Pub Date : 2025-11-27DOI: 10.1007/s10534-025-00767-6
Amanda M. Mackie, Christopher J. Schuler, Darcy L. McRose
The macronutrient phosphorus is vital for sustaining cellular processes in all life forms. Due to its frequent adsorption on iron minerals, phosphorus bioavailability is low in many soils. While the abiotic adsorption of phosphate on iron minerals has been well studied, the direct effects of this process on bioavailability to plants and microbes has not been thoroughly investigated in a simplified laboratory system. We developed a hydroponic growth system that uses hydrous ferric oxide (HFO) to induce phosphorus limitation and can enable both plant and microbial cultivation as well as gnotobiotic co-culture. We demonstrate that this system can be used for phosphorus-limited growth of the model plant Arabidopsis thaliana as well as two root-associated bacterial isolates (from the genera Rhizobium and Pseudomonas). Elemental analysis of phosphorus and iron concentration in A. thaliana shoots reveals that the addition of increasing amounts of HFO leads to a progressive decrease in phosphorus concentration but does not affect iron quotas. We also report that phosphorus concentrations in both bacterial isolates decrease when cultivated in media supplemented with HFO. We further show that A. thaliana can be co-cultured with a Rhizobium isolate in our phosphorus-limited hydroponic system with bacteria relying on plant photosynthate as their sole carbon source. Our work provides a controlled demonstration of the effects of mineral adsorption on phosphorus bioavailability and a tool for further investigation of how plants and microbes access phosphorus in the environment.
{"title":"Gnotobiotic growth and phosphorus limitation of Arabidopsis thaliana and co-occurring microbes on phosphated iron oxides","authors":"Amanda M. Mackie, Christopher J. Schuler, Darcy L. McRose","doi":"10.1007/s10534-025-00767-6","DOIUrl":"10.1007/s10534-025-00767-6","url":null,"abstract":"<div><p>The macronutrient phosphorus is vital for sustaining cellular processes in all life forms. Due to its frequent adsorption on iron minerals, phosphorus bioavailability is low in many soils. While the abiotic adsorption of phosphate on iron minerals has been well studied, the direct effects of this process on bioavailability to plants and microbes has not been thoroughly investigated in a simplified laboratory system. We developed a hydroponic growth system that uses hydrous ferric oxide (HFO) to induce phosphorus limitation and can enable both plant and microbial cultivation as well as gnotobiotic co-culture. We demonstrate that this system can be used for phosphorus-limited growth of the model plant <i>Arabidopsis thaliana</i> as well as two root-associated bacterial isolates (from the genera <i>Rhizobium</i> and <i>Pseudomonas</i>). Elemental analysis of phosphorus and iron concentration in <i>A. thaliana</i> shoots reveals that the addition of increasing amounts of HFO leads to a progressive decrease in phosphorus concentration but does not affect iron quotas. We also report that phosphorus concentrations in both bacterial isolates decrease when cultivated in media supplemented with HFO. We further show that <i>A. thaliana</i> can be co-cultured with a <i>Rhizobium</i> isolate in our phosphorus-limited hydroponic system with bacteria relying on plant photosynthate as their sole carbon source. Our work provides a controlled demonstration of the effects of mineral adsorption on phosphorus bioavailability and a tool for further investigation of how plants and microbes access phosphorus in the environment.</p></div>","PeriodicalId":491,"journal":{"name":"Biometals","volume":"39 1","pages":"359 - 373"},"PeriodicalIF":3.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10534-025-00767-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1007/s10534-025-00746-x
Ibtisam Mousa, Abeer A. Ageeli, Hind Ahmed Siddiq, Nada D. Alkhathami, Nada M. Alatawi, Deemah Mizher Alenazy, Sharah A. Aldulmani, Abdel-Nasser M. A. Alaghaz
Nano-sized bivalent metal chelates of thiophene–thiol Schiff’s base Zn(II), Cu(II), Ni(II), and Co(II) were investigated by spectroscopic methods and quantum mechanical calculations. These chelates adopt the overall formula [M(TTSB)2], given that TTSB = [4-methyl-2-((E)-((2-(((E)-thiophen-2-ylmethylene)amino)phenyl)imino)methyl)-benzenethiol] (C19H16N2S2), M = Cu(II), Ni(II), Co(II), and Zn(II). Quantum chemical calculations were used to supplement the experimental investigations. The [Zn(TTSB)2] chelate with a small energy gap value ∆E (0.900 eV) is more reactive than all other chelates, according to DFT simulations that examined ∆E for molecules in LUMO and HOMO. The tridentate NNS donor Schiff base and the metal ions (II) created three coordination bonds, which produced chelates with an octahedral geometry. The bivalent metal chelates' high-resolution TEM and X-ray diffraction (XRD) data demonstrated that the particles were nanometric in size and distributed uniformly across the chelates ' surfaces. Nano-sized metal (II) chelates exhibit higher viscosity than thiophene–thiol Schiff’s base ligand (TTSB). Every synthetic molecule has undergone screening for antibacterial activity in vitro. The reference standard and test drugs' minimum inhibitory concentrations (MICs) were established. Excellent action against Candida albicans has been demonstrated by ligand, Cu(II), and Zn(II) chelates. The cytotoxicity of TTSB ligand and its chelates against HePG2 (human liver cancer cell line) and MCF-7 (Humanbreast adenocarcinoma cell line) was evaluated by the MTT assay for 24 h. The cytotoxicity experiments against HePG2 showed the order: [Zn(TTSB)2] > [Cu(TTSB)2] > [Co(TTSB)2] > [Ni(TTSB)2] > TTSB. Furthermore, biological investigations revealed that chelate Zn(II) induced apoptosis and halted the cell cycle at the G1 phase in HePG2 cancer cells. Notably, after 24 h, Zn(II) chelate significantly elevated reactive oxygen species (ROS) levels, suggesting a potential mechanism for its anticancer effects. To monitor Zn(II) chelate distribution within HePG2 cells, researchers employed confocal laser scanning microscopy. The findings demonstrated that Zn(II) chelate specifically localized to lysosomes, leading to lysosomal dysfunction.
{"title":"Synthesis, characterization, and anticancer evaluation of nano-sized schiff base metal chelates","authors":"Ibtisam Mousa, Abeer A. Ageeli, Hind Ahmed Siddiq, Nada D. Alkhathami, Nada M. Alatawi, Deemah Mizher Alenazy, Sharah A. Aldulmani, Abdel-Nasser M. A. Alaghaz","doi":"10.1007/s10534-025-00746-x","DOIUrl":"10.1007/s10534-025-00746-x","url":null,"abstract":"<div><p>Nano-sized bivalent metal chelates of thiophene–thiol Schiff’s base Zn(II), Cu(II), Ni(II), and Co(II) were investigated by spectroscopic methods and quantum mechanical calculations. These chelates adopt the overall formula [M(TTSB)<sub>2</sub>], given that TTSB = [4-methyl-2-((E)-((2-(((E)-thiophen-2-ylmethylene)amino)phenyl)imino)methyl)-benzenethiol] (C<sub>19</sub>H<sub>16</sub>N<sub>2</sub>S<sub>2</sub>), M = Cu(II), Ni(II), Co(II), and Zn(II). Quantum chemical calculations were used to supplement the experimental investigations. The [Zn(TTSB)2] chelate with a small energy gap value ∆E (0.900 eV) is more reactive than all other chelates, according to DFT simulations that examined ∆E for molecules in LUMO and HOMO. The tridentate NNS donor Schiff base and the metal ions (II) created three coordination bonds, which produced chelates with an octahedral geometry. The bivalent metal chelates' high-resolution TEM and X-ray diffraction (XRD) data demonstrated that the particles were nanometric in size and distributed uniformly across the chelates ' surfaces. Nano-sized metal (II) chelates exhibit higher viscosity than thiophene–thiol Schiff’s base ligand (TTSB). Every synthetic molecule has undergone screening for antibacterial activity in vitro. The reference standard and test drugs' minimum inhibitory concentrations (MICs) were established. Excellent action against Candida albicans has been demonstrated by ligand, Cu(II), and Zn(II) chelates. The cytotoxicity of TTSB ligand and its chelates against HePG2 (human liver cancer cell line) and MCF-7 (Humanbreast adenocarcinoma cell line) was evaluated by the MTT assay for 24 h. The cytotoxicity experiments against HePG2 showed the order: [Zn(TTSB)<sub>2</sub>] > [Cu(TTSB)<sub>2</sub>] > [Co(TTSB)<sub>2</sub>] > [Ni(TTSB)<sub>2</sub>] > TTSB. Furthermore, biological investigations revealed that chelate Zn(II) induced apoptosis and halted the cell cycle at the G1 phase in HePG2 cancer cells. Notably, after 24 h, <b>Zn(II) chelate</b> significantly elevated reactive oxygen species (ROS) levels, suggesting a potential mechanism for its anticancer effects. To monitor <b>Zn(II) chelate</b> distribution within HePG2 cells, researchers employed confocal laser scanning microscopy. The findings demonstrated that <b>Zn(II) chelate</b> specifically localized to lysosomes, leading to lysosomal dysfunction.</p></div>","PeriodicalId":491,"journal":{"name":"Biometals","volume":"38 6","pages":"2043 - 2073"},"PeriodicalIF":3.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The unique properties of nanoparticles have sparked intense research interest, driving innovation in production methodologies. Biological synthesis of nanoparticles has emerged as a game-changer, offering an efficient, cost-effective, and eco-friendly alternative. A diverse array of organisms, including bacteria, fungi, yeast, algae, and plants, can biosynthesize metallic nanoparticles with varying sizes and shapes through reduction reactions. A comprehensive analysis of existing literature reveals the bio reduction capabilities of bacterial biomass and extracts under different experimental conditions, providing valuable insights into this promising field. The applications of biosynthesized nanoparticles are vast, with notable potential in antimicrobial and anticancer activities. By exploring the achievements and current status of bacterial-mediated biosynthesis, this study aims to shed light on the opportunities and challenges in this rapidly evolving field. The surge in nanoparticle research is largely driven by the unexpected variations in surface properties that occur when particle size is reduced to the nanoscale, resulting in enhanced features such as particle size distribution and shape. The reduction of particle size to the nanoscale displays unique and improved features, including particle size distribution and shape. This variation in specific surface area is responsible for its high value, which influences critical factors such as surface reactivity. Gold particles have been employed for medicinal and Ayurvedic purposes in India and China since ancient times. Metal nanoparticles are being used globally in biomedicine and related fields. Researchers are currently focused on metal nanoparticles, nanostructures, and nanomaterial production due to their unique features. This paper examines various metal oxide nanoparticle preparation processes, including their benefits, drawbacks, and potential applications.
{"title":"Metal oxide nanoparticles: emerging stars in biomedical application","authors":"Priyadharsini Shanumuganandam, Sathiamoorthi Thangavelu","doi":"10.1007/s10534-025-00749-8","DOIUrl":"10.1007/s10534-025-00749-8","url":null,"abstract":"<div><p>The unique properties of nanoparticles have sparked intense research interest, driving innovation in production methodologies. Biological synthesis of nanoparticles has emerged as a game-changer, offering an efficient, cost-effective, and eco-friendly alternative. A diverse array of organisms, including bacteria, fungi, yeast, algae, and plants, can biosynthesize metallic nanoparticles with varying sizes and shapes through reduction reactions. A comprehensive analysis of existing literature reveals the bio reduction capabilities of bacterial biomass and extracts under different experimental conditions, providing valuable insights into this promising field. The applications of biosynthesized nanoparticles are vast, with notable potential in antimicrobial and anticancer activities. By exploring the achievements and current status of bacterial-mediated biosynthesis, this study aims to shed light on the opportunities and challenges in this rapidly evolving field. The surge in nanoparticle research is largely driven by the unexpected variations in surface properties that occur when particle size is reduced to the nanoscale, resulting in enhanced features such as particle size distribution and shape. The reduction of particle size to the nanoscale displays unique and improved features, including particle size distribution and shape. This variation in specific surface area is responsible for its high value, which influences critical factors such as surface reactivity. Gold particles have been employed for medicinal and Ayurvedic purposes in India and China since ancient times. Metal nanoparticles are being used globally in biomedicine and related fields. Researchers are currently focused on metal nanoparticles, nanostructures, and nanomaterial production due to their unique features. This paper examines various metal oxide nanoparticle preparation processes, including their benefits, drawbacks, and potential applications.</p></div>","PeriodicalId":491,"journal":{"name":"Biometals","volume":"39 1","pages":"25 - 57"},"PeriodicalIF":3.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1007/s10534-025-00752-z
Xin Xu, Caiqi Yu, Weiqi Du, Yaoting Duan, Lei Niu, Zhe Wang, Jinshan Zhang, Chunli Zheng
Soil microorganisms respond vigorously to environmental changes. However, the impact of varying levels of rare earth elements (REEs) contamination on microorganisms and their interactions remains unclear, with a scarcity of research on biomarkers for different levels of rare earth enrichment. This study categorized REE concentrations into distinct accumulation tiers. Utilizing Illumina high-throughput sequencing, the researchers investigated how different REE levels affect biodiversity, ecosystem structure, and functional dynamics. The results indicated that while the accumulation of rare earth elements (REEs) reduced soil bacterial diversity, the impact on the diversity of bacterial populations was minimal. Proteobacteria, Actinobacteria, and Chloroflexi were identified as the dominant bacterial communities near the uncommon rare earth tailings pond. According to linear discriminant analysis effect size (LEfSe), certain genera—Halomonas, Aliifodinibius, and Truepera—emerged as potential indicators of soils with elevated REE concentrations. Sphingomonas was identified as the biomarker in medium-concentration (MC) samples, whereas norank_Subgroup6, norank_Actinobacteria, and RB41 were enriched in low-concentration (LC) samples. Tax4fun function prediction revealed that the metabolic capacity of bacterial communities was inhibited under REE stress. Statistical analyses, including redundancy analysis and the Mantel test, pinpointed soil moisture and rare earth element concentrations as the primary environmental drivers in mining-affected regions. These findings illustrate that rare earth accumulation significantly alters bacterial community diversity, taxonomic composition, and ecological functions in these areas. Researchers also identified distinct microbial biomarkers corresponding to various levels of rare earth enrichment. The study offers deeper insights into how rare earth mining operations affect the composition and function of soil microbial communities.
{"title":"Soil microorganisms enrichment in different rare earth elements enrichment soils around a rare earth tailings pond","authors":"Xin Xu, Caiqi Yu, Weiqi Du, Yaoting Duan, Lei Niu, Zhe Wang, Jinshan Zhang, Chunli Zheng","doi":"10.1007/s10534-025-00752-z","DOIUrl":"10.1007/s10534-025-00752-z","url":null,"abstract":"<div><p>Soil microorganisms respond vigorously to environmental changes. However, the impact of varying levels of rare earth elements (REEs) contamination on microorganisms and their interactions remains unclear, with a scarcity of research on biomarkers for different levels of rare earth enrichment. This study categorized REE concentrations into distinct accumulation tiers. Utilizing Illumina high-throughput sequencing, the researchers investigated how different REE levels affect biodiversity, ecosystem structure, and functional dynamics. The results indicated that while the accumulation of rare earth elements (REEs) reduced soil bacterial diversity, the impact on the diversity of bacterial populations was minimal. <i>Proteobacteria</i>, <i>Actinobacteria</i>, and <i>Chloroflexi</i> were identified as the dominant bacterial communities near the uncommon rare earth tailings pond. According to linear discriminant analysis effect size (LEfSe), certain genera—<i>Halomonas</i>, <i>Aliifodinibius</i>, and <i>Truepera</i>—emerged as potential indicators of soils with elevated REE concentrations. <i>Sphingomonas</i> was identified as the biomarker in medium-concentration (MC) samples, whereas <i>norank_Subgroup6</i>, <i>norank_Actinobacteria</i>, and RB41 were enriched in low-concentration (LC) samples. Tax4fun function prediction revealed that the metabolic capacity of bacterial communities was inhibited under REE stress. Statistical analyses, including redundancy analysis and the Mantel test, pinpointed soil moisture and rare earth element concentrations as the primary environmental drivers in mining-affected regions. These findings illustrate that rare earth accumulation significantly alters bacterial community diversity, taxonomic composition, and ecological functions in these areas. Researchers also identified distinct microbial biomarkers corresponding to various levels of rare earth enrichment. The study offers deeper insights into how rare earth mining operations affect the composition and function of soil microbial communities.</p></div>","PeriodicalId":491,"journal":{"name":"Biometals","volume":"39 1","pages":"149 - 165"},"PeriodicalIF":3.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627656","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-27DOI: 10.1007/s10534-025-00769-4
Emma Michetti, Valerio Secli, Maria Luisa Astolfi, Chiara Demingo, Francesca Pacello, Serena Ammendola, Andrea Battistoni
Bacterial pathogens must rapidly adapt to fluctuating metal availability within the host, where essential micronutrients are actively sequestered as part of nutritional immunity. Among these, zinc is a critical cofactor for a wide array of enzymes and regulatory proteins, and its availability is tightly linked to the expression of key virulence traits in Pseudomonas aeruginosa. This opportunistic pathogen employs different zinc acquisition systems transcriptionally regulated by the Zinc Uptake Regulator Zur, enabling its persistence within the host. Recently, Zur-controlled operons involved in the uptake/export of cobalt have been identified. Although cobalt is primarily associated with cobalamin-dependent reactions, its selective import under zinc-limiting conditions suggests a potential role for cobalt in bacterial adaptation to zinc scarcity. Yet, the functional relevance of this metal-based compensation remains poorly defined. This study shows that cobalt supplementation alleviates key effects of severe zinc deficiency in P. aeruginosa, including reduced pyocyanin production, impaired swarming motility, and enhanced sensitivity to oxidative stress. Furthermore, in vitro assays demonstrate that cobalt can functionally replace zinc in the proteases LasA and LasB and the transcriptional regulator Zur. Finally, we found that a P. aeruginosa strain deficient in the pyochelin-cobalt receptor PA2911 exhibits impaired colonization of Galleria mellonella larvae, supporting the hypothesis that cobalt compensatory function may be crucial during infection. Our results suggest that cobalt may play a broader biological role than previously recognized, highlighting its potential to support P. aeruginosa survival and pathogenicity in zinc-limiting environments.
{"title":"Cobalt mitigates zinc-starvation effects in Pseudomonas aeruginosa.","authors":"Emma Michetti, Valerio Secli, Maria Luisa Astolfi, Chiara Demingo, Francesca Pacello, Serena Ammendola, Andrea Battistoni","doi":"10.1007/s10534-025-00769-4","DOIUrl":"10.1007/s10534-025-00769-4","url":null,"abstract":"<p><p>Bacterial pathogens must rapidly adapt to fluctuating metal availability within the host, where essential micronutrients are actively sequestered as part of nutritional immunity. Among these, zinc is a critical cofactor for a wide array of enzymes and regulatory proteins, and its availability is tightly linked to the expression of key virulence traits in Pseudomonas aeruginosa. This opportunistic pathogen employs different zinc acquisition systems transcriptionally regulated by the Zinc Uptake Regulator Zur, enabling its persistence within the host. Recently, Zur-controlled operons involved in the uptake/export of cobalt have been identified. Although cobalt is primarily associated with cobalamin-dependent reactions, its selective import under zinc-limiting conditions suggests a potential role for cobalt in bacterial adaptation to zinc scarcity. Yet, the functional relevance of this metal-based compensation remains poorly defined. This study shows that cobalt supplementation alleviates key effects of severe zinc deficiency in P. aeruginosa, including reduced pyocyanin production, impaired swarming motility, and enhanced sensitivity to oxidative stress. Furthermore, in vitro assays demonstrate that cobalt can functionally replace zinc in the proteases LasA and LasB and the transcriptional regulator Zur. Finally, we found that a P. aeruginosa strain deficient in the pyochelin-cobalt receptor PA2911 exhibits impaired colonization of Galleria mellonella larvae, supporting the hypothesis that cobalt compensatory function may be crucial during infection. Our results suggest that cobalt may play a broader biological role than previously recognized, highlighting its potential to support P. aeruginosa survival and pathogenicity in zinc-limiting environments.</p>","PeriodicalId":491,"journal":{"name":"Biometals","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627540","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-26DOI: 10.1007/s10534-025-00777-4
Julia Tiemy Leal Konno, Breno Pannia Espósito
Iron overload diseases (IOD) are harmful conditions that may lead to a significant decrease in quality of life. The only three IOD approved chelators have significant adverse effects that hinder therapeutic adherence. The search for new chelators may benefit from drug repositioning (DR), a strategy that aims to identify new applications for approved drugs. Antiresorptives (AR) are drugs that inhibit bone resorption. Here, the iron binding and antioxidant effects of four bisphosphonates (etidronate, alendronate, tiludronate, and zoledronate) and strontium ranelate AR were studied in buffer and cell models, in order to verify their potential as alternative treatments of IOD in the absence of bone disease. Competition equilibrium tests between the bisphosphonates and ferric calcein or ferric transferrin showed a moderate ability to scavenge iron. Bisphosphonates showed antioxidant activity against iron-induced reactive species generation in the presence of ascorbate. Etidronate and tiludronate helped to prevent cell death by iron-dependent oxidative stress. Although measurable, the effect of physiological levels of calcium did not prevent the desired chelating and antioxidant effects of the bisphosphonates. Our results show that etidronate and tiludronate have valuable physicochemical properties that could be employed in a DR strategy for the treatment of IOD.
{"title":"Bone antiresorptives as potential chelators for iron overload diseases.","authors":"Julia Tiemy Leal Konno, Breno Pannia Espósito","doi":"10.1007/s10534-025-00777-4","DOIUrl":"https://doi.org/10.1007/s10534-025-00777-4","url":null,"abstract":"<p><p>Iron overload diseases (IOD) are harmful conditions that may lead to a significant decrease in quality of life. The only three IOD approved chelators have significant adverse effects that hinder therapeutic adherence. The search for new chelators may benefit from drug repositioning (DR), a strategy that aims to identify new applications for approved drugs. Antiresorptives (AR) are drugs that inhibit bone resorption. Here, the iron binding and antioxidant effects of four bisphosphonates (etidronate, alendronate, tiludronate, and zoledronate) and strontium ranelate AR were studied in buffer and cell models, in order to verify their potential as alternative treatments of IOD in the absence of bone disease. Competition equilibrium tests between the bisphosphonates and ferric calcein or ferric transferrin showed a moderate ability to scavenge iron. Bisphosphonates showed antioxidant activity against iron-induced reactive species generation in the presence of ascorbate. Etidronate and tiludronate helped to prevent cell death by iron-dependent oxidative stress. Although measurable, the effect of physiological levels of calcium did not prevent the desired chelating and antioxidant effects of the bisphosphonates. Our results show that etidronate and tiludronate have valuable physicochemical properties that could be employed in a DR strategy for the treatment of IOD.</p>","PeriodicalId":491,"journal":{"name":"Biometals","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145627527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-25DOI: 10.1007/s10534-025-00774-7
Hadley England, Jacky Trinh, Jonathan Moorhead, Daniel Keaney, Cora Hinkley, Andrei Herdean, Jennifer Matthews, Emma F Camp
As coral reefs continue to decline globally, a toolbox of new interventions such as nutritional supplementation are being considered. Low level supplementation of the trace element manganese (Mn) has increasingly been shown to enhance the resilience of photosynthetic Cnidarians to thermal stress, however, questions around the timing of Mn delivery relative to a thermal stress event remain unanswered. Here we explore how the timing of Mn additions influences the response of the common reef building coral Acropora millipora to thermal stress. Coral health was assessed using a variety of different metrics including photochemical efficiency, oxygen dynamics, elementomics and symbiont densities. A. millepora displayed significantly improved thermal tolerance when exposed to either intermittent pulse (19.34 µg L-1 every second day) dosing or constant (4.24 µg L-1) supply of dissolved Mn from 7 days before heat stress exposure (32 °C). Pulse dosed corals maintained higher photosynthetic efficiency and photosynthesis to respiration rates, as well as increased Symbiodiniaceae densities compared to thermally stressed corals without Mn supplementation. Elemental analysis revealed that both coral tissue and Symbiodiniaceae in Mn-treated corals accumulated significantly more Mn than non-Mn treated corals. Collectively, our results suggest that intermittent (pulse) Mn exposure prior to the onset of thermal stress may provide the greatest support for thermal resilience in corals. This study advances understanding on how essential elements like Mn could be strategically delivered as an active intervention to enhance coral tolerance during periods of thermal stress.
随着全球范围内珊瑚礁的持续减少，人们正在考虑一系列新的干预措施，如营养补充。低水平补充微量元素锰（Mn）已越来越多地被证明可以增强光合刺胞动物对热胁迫的恢复能力，然而，关于Mn递送时间相对于热胁迫事件的问题仍未得到解决。在这里，我们探讨了Mn添加的时间如何影响普通造礁珊瑚对热应力的响应。珊瑚健康评估使用各种不同的指标，包括光化学效率、氧动力学、元素组学和共生体密度。当暴露于热应激暴露（32°C）前7天的间歇脉冲（19.34 μ g L-1 / 2天）剂量或恒定（4.24 μ g L-1）溶解Mn时，A. millepora的热耐受性显著提高。与没有补充锰的热应激珊瑚相比，脉冲剂量的珊瑚保持更高的光合效率和光合作用对呼吸速率，以及增加的共生菌科密度。元素分析表明，锰处理珊瑚的组织和共生菌科均比未锰处理珊瑚积累了更多的锰。总的来说，我们的研究结果表明，在热应力开始之前间歇性（脉冲）Mn暴露可能为珊瑚的热弹性提供最大的支持。这项研究促进了人们对锰等基本元素如何作为一种主动干预手段有策略地输送，以增强珊瑚在热应激期间的耐受性的理解。
{"title":"Timing and method of manganese supplementation effects thermal resilience of Acropora millepora.","authors":"Hadley England, Jacky Trinh, Jonathan Moorhead, Daniel Keaney, Cora Hinkley, Andrei Herdean, Jennifer Matthews, Emma F Camp","doi":"10.1007/s10534-025-00774-7","DOIUrl":"https://doi.org/10.1007/s10534-025-00774-7","url":null,"abstract":"<p><p>As coral reefs continue to decline globally, a toolbox of new interventions such as nutritional supplementation are being considered. Low level supplementation of the trace element manganese (Mn) has increasingly been shown to enhance the resilience of photosynthetic Cnidarians to thermal stress, however, questions around the timing of Mn delivery relative to a thermal stress event remain unanswered. Here we explore how the timing of Mn additions influences the response of the common reef building coral Acropora millipora to thermal stress. Coral health was assessed using a variety of different metrics including photochemical efficiency, oxygen dynamics, elementomics and symbiont densities. A. millepora displayed significantly improved thermal tolerance when exposed to either intermittent pulse (19.34 µg L<sup>-1</sup> every second day) dosing or constant (4.24 µg L<sup>-1</sup>) supply of dissolved Mn from 7 days before heat stress exposure (32 °C). Pulse dosed corals maintained higher photosynthetic efficiency and photosynthesis to respiration rates, as well as increased Symbiodiniaceae densities compared to thermally stressed corals without Mn supplementation. Elemental analysis revealed that both coral tissue and Symbiodiniaceae in Mn-treated corals accumulated significantly more Mn than non-Mn treated corals. Collectively, our results suggest that intermittent (pulse) Mn exposure prior to the onset of thermal stress may provide the greatest support for thermal resilience in corals. This study advances understanding on how essential elements like Mn could be strategically delivered as an active intervention to enhance coral tolerance during periods of thermal stress.</p>","PeriodicalId":491,"journal":{"name":"Biometals","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145601651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-23DOI: 10.1007/s10534-025-00772-9
Maya P Shetty, Priti Sule, Suresh D Kulkarni, Pradip Chaudhari, Sanjay Bharati
Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality and its rising incidence underscores the urgent need to explore novel therapeutic targets. Cancer is often characterized by dysregulated copper metabolism, which plays a crucial role in modulating tumor cell properties like cell proliferation, angiogenesis and metastasis. Therefore, exploiting their metabolic vulnerability using copper overload-based anticancer strategies has emerged as a novel approach. Despite the significant therapeutic potential of copper, its application in anticancer therapy has been limited due to systemic toxicity and non-target localization. In the present study we report targeted delivery of copper to the tumor site and its anticancer therapeutic potential of copper conjugated aminated arabinogalactan (Cu-aAG) in HCC. The synthesized compound was characterized using FT-IR, NMR, Mass spectroscopy and assessed for its anti-cancer therapeutic potential against the Wistar rat model of N-nitrosodiethylamine-induced hepatocellular carcinoma. The chemical characterization of Cu-aAG revealed successful copper complexation as evidenced by characteristic FT-IR peaks and elemental analysis showing 1.19% copper content. The involvement of amine and hydroxyl groups in the complexation was further confirmed by NMR and mass spectral analysis thus ensuring formation of stable, copper-centered co-ordination complexes. Cu-aAG treatment to tumor bearing Wistar rats significantly decreased tumor burden and tumor multiplicity (3.92 ± 2.9) as compared to untreated Tumor group (18.90 ± 3.02). Further, Cu-aAG treatment induced apoptotic cell death, cell cycle arrest, and inhibited angiogenesis. These findings highlight the potential of targeted delivery of copper overload-mediated anticancer therapy for inhibiting tumor growth and progression in HCC.
{"title":"Asialoglycoprotein receptor-mediated delivery of copper to hepatic tumors exerted inhibitory effect on tumor growth and progression.","authors":"Maya P Shetty, Priti Sule, Suresh D Kulkarni, Pradip Chaudhari, Sanjay Bharati","doi":"10.1007/s10534-025-00772-9","DOIUrl":"https://doi.org/10.1007/s10534-025-00772-9","url":null,"abstract":"<p><p>Hepatocellular carcinoma (HCC) remains a major contributor to global cancer mortality and its rising incidence underscores the urgent need to explore novel therapeutic targets. Cancer is often characterized by dysregulated copper metabolism, which plays a crucial role in modulating tumor cell properties like cell proliferation, angiogenesis and metastasis. Therefore, exploiting their metabolic vulnerability using copper overload-based anticancer strategies has emerged as a novel approach. Despite the significant therapeutic potential of copper, its application in anticancer therapy has been limited due to systemic toxicity and non-target localization. In the present study we report targeted delivery of copper to the tumor site and its anticancer therapeutic potential of copper conjugated aminated arabinogalactan (Cu-aAG) in HCC. The synthesized compound was characterized using FT-IR, NMR, Mass spectroscopy and assessed for its anti-cancer therapeutic potential against the Wistar rat model of N-nitrosodiethylamine-induced hepatocellular carcinoma. The chemical characterization of Cu-aAG revealed successful copper complexation as evidenced by characteristic FT-IR peaks and elemental analysis showing 1.19% copper content. The involvement of amine and hydroxyl groups in the complexation was further confirmed by NMR and mass spectral analysis thus ensuring formation of stable, copper-centered co-ordination complexes. Cu-aAG treatment to tumor bearing Wistar rats significantly decreased tumor burden and tumor multiplicity (3.92 ± 2.9) as compared to untreated Tumor group (18.90 ± 3.02). Further, Cu-aAG treatment induced apoptotic cell death, cell cycle arrest, and inhibited angiogenesis. These findings highlight the potential of targeted delivery of copper overload-mediated anticancer therapy for inhibiting tumor growth and progression in HCC.</p>","PeriodicalId":491,"journal":{"name":"Biometals","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145585590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-18DOI: 10.1007/s10534-025-00770-x
Hanh Van Nguyen, Sang Thi Minh Nguyen, Huong Thi Thu Tran, Loan Thi Hong Truong, Dong Van Nguyen, Linh Thi Truc Nguyen, Ba Ngoc Vu, Phuong Truc Huynh
This study aimed to assess metal exposure in the fingernails of men with nasopharyngeal cancer. Fingernail samples were analyzed using total reflection X-ray fluorescence technique. A multivariable logistic regression model was used to predict metal exposure levels, and Spearman correlations were used to identify variables associated with increased cancer risk. The results showed that the concentrations of 11 metals significantly differed between patients and healthy controls. Adjusted odds ratios (adj.OR) of metal exposure indicated significant positive associations with increased risk of cancer: Fe (adj.OR = 1.04), Cr (adj.OR = 3.70), Ni (adj.OR = 1.87), Cd (adj.OR = 2.93), As (adj.OR = 3.95), and Pb (adj.OR = 3.65). In contrast, significantly lower levels of Ca and Zn were associated with increased risk of cancer: Ca (adj.OR = 0.9976) and Zn (adj.OR = 0.96). Among smoking patients, adj.ORs followed a similar trend but at higher levels, with an increasing risk for Fe (adj.OR = 1.02) < Mn (adj.OR = 1.96) < Cr (adj.OR = 2.31) < Ni (adj.OR = 2.72) < Cd (adj.OR = 5.57) < Pb (adj.OR = 5.61) < As (adj.OR = 6.96) and a decreasing risk for Zn (adj.OR = 0.93) > Ca (adj.OR = 0.9968). Furthermore, Spearman correlations showed that significantly higher levels of Ni and Cd and lower levels of Cu were associated with patients' living environments. Meanwhile, higher levels of Cr, Mn, Fe, Ni, As, and Pb and lower levels of Ca and Zn were significantly associated with smoking habits. In conclusion, significant alterations in fingernail metal concentrations were associated with an increased risk of nasopharyngeal cancer. Exposure to toxic metals, mainly through smoking and living environments, may contribute to disease development. These findings highlight the importance of public health strategies to mitigate metal-related cancer risks.
本研究旨在评估鼻咽癌患者指甲中的金属暴露。采用全反射x射线荧光技术对指甲样品进行分析。多变量逻辑回归模型用于预测金属暴露水平，Spearman相关性用于确定与癌症风险增加相关的变量。结果表明，11种金属的浓度在患者和健康对照组之间存在显著差异。校正优势比（adjj . or）显示，金属暴露与癌症风险增加有显著正相关：铁（adjj . or = 1.04）、铬（adjj . or = 3.70）、镍（adjj . or = 1.87）、镉（adjj . or = 2.93）、砷（adjj . or = 3.95）和铅（adjj . or = 3.65）。相比之下，钙和锌水平显著降低与癌症风险增加相关：钙（adj.OR = 0.9976）和锌（adj.OR = 0.96）。在吸烟患者中，adj.OR的变化趋势相似，但水平更高，铁（adj.OR = 1.02）和钙（adj.OR = 0.9968）的风险增加。此外，Spearman相关性显示，较高的Ni和Cd水平以及较低的Cu水平与患者的生活环境有关。同时，较高的Cr、Mn、Fe、Ni、As、Pb水平和较低的Ca、Zn水平与吸烟习惯显著相关。总之，指甲金属浓度的显著变化与鼻咽癌风险增加有关。主要通过吸烟和生活环境接触有毒金属，可能导致疾病的发展。这些发现强调了公共卫生战略对减轻与金属有关的癌症风险的重要性。
{"title":"Assessment of metal exposure in fingernails of patients with nasopharyngeal cancer: a case study in Vietnamese men.","authors":"Hanh Van Nguyen, Sang Thi Minh Nguyen, Huong Thi Thu Tran, Loan Thi Hong Truong, Dong Van Nguyen, Linh Thi Truc Nguyen, Ba Ngoc Vu, Phuong Truc Huynh","doi":"10.1007/s10534-025-00770-x","DOIUrl":"https://doi.org/10.1007/s10534-025-00770-x","url":null,"abstract":"<p><p>This study aimed to assess metal exposure in the fingernails of men with nasopharyngeal cancer. Fingernail samples were analyzed using total reflection X-ray fluorescence technique. A multivariable logistic regression model was used to predict metal exposure levels, and Spearman correlations were used to identify variables associated with increased cancer risk. The results showed that the concentrations of 11 metals significantly differed between patients and healthy controls. Adjusted odds ratios (adj.OR) of metal exposure indicated significant positive associations with increased risk of cancer: Fe (adj.OR = 1.04), Cr (adj.OR = 3.70), Ni (adj.OR = 1.87), Cd (adj.OR = 2.93), As (adj.OR = 3.95), and Pb (adj.OR = 3.65). In contrast, significantly lower levels of Ca and Zn were associated with increased risk of cancer: Ca (adj.OR = 0.9976) and Zn (adj.OR = 0.96). Among smoking patients, adj.ORs followed a similar trend but at higher levels, with an increasing risk for Fe (adj.OR = 1.02) < Mn (adj.OR = 1.96) < Cr (adj.OR = 2.31) < Ni (adj.OR = 2.72) < Cd (adj.OR = 5.57) < Pb (adj.OR = 5.61) < As (adj.OR = 6.96) and a decreasing risk for Zn (adj.OR = 0.93) > Ca (adj.OR = 0.9968). Furthermore, Spearman correlations showed that significantly higher levels of Ni and Cd and lower levels of Cu were associated with patients' living environments. Meanwhile, higher levels of Cr, Mn, Fe, Ni, As, and Pb and lower levels of Ca and Zn were significantly associated with smoking habits. In conclusion, significant alterations in fingernail metal concentrations were associated with an increased risk of nasopharyngeal cancer. Exposure to toxic metals, mainly through smoking and living environments, may contribute to disease development. These findings highlight the importance of public health strategies to mitigate metal-related cancer risks.</p>","PeriodicalId":491,"journal":{"name":"Biometals","volume":" ","pages":""},"PeriodicalIF":3.6,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145538255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-15DOI: 10.1007/s10534-025-00766-7
Ella O’Sullivan, Denis O’Shea, Michael Devereux, Kevin Kavanagh, Orla Howe
<div><p>Autophagy is a process that breaks down unwanted cellular components to maintain homeostasis. While it is defined as a ‘self-protection’ process, a disruption of autophagic mechanisms can lead to cellular death. Autophagy is interconnected with many other cellular processes including innate and adaptive immunity and can therefore have therapeutic potential as it can be modulated to control immune and other cellular responses. We therefore postulated the potential of our Cu(II), Mn(II) and Ag(I) complexes coordinated with 1,10-phenanthroline to interfere with the autophagy process and to induce an immune-response. Herein, we evaluated the ability of a series of heteroleptic complexes, [Cu<sub>2</sub>(oda)(phen)<sub>4</sub>](ClO<sub>4</sub>)<sub>2</sub>, [Cu(oda)(phen)<sub>2</sub>], [Ag<sub>2</sub>(oda)(phen)<sub>3</sub>], [Ag<sub>2</sub>(udda)(phen)<sub>3</sub>], and {[Mn<sub>2</sub>(oda)<sub>3</sub>(phen)<sub>4</sub>]<sup>2−</sup>[Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<sub>2</sub>]<sup>2+</sup>}(where:oda<sup>2−</sup> = octanedioate; udda<sup>2−</sup> = undecanedioate; and phen = 1,10-phenanthroline), to modulate autophagy <i>in vitro</i> using MCF-7 (breast cancer) and MCF-12A (non-tumorigenic breast) cell lines; alongside their <i>in vivo</i> immunomodulatory effects in the <i>Galleria mellonella</i> larva model. Differential autophagy induction was observed between the two cell types through quantitative flow cytometry and fluorescence microscopy of autophagosomes using GFP-LC3, with a pronounced upregulation in non-tumorigenic MCF-12A cells compared to cancerous MCF-7 cells, underscoring the context-dependent modes of action of these complexes. Among them, the Mn(II)-phen complex ({[Mn<sub>2</sub>(oda)<sub>3</sub>(phen)<sub>4</sub>]<sup>2−</sup>[Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<sub>2</sub>]<sup>2+</sup>}) was identified as the most potent inducer of autophagy in MCF-7 cells (<i>p</i> < 0.01), highlighting its unique mechanistic interaction within this breast cancer cell line, compared to the Cu(II) and Ag(I) analogues. <i>In vivo</i> characterisation of the complexes in the larvae of <i>G. mellonella</i> revealed a high tolerance and broad therapeutic windows were established. Notably, the Ag(I)-phen complex [Ag<sub>2</sub>(udda)(phen)<sub>3</sub>] was determined as the most well-tolerated complex, with a 24-h LD<sub>50</sub> of 864.3 µg/mL, exemplifying the pronounced tolerance of the complexes in contrast to previously reported <i>in vitro</i> cytotoxicity at distinctly low micro-molar concentrations. Analysis of changes in the haemocyte density, an established marker of immune response, revealed significant immune activation in <i>G. mellonella</i>, particularly with the Ag(I) ([Ag<sub>2</sub>(oda)(phen)<sub>3</sub>] and [Ag<sub>2</sub>(udda)(phen)<sub>3</sub>]) and Mn(II) ({[Mn<sub>2</sub>(oda)<sub>3</sub>(phen)<sub>4</sub>]<sup>2−</sup>[Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<s
{"title":"Autophagy-dependent cell death and immune responses induced by heteroleptic copper(II), manganese(II), and silver(I) complexes containing dicarboxylate and 1,10-phenanthroline ligands: novel insights from in vitro and in vivo models","authors":"Ella O’Sullivan, Denis O’Shea, Michael Devereux, Kevin Kavanagh, Orla Howe","doi":"10.1007/s10534-025-00766-7","DOIUrl":"10.1007/s10534-025-00766-7","url":null,"abstract":"<div><p>Autophagy is a process that breaks down unwanted cellular components to maintain homeostasis. While it is defined as a ‘self-protection’ process, a disruption of autophagic mechanisms can lead to cellular death. Autophagy is interconnected with many other cellular processes including innate and adaptive immunity and can therefore have therapeutic potential as it can be modulated to control immune and other cellular responses. We therefore postulated the potential of our Cu(II), Mn(II) and Ag(I) complexes coordinated with 1,10-phenanthroline to interfere with the autophagy process and to induce an immune-response. Herein, we evaluated the ability of a series of heteroleptic complexes, [Cu<sub>2</sub>(oda)(phen)<sub>4</sub>](ClO<sub>4</sub>)<sub>2</sub>, [Cu(oda)(phen)<sub>2</sub>], [Ag<sub>2</sub>(oda)(phen)<sub>3</sub>], [Ag<sub>2</sub>(udda)(phen)<sub>3</sub>], and {[Mn<sub>2</sub>(oda)<sub>3</sub>(phen)<sub>4</sub>]<sup>2−</sup>[Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<sub>2</sub>]<sup>2+</sup>}(where:oda<sup>2−</sup> = octanedioate; udda<sup>2−</sup> = undecanedioate; and phen = 1,10-phenanthroline), to modulate autophagy <i>in vitro</i> using MCF-7 (breast cancer) and MCF-12A (non-tumorigenic breast) cell lines; alongside their <i>in vivo</i> immunomodulatory effects in the <i>Galleria mellonella</i> larva model. Differential autophagy induction was observed between the two cell types through quantitative flow cytometry and fluorescence microscopy of autophagosomes using GFP-LC3, with a pronounced upregulation in non-tumorigenic MCF-12A cells compared to cancerous MCF-7 cells, underscoring the context-dependent modes of action of these complexes. Among them, the Mn(II)-phen complex ({[Mn<sub>2</sub>(oda)<sub>3</sub>(phen)<sub>4</sub>]<sup>2−</sup>[Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<sub>2</sub>]<sup>2+</sup>}) was identified as the most potent inducer of autophagy in MCF-7 cells (<i>p</i> < 0.01), highlighting its unique mechanistic interaction within this breast cancer cell line, compared to the Cu(II) and Ag(I) analogues. <i>In vivo</i> characterisation of the complexes in the larvae of <i>G. mellonella</i> revealed a high tolerance and broad therapeutic windows were established. Notably, the Ag(I)-phen complex [Ag<sub>2</sub>(udda)(phen)<sub>3</sub>] was determined as the most well-tolerated complex, with a 24-h LD<sub>50</sub> of 864.3 µg/mL, exemplifying the pronounced tolerance of the complexes in contrast to previously reported <i>in vitro</i> cytotoxicity at distinctly low micro-molar concentrations. Analysis of changes in the haemocyte density, an established marker of immune response, revealed significant immune activation in <i>G. mellonella</i>, particularly with the Ag(I) ([Ag<sub>2</sub>(oda)(phen)<sub>3</sub>] and [Ag<sub>2</sub>(udda)(phen)<sub>3</sub>]) and Mn(II) ({[Mn<sub>2</sub>(oda)<sub>3</sub>(phen)<sub>4</sub>]<sup>2−</sup>[Mn<sub>2</sub>(oda)(phen)<sub>4</sub>(H<sub>2</sub>O)<s","PeriodicalId":491,"journal":{"name":"Biometals","volume":"39 1","pages":"337 - 358"},"PeriodicalIF":3.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145522454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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