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This study evaluated the effects of two herbal extract mixtures as alternatives to salinomycin on growth performance and physiological responses in broilers subjected to experimental coccidial challenge. A total of 840 Ross 308 broilers were assigned to four dietary treatments: a basal diet (CON), CON supplemented with 0.1% salinomycin (Group 1), CON supplemented with 0.015% herbal extract mixture (Group 2), and CON supplemented with 0.02% herbal extract mixture (Group 3). All birds were orally challenged with a 30-fold dose of a live coccidiosis vaccine at 14 days of age. During the post-challenge period, broilers in Group 1 and Group 3 showed significantly higher body weight gain (BWG) and lower feed conversion ratio (FCR) compared with the control group (p < 0.05), whereas feed intake was not affected. Dietary treatments induced selective changes in blood biochemical and hematological parameters, including increased serum calcium and sodium concentrations and altered leukocyte profiles (p < 0.05). However, relative organ weights, fecal oocyst shedding, intestinal morphology, and circulating cytokine levels were not significantly affected by dietary treatments (p > 0.05). Notably, ZO-1 gene expression was upregulated in selected treatment groups (p < 0.05), while other barrier- and proliferation-related genes remained unchanged. Overall, these findings suggest that herbal extract supplementation improves growth performance in broilers under coccidial challenge primarily through modulation of host physiological responses rather than direct inhibition of parasite replication.

Cancer stem cells (CSCs) represent a subset of cells within tumours that exhibit self-renewal properties and the capacity to seed tumours. CSCs are typically refractory to conventional treatments and have been associated to metastasis and relapse. Salinomycin operates as a selective agent against CSCs through mechanisms that remain elusive. Here, we provide evidence that a synthetic derivative of salinomycin, which we named ironomycin (AM5), exhibits a more potent and selective activity against breast CSCs in vitro and in vivo , by accumulating and sequestering iron in lysosomes. In response to the ensuing cytoplasmic depletion of iron, cells triggered the degradation of ferritin in lysosomes, leading to further iron loading in this organelle. Iron-mediated production of reactive oxygen species promoted lysosomal membrane permeabilization, activating a cell death pathway consistent with ferroptosis. These findings reveal the prevalence of iron homeostasis in breast CSCs, pointing towards iron and iron-mediated processes as potential targets against these cells. Cancer stem cells are typically refractory to conventional treatments. Now, an unprecedented mechanism has been discovered by which salinomycin and derivatives can sequester iron in lysosomes leading to cytoplasmic iron depletion and the subsequent production of reactive oxygen species that are lethal to the cell. This discovery of the importance of iron in cancer stem cell maintenance provides an opportunity for developing new therapeutics.

Ion homeostasis is extremely important for the survival of both normal as well as neoplastic cells. The altered ion homeostasis found in cancer cells prompted the investigation of several ionophores as potential anticancer agents. Few ionophores, such as Salinomycin, Nigericin and Obatoclax, have demonstrated potent anticancer activities against cancer stem-like cells that are considered highly resistant to chemotherapy and responsible for tumor relapse. The preclinical success of these compounds in in vitro and in vivo models have not been translated into clinical trials. At present, phase I/II clinical trials demonstrated limited benefit of Obatoclax alone or in combination with other anticancer drugs. However, future development in targeted drug delivery may be useful to improve the efficacy of these compounds. Alternatively, these compounds may be used as leading molecules for the development of less toxic derivatives.

The two-component system “AfsQ1/Q2” plays a crucial role to activate the production of antibiotics ACT, RED, and CDA through directly binding the promoters of pathway-specific activator genes actII-ORF4, redZ, and cdaR respectively when grown under glutamate-supplemented minimal medium in Streptomyces coelicolor. In this report, we demonstrated that the RspA1/A2 (a homologous protein of two-component system AfsQ1/Q2) plays a regulatory role in salinomycin biosynthesis in Streptomyces albus. Gene deletion and complementation experiments showed that the RspA1/A2 promoted salinomycin production but inhibited cell growth when cultured in YMG medium supplemented with 3% soybean oil. More importantly, RspA1/A2 strengthens salinomycin biosynthesis by directly affecting the transcription of the pathway-specific activator gene slnR. Meanwhile, RspA1/A2 plays a negative role in the regulation of nitrogen assimilation and urea decarboxylation by interacting with the promoters of genes gdhA, glnA, amtB, and SLNWT_1828/1829. Gene sigW is located downstream of rspA1/A2 and encodes an extracytoplasmic function sigma factor. Moreover, it negatively regulates the salinomycin biosynthesis and promotes cell growth, which antagonizes the function of RspA1/A2. In short, these useful findings are proved helpful to enrich the understanding of the regulatory pathways of antibiotic biosynthesis by an ECF σ factor-TCS signal transduction system in Streptomyces.

As of June 2020, the number of people infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) continues to skyrocket, with more than 6.7 million cases worldwide. Both the World Health Organization (WHO) and United Nations (UN) has highlighted the need for better control of SARS-CoV-2 infections. However, developing novel virus-specific vaccines, monoclonal antibodies and antiviral drugs against SARS-CoV-2 can be time-consuming and costly. Convalescent sera and safe-in-man broad-spectrum antivirals (BSAAs) are readily available treatment options. Here, we developed a neutralization assay using SARS-CoV-2 strain and Vero-E6 cells. We identified the most potent sera from recovered patients for the treatment of SARS-CoV-2-infected patients. We also screened 136 safe-in-man broad-spectrum antivirals against the SARS-CoV-2 infection in Vero-E6 cells and identified nelfinavir, salinomycin, amodiaquine, obatoclax, emetine and homoharringtonine. We found that a combination of orally available virus-directed nelfinavir and host-directed amodiaquine exhibited the highest synergy. Finally, we developed a website to disseminate the knowledge on available and emerging treatments of COVID-19.

The ongoing COVID-19 pandemic has caused more than 193,825 deaths during the past few months. A quick-to-be-identified cure for the disease will be a therapeutic medicine that has prior use experiences in patients in order to resolve the current pandemic situation before it could become worsening. Artificial intelligence (AI) technology is hereby applied to identify the marketed drugs with potential for treating COVID-19. An AI platform was established to identify potential old drugs with anti-coronavirus activities by using two different learning databases; one consisted of the compounds reported or proven active against SARS-CoV, SARS-CoV-2, human immunodeficiency virus, influenza virus, and the other one containing the known 3C-like protease inhibitors. All AI predicted drugs were then tested for activities against a feline coronavirus in cell-based assay. These assay results were feedbacks to the AI system for relearning and thus to generate a modified AI model to search for old drugs again. After a few runs of AI learning and prediction processes, the AI system identified 80 marketed drugs with potential. Among them, 8 drugs (bedaquiline, brequinar, celecoxib, clofazimine, conivaptan, gemcitabine, tolcapone, and vismodegib) showed activities against the proliferation of a feline infectious peritonitis (FIP) virus in Fcwf-4 cells. In addition, 5 other drugs (boceprevir, chloroquine, homoharringtonine, tilorone, and salinomycin) were also found active during the exercises of AI approaches. Having taken advantages of AI, we identified old drugs with activities against FIP coronavirus. Further studies are underway to demonstrate their activities against SARS-CoV-2 and at clinically achievable concentrations and doses. With prior use experiences in patients, these old drugs if proven active against SARS-CoV-2 can readily be applied for fighting COVID-19 pandemic.

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal’s effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.

Introduction: Breast cancer (BC) presents significant morbidity and mortality challenges. Autophagy plays a contradictory role in BC. The chemotherapeutic agent salinomycin exhibits anticancer effects, but its effectiveness is limited by over-activation of autophagy. This study aimed to investigate the effects and mechanisms of salinomycin and its combination with chloroquine in BC. Methods: The MCF-7 and MCF-7 tumor spheroids (MCF-7-TS) BC models were treated separately with salinomycin and autophagy inducer/inhibitor (rapamycin/chloroquine). Cell proliferation, apoptosis, and cell cycle progression were measured using cell counting kit-8 (CCK-8), cell colony assay, and flow cytometry. The expression of apoptosis-related, autophagy-related, and phosphoinositide 3-kinases (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway-related proteins was measured via Western blot. Light chain 3 (LC3) expression was detected via immunofluorescence. Results: In the MCF-7 and MCF-7-TS cells, salinomycin inhibited cell viability, p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR expression, and increased apoptosis and LC3 expression, with reduced tumor spheroid number and volume of MCF-7-TS cells. Interestingly, rapamycin enhanced LC3 expression but prevented apoptosis in salinomycin-treated cells, with elevated tumor spheroid number and volume of MCF-7-TS cells. Moreover, after screening for a suitable ratio of salinomycin and chloroquine (1:2.5), compared to salinomycin group, salinomycin + chloroquine group exhibited decreased tumor spheroid number and volume of MCF-7-TS cells; reduced B-cell lymphoma-2 (Bcl-2), LC3, LC3II/LC3I, and Beclin-1 expression; and enhanced G0/G1 phase arrest and Bcl-2-associated X protein expression in MCF-7 and MCF-7-TS cells. Conclusion: Chloroquine enhanced the anticancer efficacy of salinomycin by suppressing salinomycin-induced autophagy, providing a solid theoretical basis for its clinical application in BC.

Recently, the interplay between autophagy and apoptosis has become an important factor in chemotherapy for cancer treatment. Inhibition of autophagy may be an effective strategy to improve the treatment of chemo-resistant cancer by consistent exposure to chemotherapeutic drugs. However, no reports have clearly elucidated the underlying mechanisms. Therefore, in this study, we assessed whether salinomycin, a promising anticancer drug, induces apoptosis and elucidated potential antitumor mechanisms in chemo-resistant prostate cancer cells. Cell viability assay, Western blot, annexin V/propidium iodide assay, acridine orange (AO) staining, caspase-3 activity assay, reactive oxygen species (ROS) production, and mitochondrial membrane potential were assayed. Our data showed that salinomycin alters the sensitivity of prostate cancer cells to autophagy. Pretreatment with 3-methyladenine (3-MA), an autophagy inhibitor, enhanced the salinomycin-induced apoptosis. Notably, salinomycin decreased phosphorylated of AKT and phosphorylated mammalian target of rapamycin (mTOR) in prostate cancer cells. Pretreatment with LY294002, an autophagy and PI3K inhibitor, enhanced the salinomycin-induced apoptosis by decreasing the AKT and mTOR activities and suppressing autophagy. However, pretreatment with PD98059 and SB203580, an extracellular signal-regulated kinases (ERK), and p38 inhibitors, suppressed the salinomycin-induced autophagy by reversing the upregulation of ERK and p38. In addition, pretreatment with N-acetyl-l-cysteine (NAC), an antioxidant, inhibited salinomycin-induced autophagy by suppressing ROS production. Our results suggested that salinomycin induces apoptosis, which was related to ROS-mediated autophagy through regulation of the PI3K/AKT/mTOR and ERK/p38 MAPK signaling pathways.

The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells’ proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo . This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and β -catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy.