Manganese-based nanomaterials promote synergistic photo-immunotherapy: green synthesis, underlying mechanisms, and multiple applications.

Single phototherapy and immunotherapy have individually made great achievements in tumor treatment. However, monotherapy has difficulty in balancing accuracy and efficiency. Combining phototherapy with immunotherapy can realize the growth inhibition of distal metastatic tumors and enable the remote monitoring of tumor treatment. The development of nanomaterials with photo-responsiveness and anti-tumor immunity activation ability is crucial for achieving photo-immunotherapy. As immune adjuvants, photosensitizers and photothermal agents, manganese-based nanoparticles (Mn-based NPs) have become a research hotspot owing to their multiple ways of anti-tumor immunity regulation, photothermal conversion and multimodal imaging. However, systematic studies on the synergistic photo-immunotherapy applications of Mn-based NPs are still limited; especially, the green synthesis and mechanism of Mn-based NPs applied in immunotherapy are rarely comprehensively discussed. In this review, the synthesis strategies and function of Mn-based NPs in immunotherapy are first introduced. Next, the different mechanisms and leading applications of Mn-based NPs in immunotherapy are reviewed. In addition, the advantages of Mn-based NPs in synergistic photo-immunotherapy are highlighted. Finally, the challenges and research focus of Mn-based NPs in combination therapy are discussed, which might provide guidance for future personalized cancer therapy.

Supplemental trace minerals as complexed or inorganic sources for beef cattle during the receiving period.

To investigate effects of inorganic or complexed trace mineral source (zinc, copper, manganese, and cobalt) on receiving period performance and morbidity, crossbred beef heifer calves (n = 287) arriving on three delivery dates were used in a 42-d receiving trial. Heifers were processed after arrival, stratified by day -1 body weights (BW) and allocated randomly to eight pens (11 to 13 heifers/pen, 24 pens total). Within truckload, pens were assigned randomly to dietary treatment (n = 12 pens/treatment). Heifers were housed on 0.42-ha grass paddocks, provided ad libitum bermudagrass hay and provided dietary treatments in grain supplements fed daily. Treatments consisted of supplemental zinc (360 mg/d), copper (125 mg/d), manganese (200 mg/d), and cobalt (12 mg/d) from complexed (Zinpro Availa 4, Zinpro Corp. Eden Prairie, MN) or inorganic sources (sulfates). Heifers were observed daily for clinical bovine respiratory disease (BRD). If presenting BRD symptoms and rectal temperature ≥ 40 °C, heifers were deemed morbid and treated with antibiotics. Six heifers/pen were bled to determine serum haptoglobin concentrations on days 0, 14, and 28. Liver biopsies were taken on day 5 ±â€…2 and 43 ±â€…1 from three calves selected randomly from each pen for mineral status comparisons. Statistical analyses were performed using the MIXED, GLIMMIX, and repeated measures procedures of SAS 9.4 with truckload as a random effect and pen within truckload specified as subject. There tended to be a treatment by day interaction for BW (P = 0.07). Heifer BW did not differ on day 0 (P = 0.82) and day 14 (P = 0.36), but heifers fed complexed trace minerals had greater BW on day 28 (P = 0.04) and day 42 (P = 0.05). Overall average daily gains were greater for heifers fed complexed trace minerals (P = 0.05; 0.78 vs. 0.70 kg, SE = 0.03). Heifers supplemented with inorganic trace minerals had greater BRD incidence (P = 0.03; 58 vs. 46%, SE = 3.6). Haptoglobin concentrations decreased throughout the trial (P < 0.001), and heifers fed complexed trace minerals tended to have a decrease in haptoglobin concentrations (P = 0.07). The source of trace mineral supplementation had no effect (P ≥ 0.20) on liver mineral concentrations and there were no treatment × day interactions (P ≥ 0.35). In conclusion, supplementing diets for the first 42 d after arrival with complexed trace mineral sources improved heifer performance as compared to heifers supplemented with inorganic trace minerals.

Issues associated with health and management of newly received cattle continue to pose significant animal welfare and economic challenges for the beef industry. Diagnosis of bovine respiratory disease, accompanied with poor growth performance, can be addressed by nutritional intervention in receiving cattle. Trace mineral inclusion in receiving rations is vital to calf performance. There are numerous sources of trace mineral supplements that exist commercially for cattle and their effects on immune function, growth, and performance measures were evaluated. Organic trace mineral supplements are being used in replacement of inorganic salts due to potentially greater bioavailability and functionality. An organic source that is commonly used are amino acid complexes. Replacing inorganic sources with complexed sources of trace minerals (zinc, copper, manganese, and cobalt) improved growth performance and decreased sickness during the 42-d receiving study.

Effects of manganese glycine on eggshell quality, eggshell ultrastructure, and elemental deposition in aged laying hens.

Poor eggshell quality of eggs laid by aged laying hens is the major problem affecting the length of the rearing period in the laying hen industry. Trace elements are required and play vital roles in the eggshell quality of laying hens. Appropriate dose of organic microelements is environmentally friendly and sufficient to satisfy the needs of hens because of their greater bioavailability and lower excretion than inorganic forms. The aim of this experiment was to investigate the effects of manganese (Mn) glycine (MG) on eggshell quality, elemental deposition, and eggshell ultrastructure in aged laying hens. A total of 720 Hy-Line Brown hens 70 weeks old were assigned equally to four groups with six replicates of 30 birds each. The hens were fed basal diets (without Mn supplementation) supplemented with 120 mg/kg of Mn from manganese sulfate monohydrate (MSM), or 40, 80, or 120 mg/kg Mn from MG for 12 weeks. Dietary supplementation with 80 mg/kg Mn from MG resulted in the greatest eggshell strength after 6 weeks of treatment (P = 0.047), and in greater eggshell strength than observed in the MSM control after 12 weeks of treatment (P = 0.025). After 12 weeks of treatment, the eggs of hens in the MG groups showed lower mammillary layer thickness in the blunt end, equator, and acute end than observed in the MSM control group (P < 0.001). With the exception of the blunt ends of eggs from hens in the 120 mg/kg MG group, the eggs of hens in the MG groups, compared with the MSM control group, exhibited a lower mammillary layer ratio, and greater palisade layer ratio and effective layer ratio in the blunt end, equator, and acute end (P < 0.001). Dietary supplementation with 80 mg/kg Mn from MG, compared with the MSM control and 40 and 120 mg/kg MG, resulted in the greatest palisade layer thickness and effective layer thickness, and the lowest mammillary layer thickness in the equator (P < 0.001, P = 0.001, P < 0.001, respectively). Furthermore, supplementation with 80 mg/kg Mn from MG exhibited the greatest ratio of the palisade layer and effective layer, and the lowest mammillary layer ratio in the blunt end and equator (all P < 0.001). The Mn content of eggshells in hens-fed diets supplemented with 80 and 120 mg/kg Mn from MG was greater than that in the MSM control and 40 mg/kg MG groups (P = 0.035). Dietary supplementation with 80 or 120 mg/kg Mn from MG resulted in greater tibia Mn content than observed in the 40 mg/kg MG group (P = 0.019), and greater yolk Mn content than observed in the 40 mg/kg MG and MSM control groups (P = 0.018). In conclusion, dietary supplementation with 80 mg/kg Mn from MG, compared with the MSM control (120 mg/kg Mn), may increase the deposition efficiency of Mn, alter eggshell elemental composition, improve eggshell ultrastructure, and enhance eggshell strength in aged laying hens.

Manganese and IL-12 treatment alters the ovarian tumor microenvironment.

Metal immunotherapy is a novel adjuvant immunotherapy. Mn2+ can activate STING-a type I IFN response protein-that promotes innate immunity and increases anti-tumor activity by promoting macrophage phagocytosis. IL-12, a cytokine that increases the antigen-presenting ability to promote effector T-cell activation, has potent antitumor activity, albeit with severe adverse effects. In this study, we observed that the combination of Mn2+ and IL-12 has a better antitumor effect and possibly reflects a better safety profile, providing a novel approach and theoretical basis for safe and rapid cancer treatment.

The effect of maternal organic manganese supplementation on performance, immunological status, blood biochemical and antioxidant status of Afshari ewes and their newborn lambs in transition period.

It has been documented that adequate maternal manganese (Mn) status is vital for performance and health of ewes and their newborn lambs. However, required level and form of dietary Mn in ruminants are not well defined. The current study was conducted to evaluate the effect of maternal organic Mn supplementation on performance, immunological status, blood biochemical and antioxidant status of Afshari ewes and their newborn lambs in transition period. For this purpose, various organic Mn concentrations were utilized as a supplementary ingredient in formulating the diets of ewes. The ewes were randomly allocated into three groups, fed with 0, and 80 mg/kg organic Mn supplemented diet. At the end of the experiment, the parameters including the performance of newborn lambs, as well as biochemical factors, immune status and antioxidant status in ewes and their newborn lambs were evaluated. The results showed a significant increase in the plasma concentrations of Mn, glucose, insulin, thyroid hormones (T3 , T4 ) and enzymatic antioxidants (SOD, GPX , CAT) in ewes and their newborn lambs that were treated with maternal organic Mn. Moreover, inorganic Mn treatments, the concentration of IgG in newborn lamb's plasma, and colostrum of ewes increased. According to this research, organic Mn acts as a valuable and safe supplementary material that could be exploited for enhancing health of ewes and their newborn lambs.

Impact of Early Arsenic Exposure on the Mineral Content and Oxidative Status of the Liver and Kidney of Pubescent and Adult Rats.

This study evaluated the effect of prepubertal arsenic exposure in the liver and kidney of pubescent rats and their reversibility 30 days after arsenic withdrawal. Male pups of Wistar rats (21 days old) were divided into two groups (n = 20/group): control animals received filtered water, and exposed rats received 10 mg L-1 arsenic from postnatal day (PND) 21 to PND 51. The liver and kidney of 52 days old rats (n = 10/group) were examined to investigate the effects of arsenic on micromineral content, antioxidant enzyme activity, histology, and biochemistry parameters. The other animals were kept alive under free arsenic conditions until 82 days old and further analyzed by the same parameters. Our results revealed that 52-day-old rats increased arsenic content in their liver and arsenic and manganese in their kidney. In those animals, glycogen and zinc content and catalase activity were reduced in the liver, and the selenium content decreased in the kidney. Thirty days later, arsenic reduced the manganese and iron content and SOD and CAT activity in the liver of 82-day-old rats previously exposed to arsenic, while glycogen and selenium content decreased in their kidney. In contrast, PND 82 rats exhibited higher retention of copper in the liver, an increase in iron and copper content, and CAT and GST activity in the kidney. Significant histological alterations of liver and kidney tissues were not observed in rats of both ages. We conclude that arsenic-induced toxicity could alter differently the oxidative status and balance of trace elements in pubertal and adult rats, demonstrating that the metalloid can cause effects in adulthood.

PhotoPyro-Induced cGAS-STING Pathway Activation Enhanced Anti-Melanoma Immunotherapy via a Manganese-Coordinated Nanomedicine.

Malignant melanoma is an aggressive skin cancer with a high metastatic and mortality rate. Owing to genetic alterations, melanoma cells are resistant to apoptosis induction, which reduces the efficacy of most adjuvant systemic anticancer treatments in clinical. Here, a noninvasive strategy for anti-melanoma immunotherapy based on a manganese-coordinated nanomedicine is provided. Supplemented with photoirradiation, photon-mediated reactive oxygen species generation by photosensitizer chlorin e6 initiates photon-controlled pyroptosis activation (PhotoPyro) and promotes antitumor immunity. Simultaneously, photoirradiation-triggered double-stranded DNA generation in the cytosol would activate the Mn2+ -sensitized cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which further augment the PhotoPyro-induced immune response. The syngeneic effect of these immunostimulatory pathways significantly benefits dendritic cell maturation by damage-associated molecular patterns and proinflammatory cytokines secretion, thereby activating T cells and remarkably eliciting a systemic antitumor immune response to inhibiting both primary and distant tumor growth. Collaboratively, the photoirradiation-triggered PhotoPyro and cGAS-STING pathway activation by nanomedicine administration could enhance the antitumor capacity of immunotherapy and serve as a promising strategy for melanoma treatment.

Effect of Melissa officinalis L. leaf extract on manganese-induced cyto-genotoxicity on Allium cepa L.

Although the antioxidant properties of Melissa officinalis extract (Mox) are widely known, little work has focused on its protective capacity against heavy metal stress. The primary objective of this study was to determine the potential of Mox to mitigate manganese (II) chloride (MnCI2)-induced cyto-genotoxicity using the Allium and comet assays. Physiological, genotoxic, biochemical and anatomical parameters as well as the phenolic composition of Mox were examined in Allium cepa (L.). Application of 1000 µM MnCl2 reduced the rooting percentage, root elongation, weight gain, mitotic index and levels of chlorophyll a and chlorophyll b pigments compared to the control group. However, it increased micronuclei formation, chromosomal abnormality frequencies, tail DNA percentage, proline amount, lipid peroxidation level and meristematic damage severity. The activities of superoxide dismutase and catalase also increased. Chromosomal aberrations induced by MnCl2 were fragment, sticky chromosome, vagrant chromosome, unequal distribution of chromatin and bridge. Application of 250 mg/L Mox and 500 mg/L Mox along with MnCl2 significantly alleviated adverse effects dose dependently. The antioxidant activity bestowed by the phenolic compounds in Mox assisted the organism to combat MnCl2 toxicity. Consequently, Mox exerted remarkable protection against MnCl2 toxicity and it needs to be investigated further as a potential therapeutic option.

Impact of zinc, copper, manganese and chromium supplementation on growth performance and blood metabolic profile of Sahiwal (Bos indicus) male calves.

This study aimed to see the effect of oral supplementation of specific trace minerals mixture on the growth, immunity, and reproductive development of indigenous growing bull calves. Eighteen Sahiwal bull calves, with an average age of 6 months were chosen and divided into three groups. Group 1 was fed with a basal diet, Group 2 was provided with an additional specific trace mineral supplement to achieve a diet containing 70 ppm of Zn, 17.50 ppm of Cu, 65 ppm of Mn, and 1.75 ppm of Cr. Group 3 received a 25% extra supplement to achieve a diet containing 87.50 ppm of Zn, 21.87 ppm of Cu, 81.25 ppm of Mn, and 2.18 ppm of Cr. The experiment was carried out for a total of 180 days. According to the findings, there was no significant impact of specific trace minerals supplementation on the animals' body weight, morphometric parameters, dry matter intake, average daily gain, nutritional value, digestibility and nitrogen retention. However, higher levels of Zn, Cu, and Mn led to increased (p < 0.05) total retention, while Cr retention remained the same. Serum mineral concentrations of Zn, Cu, and Mn increased significantly (p < 0.05) in G2 and G3 compared to the G1 group while Ca, P, and Cr had no significant change. Blood plasma glucose, albumin, globulin, and total protein showed no significant differences. Plasma alkaline phosphatase activity improved significantly (p < 0.05) in G2 and G3 but alanine transaminase, aspartate aminotransferase, hemoglobin, hematocrit, and IGF-1 remained unchanged. Superoxide dismutase activity, ferric-reducing antioxidant power, and total immunoglobulin concentration increased significantly (p < 0.05) in G2 and G3 groups, however, catalase activity and IgG count did not change among the groups. Mineral-supplemented groups (G2 and G3) showed a significant change (p < 0.05) in testosterone production during the 120th and the 180th day of the trial. Scrotal circumference and temperature gradient of the scrotal surface did not show any significant change. Supplementing growing bull calves with specific trace minerals above the basal level (70, 17.50, 65 and 1.75 ppm of Zn, Cu, Mn and Cr) has no direct beneficial effect on the growth parameters but can have positive effects on their antioxidant status, immunity and reproductive development as the related blood parameters were positively affected.

Effects of Diabetes on Elemental Levels and Nanostructure of Root Canal Dentin.

INTRODUCTION: This study evaluated the effects of diabetes mellitus (DM) on the nanostructure of root canal dentin using high-resolution transmission electron microscopy (HRTEM) and inductively coupled plasma mass spectrometry (ICP-MS). METHODS: Twenty extracted human premolars from diabetic and nondiabetic patients (n = 10 in each group) were decoronated and sectioned horizontally into 40 2-mm-thick dentin discs, with each disc designated for a specific test. ICP-MS was used to determine the different elemental levels of copper, lithium, zinc, selenium, strontium, manganese, and magnesium in diabetic and nondiabetic specimens. HRTEM was used to analyze the shape and quantity of the apatite crystals in diabetic and nondiabetic dentin at the nanostructural level. Statistical analysis was performed using Kolmogorov-Smirnov and Student t test (P < .05). RESULTS: ICP-MS revealed significant differences in trace element concentrations between the diabetic and nondiabetic specimens (P < .05), with lower levels of magnesium, zinc, strontium, lithium, manganese, and selenium (P < .05), and higher levels of copper in diabetic specimens (P < .05). HRTEM revealed that diabetic dentin exhibited a less compact structure with smaller crystallites and significantly more crystals in the 2500 nm2 area (P < .05). CONCLUSION: Diabetic dentin exhibited smaller crystallites and altered elemental levels more than nondiabetic dentin, which could explain the higher root canal treatment failure rate in diabetic patients.

Preparation of Biocompatible Manganese Selenium-Based Nanoparticles with Antioxidant and Catalytic Functions.

The specificity of the tumor microenvironment (TME) severely limits the effectiveness of tumor treatment. In this study, we prepared a composite nanoparticle of manganese dioxide and selenite by a one-step redox method, and their stability under physiological conditions was improved with a bovine serum protein modification to obtain MnO2/Se-BSA nanoparticles (SMB NPs). In the SMB NPs, manganese dioxide and selenite endowed the SMB NPs with acid-responsive and catalytic, and antioxidant properties, respectively. The weak acid response, catalytic activity, and antioxidant properties of composite nanoparticles were verified experimentally. Moreover, in an in vitro hemolysis assay, different concentrations of nanoparticles were incubated with mouse erythrocytes, and the hemolysis ratio was less than 5%. In the cell safety assay, the cell survival ratio was as high as 95.97% after the co-culture with L929 cells at different concentrations for 24 h. In addition, the good biosafety of composite nanoparticles was verified at the animal level. Thus, this study helps to design high-performance and comprehensive therapeutic reagents that are responsive to the hypoxia, weak acidity, hydrogen peroxide overexpression nature of TME and overcome the limitations of TME.

Impacts of organic manganese supplementation on blood mineral, biochemical, and hematology in Afshari Ewes and their newborn lambs in the transition period.

OBJECTIVE: Maternal mineral status, including manganese (Mn), is critical for fetal growth as well as the health of the newborn lamb. Consequently, it is essential to supply minerals at sufficient levels for the pregnant animal to achieve the development of the embryo and fetus during gestation. METHODS: The current research was conducted to investigate the impact of organic Mn supplementation on blood biochemical, other mineral and, hematology in Afshari ewes and their newborn lambs in the transition period. Twenty-four ewes were randomly divided into three groups with eight replications. The control group was fed with a diet without organic Mn. The other groups were fed a diet supplemented with 40 (recommended by the NRC) and 80 (twice-recommended by the NRC) mg/kg of DM organic Mn. RESULTS: In this study, the consumption of organic Mn caused a significant increase in ewes and lambs plasma Mn concentration. Moreover, in the groups mentioned, levels of glucose, insulin, and superoxide dismutase were significantly increased in both ewes and lambs. Concentrations of total protein and albumin were higher in ewes fed whit organic Mn. In both ewes and newborn lambs, the levels of red blood cells, hemoglobin, hematocrit, mean corpuscular hemoglobin, and mean corpuscular concentration in groups fed with organic Mn raised. CONCLUSION: In general, the nutrition of organic Mn, improved factors of blood biochemical and hematology in ewes and their newborn lambs, and since the twice-recommended NRC level did not cause poisoning, it was recommended to supplement the diet with 80 mg of organic Mn per kg of DM.

Manganese alleviates heat stress of primary cultured chick embryonic myocardial cells via enhancing manganese superoxide dismutase expression and attenuating heat shock response.

Manganese (Mn) is an essential trace element that has been shown to attenuate the adverse effects of heat stress in the heart of broiler breeders and embryos. However, the underlying molecular mechanisms involving this process remain unclear. Therefore, two experiments were conducted to investigate the possible protective mechanisms of Mn on primary cultured chick embryonic myocardial cells exposed to heat challenge. In experiment 1, the myocardial cells were exposed to 40 °C (normal temperature, NT) and 44 °C (high temperature, HT) for 1, 2, 4, 6 or 8 h. In experiment 2, the myocardial cells were preincubated with no Mn supplementation (CON), 1 mmol/L of Mn as the inorganic MnCl2 (iMn) or organic Mn proteinate (oMn) under NT for 48 h, and then continuously incubated under NT or HT for another 2 or 4 h. The results from experiment 1 showed that the myocardial cells incubated for 2 or 4 h had the highest (P < 0.0001) heat-shock protein 70 (HSP70) or HSP90 mRNA levels than those incubated for other incubation times under HT. In experiment 2, HT increased (P < 0.05) the heat-shock factor 1 (HSF1) and HSF2 mRNA levels as well as Mn superoxide dismutase (MnSOD) activity of myocardial cells compared with NT. Furthermore, supplemental iMn and oMn increased (P < 0.02) HSF2 mRNA level and MnSOD activity of myocardial cells compared with the CON. Under HT, the HSP70 and HSP90 mRNA levels were lower (P < 0.03) in iMn group than in the CON group, in oMn group than in iMn group; and the MnSOD mRNA and protein levels were higher (P < 0.05) in oMn group than in the CON and iMn groups. These results from the present study indicate that supplemental Mn, especially oMn, could enhance the MnSOD expression and attenuate heat shock response to protect against heat challenge in primary cultured chick embryonic myocardial cells.

Effects of replacing inorganic salts of trace minerals with organic trace minerals in the pre- and postpartum diets on mineral status, antioxidant biomarkers, and health of dairy cows.

Our objectives were to evaluate the effects of complete replacement of supplementary inorganic salts of trace minerals (ITM; cobalt (Co), copper (Cu), manganese (Mn), zinc (Zn) sulfates and sodium (Na) selenite) by organic trace minerals (OTM; Co, Cu, Mn, Zn proteinates, and selenized yeast) in both pre- and postpartum diets on trace minerals (TM) concentrations in body fluids and liver, antioxidant and inflammation biomarkers in blood, and postpartum health of dairy cows. Pregnant cows were blocked by parity and body condition score and randomly assigned to ITM (n = 136) or OTM (n = 137) 45 d before expected calving. Both groups received the same pre- and postpartum diets except for the source of supplementary TM. The day of calving was considered study d 0 and blood was collected on d -45, -21, -14, -10, -7, -3, 0, 3, 7, 10, 14, 23, 65, and 105 for analyses of TM and biomarkers. Concentrations of TM were also investigated in the liver (d 105), milk (d 7, 23, 65, 105), urine (d -21, 21, 65, 105), ruminal fluid and feces (d -21, 21, 65). Incidence of clinical and subclinical health conditions were evaluated. Complete replacement of ITM by OTM resulted in greater concentration of selenium (Se) in serum (0.084 vs. 0.086 µg/mL; P < 0.01), milk (0.24 vs. 0.31 µg/g; P < 0.01), and ruminal fluid (0.54 vs. 0.58 µg/g; P = 0.06), and reduced concentration of Se in urine (1.54 vs. 1.23 µg/g; P<0.01). For concentration of Co in serum, an interaction between treatment and time was detected (P < 0.01). Cows supplemented with OTM had greater concentrations of Co on d -7 and 0 (0.30 vs. 0.33 ng/mL; P < 0.01) but lower concentrations of Co on d 23, 65, and 105 (0.34 vs. 0.31 ng/mL; P < 0.05), in addition to reduced concentration of Co in feces (1.08 vs. 0.99 µg/g; P = 0.04) and, for multiparous only, in urine (0.019 vs. 0.014 µg/g; P < 0.01). Cows supplemented with OTM had lower postpartum concentrations of glutamate dehydrogenase (20.8 vs. 17.8 U/L; P < 0.05) and higher albumin on d -10 (36.0 vs. 36.7 g/L; P = 0.04) and 23 (36.9 vs. 37.6 g/L; P = 0.03) relative to calving. Primiparous cows fed OTM had lower concentration of ceruloplasmin in plasma (55 vs. 51 mg/L; P ≤ 0.05). Cows supplemented with OTM had less incidence of lameness (14% vs. 7%; P = 0.05), elevated nonesterified fatty acids (NEFA) (61% vs. 44%; P < 0.01), and multiple metabolic problems (35% vs. 20%; P < 0.01). Despite the lack of differences in Cu, Mn, and Zn concentrations and antioxidant capacity, complete replacement of ITM by OTM altered concentrations of Se and Co, supported liver and hoof health, and reduced the risk of postpartum elevated NEFA.

Trace minerals (TM) are important for oxidative balance and immunity of cows. Different forms of TM are available for dietary supplementation of dairy cows. We tested whether replacing inorganic salts of TM by organic sources of TM in both pre- and postpartum diets improve TM concentration in body fluids and liver, antioxidant capacity in blood, and postpartum health of dairy cows. Despite the lack of difference in antioxidant capacity and in concentrations of Cu, Mn, and Zn, the complete replacement of inorganic salts by organic sources altered concentrations of Se and Co in circulation, and reduced the concentration of biomarkers associated with inflammation and liver damage, and the risk of lameness and postpartum metabolic problems.

Zinc homeostasis may reverse the synergistic neurotoxicity of heavy metal mixtures in Caenorhabditis elegans.

Heavy metal mixtures can cause nerve damage. However, the combined effects of metal mixtures are extremely complex and rarely studied. Zinc (Zn) homeostasis plays an integral role in neural function, but the role of Zn homeostasis in the toxicity of metal mixtures is not well understood. Here, we investigated the combined effects of manganese (Mn), lead (Pb) and arsenic (As) on nerves and the effect of Zn homeostasis on metal toxicity. Caenorhabditis elegans (Maupas, 1900) were exposed to single and multiple metals for 8 days, their movement, behavior, neurons and metal concentration were detected to evaluate the combined effect of metal mixtures. After nematodes were co-treated with metal mixtures and Zn, the nerve function, Zn concentration and redox balance were detected to evaluate the effect of Zn homeostasis on metal toxicity. The results showed that Mn + Pb and Pb + As mixtures induced synergistic toxicity for nematode nerves, which damaged movement, behavior and neurons, and decreased Zn concentration. While Zn supplementation recovered Zn homeostasis and promoted redox balance on nematodes, and then improved the nerve function. Our study demonstrated the combined effects of metal mixtures and the neuroprotective effect of Zn homeostasis. Therefore, assessment of metal mixtures toxicity should consider their interaction and the impacts of essential metals homeostasis.

Integrated manganese (III)-doped nanosystem for optimizing photothermal ablation: Amplifying hyperthermia-induced STING pathway and enhancing antitumor immunity.

Despite the great promise initially demonstrated by photothermal ablation (PTA) therapy, its inability to completely ablate large tumors is problematic, because this has been found to result in residual tumors at ablation margins and bring a relative high rate of subsequent recurrences and metastases. To address this issue, we herein report a smart photothermal nanosystem (PBM) based on FDA-approved Prussian blue (PB) nanoparticles, doped with Mn (III) to suppress the tumor debris left by incomplete ablation. Notably, our study demonstrated that PTA-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway by generating damaged cytosolic DNA. This PBM nanosystem, which consumes glutathione and continuously releases Mn(II), further amplifies the PTA-induced cGAS-STING pathway in CT26 colon and 4T1 breast tumor models. Moreover, treatment with PBM following PTA boosted the robust immune response in situ and extended to the whole body with a remarkable suppression effect on both local residual and distant tumors. This work, which improves the antitumor efficacy of nonablated areas utilizing hyperthermia-enhanced immune therapy, may therefore provide a promising adjuvant antitumor strategy for the issue of incomplete ablation. STATEMENT OF SIGNIFICANCE: This work discovered, for the first time, that photothermal ablation-induced hyperthermia plays a crucial role in initiating the cGAS-STING pathway. Taking advantage of this finding, we developed a smart photothermal material (PBM) tailored for incomplete tumor ablation. This integrated Mn(III)-doped nanosystem (PBM) demonstrated superior therapeutic benefits due to the thermal ablation process and immune enhancement. As the photothermal ablation-induced cGAS-STING pathway was triggered, the released Mn(III) consumes GSH while continuously transferred to Mn(II), which further amplified STING activation and facilitated a more robust antitumor immunity, thereby remarkably inhibiting both local residual and distant tumors in virtue of the biological changes under thermal ablation.

Effects of Zinc, Manganese, and Taurine on Egg Shell Microstructure in Commercial Laying Hens After Peak Production.

Much strive has been made to improve egg shell quality in laying hens. This study was conducted to evaluate the effects of two microminerals, zinc and manganese, besides taurine semi-essential amino acid on eggshell quality after peak production of Hy-line laying hens. A total of 720 laying hens were assigned to 18 treatments in a completely randomized design (3 × 3 × 2 factorial) at week 71. Experimental period included 8-week adaptation and using 18 dietary treatments for about 6 weeks. Dietary treatments included Zn (0, 80, and 160 mg/kg), Mn (0, 90, and 180 mg/kg), and taurine (0 and 1960 mg/kg). Supplementation of 90 mg Mn and 1960 mg taurine in laying hens' diet after peak of production improved egg shell quality without any negative effect on the internal quality of the egg. Egg specific gravity significantly increased in response to Zn, Mn, and taurine in comparison with control treatment (P < 0.05). Applying 1960 mg taurine/kg diet significantly improved calcite crystal's structure and eggshell strength in comparison with control treatment (P < 0.05). It was concluded that adding Mn and taurine can positively affect eggshell quality of laying hens post peak period.

Trace mineral mixture supplemented to in vitro maturation medium improves subsequent embryo development and embryo quality in cattle.

Trace minerals participate in reproductive processes and are crucial for oocyte maturation. The objective of the present study was to investigate the effect of combined supplementation with copper (Cu), manganese (Mn), selenium (Se) and zinc (Zn) during bovine in vitro maturation (IVM) on subsequent embryo development and quality. The IVM medium was supplemented as follows: a) Control (no mineral supplementation); b) MScz (6 ng/mL Mn + 100 ng/mL Se + 200 ng/mL Cu + 400 ng/mL Zn); c) MScZ (6 ng/mL Mn + 100 ng/mL Se + 200 ng/mL Cu + 1200 ng/mL Zn); d) MSCz (6 ng/mL Mn + 100 ng/mL Se + 600 ng/mL Cu + 400 ng/mL Zn). Supplementation with MScz and MSCz produced more blastocysts compared with the control. Total blastocyst cell number was higher when minerals were added at any combination. Day-8 blastocysts derived from oocytes treated with minerals had lower intracellular reactive oxygen species concentration and lipid content than the control. In conclusion, combined supplementation with Cu, Mn, Se and Zn during bovine oocyte IVM increased in vitro production performance, improving embryo developmental ability and quality.

Manganese Modulates Metabolic Activity and Redox Homeostasis in Translationally Blocked Lactococcus cremoris, Impacting Metabolic Persistence, Cell Culturability, and Flavor Formation.

Manganese (Mn) is an essential trace element that is supplemented in microbial media with varying benefits across species and growth conditions. We found that growth of Lactococcus cremoris was unaffected by manganese omission from the growth medium. The main proteome adaptation to manganese omission involved increased manganese transporter production (up to 2,000-fold), while the remaining 10 significant proteome changes were between 1.4- and 4-fold. Further investigation in translationally blocked (TB), nongrowing cells showed that Mn supplementation (20 µM) led to approximately 1.5 X faster acidification compared with Mn-free conditions. However, this faster acidification stagnated within 24 h, likely due to draining of intracellular NADH that coincides with substantial loss of culturability. Conversely, without manganese, nongrowing cells persisted to acidify for weeks, albeit at a reduced rate, but maintaining redox balance and culturability. Strikingly, despite being unculturable, α-keto acid-derived aldehydes continued to accumulate in cells incubated in the presence of manganese, whereas without manganese cells predominantly formed the corresponding alcohols. This is most likely reflecting NADH availability for the alcohol dehydrogenase-catalyzed conversion. Overall, manganese influences the lactococcal acidification rate, and flavor formation capacity in a redox dependent manner. These are important industrial traits especially during cheese ripening, where cells are in a non-growing, often unculturable state. IMPORTANCE In nature as well as in various biotechnology applications, microorganisms are often in a nongrowing state and their metabolic persistence determines cell survival and functionality. Industrial examples are dairy fermentations where bacteria remain active during the ripening phases that can take up to months and even years. Here we investigated environmental factors that can influence lactococcal metabolic persistence throughout such prolonged periods. We found that in the absence of manganese, acidification of nongrowing cells remained active for weeks while in the presence of manganese it stopped within 1 day. The latter coincided with the accumulation of amino acid derived volatile metabolites. Based on metabolic conversions, proteome analysis, and a reporter assay, we demonstrated that the manganese elicited effects were NADH dependent. Overall the results show the effect of environmental modulation on prolonged cell-based catalysis, which is highly relevant to non-growing cells in nature and biotechnological applications.

Manganese-Induced Oxidative Stress Contributes to Intestinal Lipid Deposition via the Deacetylation of PPARγ at K339 by SIRT1.

Aims: Excessive manganese (Mn) exposure is toxic, and induces lipid deposition, but the underlying mechanisms remain elusive. Herein, we explored how dietary Mn supplementation affects lipid deposition and metabolism in the intestine of vertebrates using the yellow catfish Pelteobagrus fulvidraco as the model. Results: High-Mn (H-Mn) diet increased intestinal Mn content, promoted lipid accumulation and lipogenesis, and inhibited lipolysis. In addition, it induced oxidative stress, upregulated metal-response element-binding transcription factor-1 (MTF-1), and peroxisome proliferator-activated receptor gamma (PPARγ) protein expression in the nucleus, induced PPARγ acetylation, and the interaction between PPARγ and retinoid X receptor alpha (RXRα), while it downregulated sirtuin 1 (SIRT1) expression and activity. Mechanistically, Mn activated the MTF-1/divalent metal transporter 1 (DMT1) pathway, increased Mn accumulation in the mitochondria, and induced oxidative stress. This in turn promoted lipid deposition via deacetylation of PPARγ at K339 by SIRT1. Subsequently, PPARγ mediated Mn-induced lipid accumulation through transcriptionally activating fatty acid translocase, stearoyl-CoA desaturase 1, and perilipin 2 promoters. Innovation: These studies uncover a previously unknown mechanism by which Mn induces lipid deposition in the intestine via the oxidative stress-SIRT1-PPARγ pathway. Conclusion: High dietary Mn intake activates MTF-1/DMT1 and oxidative stress pathways. Oxidative stress-mediated PPARγ deacetylation at K339 site contributes to increased lipid accumulation. Our results provided a direct link between Mn and lipid metabolism via the oxidative stress-SIRT1-PPARγ axis. Antioxid. Redox Signal. 37, 417-436.