spheroid culture confirmed that the treatment modality was more effective than a single administration of chemotherapy. The pretreatment of PC3 cells increased the rate of apoptosis compared to single administration of cabazitaxel, which downregulated Bcl-2 and upregulated caspase 3, caspase 8 expressions. The pretreatment suppressed cell migration, downregulated the expression of Sox2 and Nanog, and significantly reduced CD44 + CSC numbers. Notably, the treatment modality reduced pAKT, p-P38 MAPK, and pERK1/2. The data suggest that pretreatment of prostate cancer cells with salinomycin and Wnt inhibitor may increase the efficacy of cabazitaxel therapy by inhibiting cell proliferation and migration, and eliminating cancer stem cells. [ABSTRACT FROM AUTHOR]

The largely uncharted complexation chemistry of the veterinary polyether ionophores, monensic and salinomycinic acids (HL) with metal ions of type M4+ and the known antiproliferative potential of antibiotics has provoked our interest in exploring the coordination processes between MonH/SalH and ions of Ce4+. (1) Methods: Novel monensinate and salinomycinate cerium(IV)-based complexes were synthesized and structurally characterized by elemental analysis, a plethora of physicochemical methods, density functional theory, molecular dynamics, and biological assays. (2) Results: The formation of coordination species of a general composition [CeL2(OH)2] and [CeL(NO3)2(OH)], depending on reaction conditions, was proven both experimentally and theoretically. The metal(IV) complexes [CeL(NO3)2(OH)] possess promising cytotoxic activity against the human tumor uterine cervix (HeLa) cell line, being highly selective (non-tumor embryo Lep-3 vs. HeLa) compared to cisplatin, oxaliplatin, and epirubicin. [ABSTRACT FROM AUTHOR]

Background: Autophagy and the unfolded protein response (UPR) are important pathways in colorectal tumorigenesis and drug resistance, rendering them potential therapeutic targets for treating this cancer. As an ionophoric polyether antibiotic, salinomycin has anti-cancer effects and overcomes drug resistance in cancer cells. Considering the minimal information on the molecular action mechanism of salinomycin in colorectal cancer (CRC), this study was designed to investigate the effect of this compound on autophagy and UPR pathways in CRC cells. Methods: The in vitro cytotoxicity of salinomycin on CRC cell line HCT116 was determined using the MTT assay by treating the cells with different concentrations of salinomycin for 24 and 48 h. The gene expression analysis of three main autophagy biomarkers (Beclin1, LC3, and P62) and two UPR biomarkers (XBP-1s and CHOP) was performed using quantitative real-time polymerase chain reaction (RT-PCR). Data were analyzed with GraphPad Prism 8 software. Results: Salinomycin had cytotoxic effects on HCT116 cells in a time- and dose-dependent manner. The expression analysis of the UPR and autophagy-related genes showed UPR activation at both 24 h and 48 h (increase of XBP-1s and CHOP), autophagy activation at 24 h (increase of Beclin 1, LC3II, and decrease of P62), and autophagy flux inhibition at 48 h (increase of Beclin 1, LC3II and P62). Conclusion: The anti-cancer activity of salinomycin against the HCT116 cell line seems to be through triggering cell death by targeting UPR and autophagy pathways. Further studies are required to confirm our results. [ABSTRACT FROM AUTHOR]

Cancer stem cells (CSCs) are the cells in a primary tumor that have the opportunity to self-renew as well as differentiate into certain cell types, thus forming a mixed tumor. CSCs have been shown to be involved in every aspect of cancer development, including tumor initiation, proliferation, and metastatic activity; they are also involved in chemotherapeutic drug resistance and the recurrence of certain cancers. Based on these capabilities, CSCs have been explored as the next target for the treatment and management of cancer. Salinomycin (SAL), a polyether ionophore antibiotic being used in the poultry industry, was identified as a powerful anti-cancer compound that possesses broad-spectrum activities, especially against CSCs. Here we point out the noteworthy work reported on SAL's mechanism of action, anticancer activities, toxicity, and clinic applications. In addition, SAL derivatives synthesized by different research groups and their biological activity will also be highlighted. [ABSTRACT FROM AUTHOR]

Low-density lipoprotein receptor-related protein-6 (LRP6) is overexpressed in various cancers. The small molecule salinomycin sodium inhibits LRP6. We observed a higher proportion of subjects with non-germinal center B (non-GCB) subtypes having high LRP6 expression than those with GCB subtypes by immunohistochemistry. The PCR and Western blot assays demonstrated increased LRP6 expression in non-GCB subtype cells. In addition, CCK-8 assays and transwell cell migration assays revealed that salinomycin sodium exhibited dose- and time-dependent inhibition of proliferation and migration in non-GCB subtype cells. Furthermore, Western blot assays showed that salinomycin sodium decreased the expression of Bcl2, while increasing the expression of Bax. Additionally, salinomycin sodium suppressed LRP6 expression, blocked LRP6 phosphorylation, and inhibited the Wnt/β-catenin and mTORC1 signaling pathways. Our results suggest that LRP6 is highly expressed in non-GCB subtype. Furthermore, salinomycin sodium inhibited LRP6 expression and the Wnt/β-catenin and mTORC1 signaling in non-GCB subtype cells, and displayed potent anticancer activity. [ABSTRACT FROM AUTHOR]

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Divalent metal transporter 1 (DMT1) inhibitors can selectively kill iron-addicted cancer stem cells by causing lysosomal iron overload, but their role in head and neck cancer (HNC) is unknown. We examined the role of DMT1 inhibition or salinomycin in promoting ferroptosis by lysosomal iron targeting in HNC cells. RNA interference was performed by transfection of siRNA targeting DMT1 or scrambled control siRNA in HNC cell lines. Cell death and viability, lipid peroxidation, iron contents, and molecular expression were compared between the DMT1 silencing or salinomycin group and the control. DMT1 silencing markedly accelerated cell death induced by the ferroptosis inducers. DMT1 silencing marked increases in the labile iron pool, intracellular ferrous and total iron contents, and lipid peroxidation. DMT1 silencing revealed molecular changes in iron starvation response, resulting in increases in TFRC, and decreases in FTH1. Salinomycin treatment also showed similar results to the above DMT1 silencing. DMT1 silencing or salinomycin can promote ferroptosis in HNC cells, suggesting a novel strategy for killing iron-avid cancer cells. [ABSTRACT FROM AUTHOR]

THz radiation induces a variety of processes in cells and has attracted the attention of researchers in recent decades. Here, data on the effects of high-intensity terahertz (THz) radiation on human directly reprogrammed neural progenitor cells (drNPCs) and on neuroblastoma cells (SK-N-BE (2)) were obtained for the first time. The results demonstrated that the exposure of non-tumor and tumor cells to broadband (0.1–3 THz) THz pulses with the intensity of 21 GW/cm2 and the electric field strength of 2.8 MV/cm for 30 min induced neither a noticeable genotoxic effect nor a statistically significant change in the proliferative activity and cell differentiation. It was also shown that the combined effect of THz radiation and salinomycin, a promising antitumor agent, on neuroblastoma cells did not enhance the genotoxic effect of this antibiotic. However, further studies involving chemotherapy drugs and other exposure parameters are warranted to introduce this new concept into anti-tumor clinical practice and to enhance the efficacy of the existing approaches. [ABSTRACT FROM AUTHOR]

Background and Aim: Salinomycin sodium, a licensed coccidiostat in rabbits, is used for fattening at a dose of 20–25 mg/kg. Salinomycin toxicity may arise from many risk factors (e.g., overdosage or use in non-target animal species). Silymarin extracted from milk thistle has antioxidant, anti-inflammatory, and antiviral properties. This study aimed to investigate the adverse impacts of oral administration of salinomycin for 28 consecutive days and how to reduce its risks and side effects by administering silymarin. Materials and Methods: Eighty-four male New Zealand White bucks (1.750–2.000 kg) were randomly divided into seven groups (12 each). Group one was the control. Groups two and three were administered salinomycin orally (doses of 20 and 40 mg/kg ration). Group four was administered salinomycin (20 mg/kg ration) and silymarin (6.5 mg/kg body weight [BW]). Group five received salinomycin (40 mg/kg ration) and silymarin (13 mg/kg BW). Groups six and seven were administered silymarin at doses of 6.5 and 13 mg/kg BW. Rabbits were euthanized and slaughtered on day 29 using the Halal method. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, urea, total proteins, albumin, total cholesterol, and high- and low-density lipoprotein (HDL and LDL) were analyzed in serum. Glutathione (GSH), superoxide dismutase (SOD), catalase, and malondialdehyde (MDA) were estimated in the liver. A histopathological investigation was performed on the liver and kidney. Results: The MDA activity, AST, ALT, total protein, albumin, total cholesterol, triglyceride, LDL, urea, and creatinine values were significantly elevated in groups two and three. The GSH, catalase, SOD, and HDL were significantly lower in these groups than in the control group. There were moderate pathologic changes in the liver and kidney of the third group . However, the results of the fourth and fifth groups improved more than those of the second and third groups. The results of the sixth and seventh groups were nearly the same as those of the control group. Conclusion: Salinomycin toxicity was caused by oxidative damage because of reactive oxygen species formation. Silymarin (6.5 or 13 mg/kg BW) tends to prevent and treat accidental toxicity. However, the high dose of silymarin (13 mg/kg BW) had more renal and hepatoprotective capacities.

Miao Zou, Xirui Yin, Xuan Zhou, Xinhui Niu, Yi Wang, Manman Su Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, ChangChun, People’s Republic of ChinaCorrespondence: Manman Su; Yi Wang, Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, 1266 Fujin Road, Changchun, 130021, People’s Republic of China, Tel/Fax +86 431 85619252, Email summ@jlu.edu.cn; wangyi@jlu.edu.cnBackground: Effective treatments for ovarian cancer remain elusive, and survival rates have long been considered grim. Ovarian cancer stem cells (OCSCs) and epithelial–mesenchymal transition (EMT) are associated with cancer progression and metastasis, as well as drug resistance and eventual treatment failure. Salinomycin (Sal) has an extensive effect on a variety of cancer stem cells (CSCs); however, its poor water solubility and toxicity to healthy tissues at high doses limit further research into its potential as an anti-cancer drug. We proposed a therapeutic strategy by constructing a tumor-targeting carrier that mimics high-density lipoprotein (HDL) to synthesize salinomycin-loaded high-density lipoprotein (S-HDL). This strategy helps reduce the side effects of salinomycin, thereby improving its clinical benefits.Methods: OCSCs were isolated from ovarian cancer cells (OCCs) and the uptake of HDL nanoparticles was observed using laser confocal microscopes. After the cell viability analysis revealed the inhibitory effect of S-HDL on OCCs and OCSCs, the main biological processes influenced by S-HDL were predicted with a transcriptome sequencing analysis and verified in vitro and in vivo.Results: Cellular uptake analysis showed that the HDL delivery system was able to significantly enhance the uptake of Sal by OCCs, tentatively validating the targeting role of recombinant HDL, so that S-HDL could reduce the toxicity of Sal and increase its anti-ovarian cancer effects. Conversely, S-HDL could exert anti-ovarian cancer effects by inhibiting the proliferation of OCCs and OCSCs, promoting apoptosis, blocking EMT, and suppressing stemness and angiogenesis-related protein expression in vitro and in vivo.Conclusion: S-HDL had stronger anti-ovarian cancer effects than unencapsulated Sal. Thus, it may be a potential agent for ovarian cancer treatment in the future.Keywords: ovarian cancer, ovarian cancer stem cells, epithelial–mesenchymal transition, salinomycin, high-density lipoprotein

Salinomycin (SM), a naturally occurring anti-tumour agent, is beneficial in treating a broad range of cancerous tumours. This is due to SM's limited aqueous solubility and poor bioavailability. Polyethylene glycol was conjugated to SM via a disulfide bond to alleviate the limitations of the previous technique. Small micelles (diameter ~ 63.5 nm) with excellent drug loading efficacy (~ 16.7%) and reduction and pH dual-sensitivity may be synthesized using this formulation, which self-assembles into micelles (SM-SS-Ms) in the aqueous solutions. A liver HepG2 cancer cell and its mice model xenograft were slandered methods in cell and animal investigations to demonstrate that SM-SS-Ms formulation could substantially extend the blood circulation and encourage tumour tissue accumulation. Antitumor effectiveness is achieved by SM-SS-Ms being targeted for accumulation in cancer cells, where they are quickly released into the intracellular microenvironment, which is acidic and glutathione-rich. [ABSTRACT FROM AUTHOR]

The targeted combinational chemotherapy can produce much higher cytotoxicity than the other therapies. This study aimed to fabricate the polymeric nanoparticles for the co-delivery of gemcitabine (GEM) and salinomycin (SAL) and to investigate the anticancer activity of the drug delivery mechanism (GEM/SAL@NPs) against in vitro liver cancer cells. The fabricated GEM/SAL@NPs were 32.1 ± 0.1 nm in nanoparticles size, and the polydispersity index was 0.156 ± 0.030. GEM and SAL were released gradually from the drug without any burst profile. Furthermore, GEM/SAL@NPs demonstrated dose-dependent in vitro cytotoxic properties in HEPG2 and SNU-475 cell lines compared to free drugs. In the cellular uptake analysis, the drugs-loaded NPs were more easily bound with cancer cells uptake in vitro conditions. Further, the fluorescence staining assays confirmed the apoptotic features established by the acridine orange, ethidium bromide, and nuclear Hoechst 33342 staining methods in vitro condition. The outcomes of fluorescence staining assays reveal that GEM/SAL@NPs induce mainly apoptosis in HEPG2 and SNU-475 liver cancer cells. Additionally, the apoptosis cell death mechanism was displayed that GEM/SAL@NPs significantly induce apoptosis in the HEPG2 and SNU-475 cancer cell lines. The in vivo systemic toxicity of the animal model shows an excellent toxicity profile in GEM/SAL@NPs using 150 µg/mL concentration. The potential cancer-selective delivery of versatile GEM/SAL@NPs indicated the effective payloads towards the targeting cancer site, enhanced apoptosis in liver cancer cells and improved systemic toxicity in the animal model. [ABSTRACT FROM AUTHOR]

A confirmatory, highly selective multi-residue method based on liquid chromatography coupled to hybrid high resolution mass spectrometry (LC-Q-Orbitrap) was developed and validated for the determination of 12 regulated coccidiostats in eggs and muscle. Particularly, ionophore antibiotics (lasalocid, maduramicin, monensin, narasin, salinomycin and semduramicin) and synthetic coccidiostats (diclazuril, halofuginone, nicarbazin as 4,4′-dinitrocarbanilide fraction, robenidine and toltrazuril as toltrazuril-sulphone) were included in the method. The sample preparation consisted in the extraction of the analytes from the matrix with acetonitrile, followed by a clean-up step with Oasis® PRiME HLB SPE and a defatting procedure with n-hexane. Validation was successfully performed according to Commission Implementing Regulation (EU) 2021/808, starting from 1 µg kg−1. The procedure was verified through the analysis of a certified reference material (CRM) and the occurrence of the residues was assessed in the context of the Italian National Residue Control Plan (NRCP). [ABSTRACT FROM AUTHOR]

Lead (Pb) is a highly toxic heavy metal that has deleterious effects on the central nervous system. This study aimed to investigate the effects of salinomycin (Sal) and deferiprone (DFP) on brain morphology and on the content of some essential elements in Pb-exposed mice. Adult male Institute of Cancer Research (ICR) mice were exposed to a daily dose of 80 mg/kg body weight (b.w.) Pb(II) nitrate for 14 days and subsequently treated with Sal (16 mg/kg b.w.) or DFP (19 mg/kg b.w.) for another 14 days. At the end of the experimental protocol, the brains were processed for histological and inductively coupled plasma mass spectrometry (ICP-MS) analyses. Pb exposure resulted in a 50-fold increase in Pb concentration, compared with controls. Magnesium (Mg) and phosphorus (P) were also significantly increased by 22.22% and 17.92%, respectively. The histological analysis of Pb-exposed mice revealed brain pathological changes with features of neuronal necrosis. Brain Pb level remained significantly elevated in Sal- and DFP-administered groups (37-fold and 50-fold, respectively), compared with untreated controls. Treatment with Sal significantly reduced Mg and P concentrations by 22.56% and 18.38%, respectively, compared with the Pb-exposed group. Administration of Sal and DFP ameliorated brain injury in Pb-exposed mice and improved histological features. The results suggest the potential application of Sal and DFP for treatment of Pb-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Enrofloxacin (ENR) is one of the most common drugs used in poultry production to treat bacterial diseases, and there is a high risk of drug interactions (DDIs) between polyether anticoccidial drugs added to poultry feed over time. This may affect the efficacy of antibiotics or lead to toxicity, posing a potential risk to the environment and food safety. This study aimed to investigate the DDI of ENR and salinomycin (SAL) in broilers and the mechanism of their DDI. We found that SAL increased the area under the curve and elimination half-life of ENR and ciprofloxacin (CIP) by 1.3 and 2.4 times, 1.2 and 2.5 times, respectively. Cytochrome 3A4 (CYP3A4), p-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) were important factors for the DDI between ENR and SAL in broilers. ENR and SAL are substrates of CYP3A4, P-gp and BCRP in broilers; ENR and SAL inhibited the expression of CYP3A4 activity in a time- and concentration-dependent. Meanwhile, ENR downregulated the expression of P-gp and BCRP in a time- and concentration-dependent manner. A single oral administration of SAL inhibited CYP3A4, P-gp, and BCRP, but long-term mixed feeding upregulated the expression of CYP3A4, P-gp, and BCRP. Molecular docking revealed that ENR and SAL compete with each other for CYP3A4 to affect hepatic metabolism, and compete with ATP for P-gp and BCRP binding sites to inhibit efflux. ENR and SAL in broilers can lead to severe DDI. Drug residues and resistance following co-administration of ENR and SAL and other SAL-based drug-feed interactions warrant further study. [ABSTRACT FROM AUTHOR]

Long-term hyperuricemia can induce kidney damage, clinically referred to as hyperuricemic nephropathy (HN), which is characterized by renal fibrosis, inflammation, and oxidative stress. However, currently used uric acid-lowering drugs are not capable of protecting the kidneys from damage. Therefore, uric acid-lowering drugs that can also protect the kidneys are urgently needed. In this study, we first discovered that salinomycin, an antibiotic, can regulate uric acid homeostasis and ameliorate kidney damage in mice with HN. Mechanistically, salinomycin inhibited serum and hepatic xanthine oxidase (XOD) activities and downregulated renal urate transporter 1 (URAT1) expression and transport activity, thus exerting uric acid-lowering effects in mice with HN. Furthermore, we found that salinomycin promoted p -NRF2 Ser40 expression, resulting in increased nuclear translocation of NRF2 and activation of NRF2. More importantly, salinomycin affected the gut microbiota and promoted the generation of short-chain fatty acids (SCFAs) in mice with HN. In conclusion, our results revealed that salinomycin maintains uric acid homeostasis and alleviates kidney injury in mice with HN by multiple mechanisms, suggesting that salinomycin might be a desirable candidate for HN treatment in the clinic. Salinomycin maintains the uric acid homeostasis in HN mice by inhibiting XOD and URAT1. Besides, it also improves renal fibrosis, inflammation and oxidative stress in HN mice by activating NRF2 and regulating gut microbiota as well as promoting SCFA production. The multiple effects of salinomycin contribute to its protective effect on the kidney damage in HN mice. [Display omitted] • Salinomycin decreases serum uric acid level via inhibiting XOD and URAT1 in HN mice. • Salinomycin alleviates renal fibrosis, inflammation and oxidative stress in HN mice. • Salinomycin improves kidney injury by regulating gut microbiota and promoting SCFAs production in HN mice. • Salinomycin ameliorates hyperuricemic nephropathy via regulating NRF2 pathway. [ABSTRACT FROM AUTHOR]

Salinomycin (Sal) has attracted considerable attention in the field of tumor treatment, especially for its inhibitory effect on cancer stem cells (CSCs) and drug-resistant tumor cells. However, its solubility and targeting specificity pose significant challenges to its pharmaceutical development. Sal-A6, a novel peptide-drug conjugate (PDC), was formed by linking the peptide A6 targeting the CSC marker CD44 with Sal using a specific linker. This conjugation markedly enhances the physicochemical properties of Sal and compared to Sal, Sal-A6 demonstrated a significantly increased activity against ovarian cancer. Furthermore, Sal-A6, employing a disulfide bond as a linker, exhibited bystander killing effect. Moreover, it induces substantial cytotoxic effect on both cancer stem cells and drug-resistant cells in addition to enhance chemosensitivity of resistant ovarian cancer cells. In summary, the results indicated that Sal-A6, a novel PDC derived from Sal, has potential therapeutic applications in the treatment of ovarian cancer and drug-resistant patients. Additionally, this discovery offers insights for developing PDC-type drugs using Sal as a foundation. [Display omitted] • Novel Sal-A6 conjugate with a significant solubility improvement. • Sal-A6 specifically targets CD44 with a threefold increase in cell toxicity. • Sal-A6 demonstrated bystander killing effects. • Sal-A6 demonstrates a substantial inhibitory effect on CSCs surpassing Sal activity. • Significant cytotoxicity against drug-resistant tumor cells with drug-sensitizing effects. [ABSTRACT FROM AUTHOR]

The health and productivity of broilers may be improved by optimizing the availability and levels of trace minerals (TM) in their feed, especially in the presence of parasites. This study investigated the effects of replacing inorganic TM (ITM) with an advanced chelate technology-based 7 TM (ACTM) on performance, hematology, lesion score, oocyst shedding, gut morphology, and tight junction structure in broilers challenged with mixed Eimeria species. There were 480 1-day-old broiler chickens divided into 5 groups: uninfected negative control and recommended levels of ITM (NC); infected positive control and recommended levels of ITM (PC); or PC supplemented with salinomycin (SAL); PC diet with 50 % ACTM instead of ITM (ACTM50); or PC diet with 100 % ACTM instead of ITM (ACTM100). All groups, except NC, were orally challenged with mixed Eimeria spp. oocysts on day 14. Each group had 6 replicate cages, with 16 birds per replicate. The results showed that the NC, SAL, and ACTM100 groups had higher (P < 0.05) body weight, average daily gain (ADG), and European production efficiency index (EPEI), as well as a lower (P < 0.05) feed conversion, mortality rate, and heterophile to lymphocyte ratio compared to the PC group, with the NC group having the highest ADG and EPEI throughout the experiment. The SAL and ACTM100 groups had lower (P < 0.05) intestinal lesion scores and oocyst numbers compared to the PC group, although all coccidiosis-challenged groups had higher oocyst shedding compared to the NC group. On day 24, the challenged birds in the SAL and ACTM100 groups had higher (P < 0.05) villus height and surface area in the duodenum and ileum, as well as a higher (P < 0.05) villus height to crypt depth ratio in the jejunum. The expression levels of jejunal CLDN1 and ZO-1 were also higher (P < 0.05) in the ACTM100 and SAL groups compared to the PC and ACTM50 groups at 24 days of age. In conclusion, while using ACTM in broiler diets at 50 % of the commercial recommended levels maintained performance and physiological responses, complete replacement with ACTM improved growth performance and intestinal health characteristics, similar to salinomycin under Eimeria challenge conditions. • Replacement of inorganic TM with advanced chelated TM (ACTM) was studied in Eimeria -infected broilers. • Complete replacement (ACTM100 group), similar to salinomycin (SAL), improved performance. • ACTM100 and SAL groups also decreased intestinal lesion scores and oocyst numbers. • ACTM100 group improved gut morphology compared to the control-infected group. • Expression levels of jejunal CLDN1 and ZO-1 were increased in ACTM100 and SAL groups. [ABSTRACT FROM AUTHOR]

To ensure food safety, coccidiostats' residue levels in food of animal origin are monitored to see if they comply with the established Maximum Residue Limits (MRL) and Maximum Levels (ML). The incidence of non-compliant (exceeding permitted limits) results in Europe dropped from 1.01% in 2009 to 0.13% in 2021. Nicarbazin, narasin, lasalocid, and salinomycin were the most frequently reported analytes. During monitoring in Poland in 2016–2022, 14.3% positive samples (above LOQ), and 0.85% non-compliant samples were reported, mostly in eggs and poultry. Based on data collected in Polish monitoring, a risk assessment was performed. In the worst-case, estimated daily intake (EDI) exceeded the acceptable daily intake (ADI) only for toltrazuril, up to three times in every assessed age group. In the average scenario, EDIs of all assessed coccidiostats (decoquinate, diclazuril, lasalocid, nicarbazin, robenidine, salinomycin, and toltrazuril) were well below their corresponding ADIs. The results indicate no direct health risk resulting from the consumption of food of animal origin. • Coccidiostat residues are found mostly in eggs and poultry samples. • The incidence of positive results is high but residues rarely exceed legal limits. • Nicarbazin, narasin, lasalocid, and salinomycin were found the most frequently. • Exposure to coccidiostat residues from food poses no direct risk to human health. [ABSTRACT FROM AUTHOR]

The presence of antimicrobial residues in products of animal origin is a constant problem for consumer health. The aim of this study was to observe the effect of the addition of humic substances (H), fermented products (F) and a mixture of both (FH) to feed supplemented with the coccidiostat salinomycin, compared with a control group (C), on the content of salinomycin residues in the edible tissues of broiler chickens using two microbial inhibition screening methods, Explorer 2.0 test and the Screening Test for Antibiotic Residues (STAR), and a confirmatory competitive enzyme immunoassay analysis (Salinomycin ELISA Kit). The results of the microbial inhibition tests showed a gradual decline in the positive results in the tissue samples from the last day of salinomycin administration (30th day) tothe last day of fattening (37th day, day of slaughter) in group C and no positive results in the tissue samples from experimental groups H, F and FH slaughtered on the last day of fattening. Using the Salinomycin ELISA Kit, salinomycin was detected in the chicken muscle tissues of all the control and experimental groups. However, no sample from any group contained salinomycin at a concentration exceeding the maximum residue limits set by European law. The high level of significance (p < 0.001) confirmed the positive influence of the administration of humic substances and fermented products on the content of salinomycin residues in chicken tissues.

Aquaculture, a crucial sector of the global food industry, faces a myriad of issues due to parasitic invasions. One such parasite, Microcotyle sebastis, which afflicts Korean rockfish in South Korea, has a significant economic impact. The impending danger of resistance to traditional anthelmintics necessitates the exploration of new antiparasitic candidates. Although the efficacy of salinomycin against aquatic parasites such as ciliates and sporozoans is known, its influence on monogeneans has yet to be studied. Therefore, this study investigated the efficacy and safety of salinomycin for the treatment of M. sebastis infections, presenting the first exploration of salinomycin’s therapeutic potential against monogeneans. In vitro examinations revealed a minimum effective concentration of salinomycin of 5 mg/kg, which led to necrosis of the haptor upon dislodging from the gill filaments. The one-time oral administration of the drug at concentrations of 5 mg/kg and 10 mg/kg showed a significant dose-dependent reduction in parasite counts, with no apparent behavioral side effects in Korean rockfish. Biochemical analyses monitored the liver, heart, and kidney enzymes, specifically aspartate transaminase (AST), alanine transaminase (ALT), blood urea nitrogen (BUN), and creatine kinase–myocardial band (CK-MB). At both 20 °C and 13 °C, no significant differences were observed in the levels of AST and ALT. However, at 20 °C, alterations in BUN levels were evident on Day 14, a deviation not observed at 13 °C. The CK-MB analysis revealed elevated enzyme levels at both temperatures when compared to the control group, reflecting the similar changes observed in terrestrial animals administered salinomycin. The biochemical data suggest that the oral administration of salinomycin is potentially more favorable at 13 °C than at 20 °C. Although our findings warrant further comprehensive studies, including on the long-term and potential effects on nontarget species and water quality, they also suggest that salinomycin could be considered as an alternative or adjunctive treatment if resistance to the currently used praziquantel against M. sebastis is confirmed.

Streptomyces is well known for synthesis of many biologically active secondary metabolites, such as polyketides and non‐ribosomal peptides. Understanding the coupling mechanisms of primary and secondary metabolism can help develop strategies to improve secondary metabolite production in Streptomyces. In this work, Streptomyces albus ZD11, an oil‐preferring industrial Streptomyces strain, was proved to have a remarkable capability to generate abundant acyl‐CoA precursors for salinomycin biosynthesis with the aid of its enhanced β‐oxidation pathway. It was found that the salinomycin biosynthetic gene cluster contains a predicted 3‐hydroxyacyl‐CoA dehydrogenase (FadB3), which is the third enzyme of β‐oxidation cycle. Deletion of fadB3 significantly reduced the production of salinomycin. A variety of experimental evidences showed that FadB3 was mainly involved in the β‐oxidation pathway rather than ethylmalonyl‐CoA biosynthesis and played a very important role in regulating the rate of β‐oxidation in S. albus ZD11. Our findings elucidate an interesting coupling mechanism by which a PKS biosynthetic gene cluster could regulate the β‐oxidation pathway by carrying β‐oxidation genes, enabling Streptomyces to efficiently synthesize target polyketides and economically utilize environmental nutrients. [ABSTRACT FROM AUTHOR]

Epithelial-specific Maspin is widely known as a tumor suppressor. However, while the level of maspin expression is inversely correlated with tumor grade and stage, emerging clinical evidence shows a correlation between seemingly better differentiated tumor cells that express Maspin in both the nucleus and the cytoplasm, (n + c)Maspin, with a poor prognosis of many types of cancer. Biological studies demonstrate that Maspin plays an essential role in stem cell differentiation. In light of the recently established characterization of primed stem cells (P-SCs) in development, we propose, for the first time, that cancer stem cells (CSCs) also need to undergo priming (P-CSCs) before their transition to various progeny phenotypes. We envisage major differences in the steady state kinetics between P-SCs and P-CSCs. We further propose that P-CSCs of carcinoma are both marked and regulated by (n + c)Maspin. The concept of P-CSCs helps explain the apparent dichotomous relationships of (n + c)Maspin expression with cancer diagnosis and prognosis, and is supported by the evidence from mechanistic studies. We believe that the potential utility of (n + c)Maspin as a molecular marker of P-CSCs may significantly accelerate the advancement in our understanding of the genesis of tumor phenotypic plasticity in response to changes of tumor microenvironments (TME) or drug treatments. The vulnerabilities of the cellular state of (n + c)Maspin-expressing P-CSCs are also discussed as the rationale for future development of P-CSC-targeted chemotherapeutic and immunotherapeutic strategies. [ABSTRACT FROM AUTHOR]