Hormesis effect has been observed in the secondary metabolite synthesis of microorganisms induced by rare earth elements. However, the underlying molecular mechanism remains unclear. To analyze the molecular mechanism of the regulatory effect of Rhodotorula mucilaginosa in the presence of lanthanum chloride, different concentrations of lanthanum chloride were added to the fermentation medium of Rhodotorula mucilaginosa, and the carotenoid content was subsequently measured. It was found that the concentrations of La³⁺ exerting the promotional and inhibitory effects were 0-100 mg/L and 100-400 mg/L, respectively. Furthermore, the expression of 33 genes and the synthesis of 55 metabolites were observed to be up-regulated, while the expression of 85 genes and the synthesis of 123 metabolites were found to be down-regulated at the concentration range of the promotional effect. Notably, the expression of carotenoid synthesis-related genes except AL1 was up-regulated. Additionally, the content of β-carotene, lycopene, and astaxanthin demonstrated increases of 10.74%, 5.02%, and 3.22%, respectively. The expression of 5 genes and the synthesis of 91 metabolites were up-regulated, while the expression of 35 genes and the synthesis of 138 metabolites were down-regulated at the concentration range of the inhibitory effect. Meanwhile, the content of β-carotene, lycopene, and astaxanthin decreased by 21.73%, 34.81%, and 35.51%, respectively. In summary, appropriate concentrations of rare earth ions can regulate the synthesis of secondary metabolites by modulating the activities of various enzymes involved in metabolic pathways, thereby exerting the hormesis effect. The findings of this study not only contribute to our comprehension for the mechanism of rare earth elements in organisms but also offer a promising avenue for the utilization of rare earth elements in diverse fields, including agriculture, pharmaceuticals, and healthcare.
Lanthanum/pharmacology* ; Rhodotorula/genetics* ; Carotenoids/metabolism* ; Hormesis/drug effects* ; Fermentation ; Multiomics

Objective: To investigate the effect of nuclear factor erythroid 2-related factor 2 (Nrf2) in the alteration of tight junction protein expression in choroid plexus epithelial cells created by lanthanum-activated matrix metalloproteinase 9 (MMP9) . Methods: In October 2020, immortalized rat choroid plexus epithelial cell line (Z310) cells were used as the blood-cerebrospinal fluid barrier in vitro, and were divided into control group and 0.125, 0.25, 0.5 mmol/L lanthanum chloride (LaCl(3)) treatment group. After treating Z310 cells with different concentrations of LaCl(3) for 24 hours, the morphological changes of Z310 cells were observed under inverted microscope, the protein expression levels of MMP9, occludin and zonula occludens-1 (ZO-1) were observed by cellular immunofluorescence method, and the protein expression levels of MMP9, tissue inhibitors of metalloproteinase1 (TIMP1) , occludin, ZO-1 and Nrf2 were detected by Western blotting. The level of reactive oxygen species (ROS) in cells was detected by flow cytometry. Results: Compared with the control group, Z310 cells in the LaCl(3) treatment group were smaller in size, with fewer intercellular junctions, and more dead cells and cell fragments. The expression level of MMP9 protein in cells treated with 0.25 and 0.5 mmol/L LaCl(3) was significantly higher than that in the control group (P<0.05) , and the expression level of TIMP1 and tight junction proteins occudin and ZO-1 was significantly lower than that in the control group (P<0.05) . Compared with the control group, the ROS production level in the 0.25, 0.5 mmol/L LaCl(3) treatment group was significantly increased (P<0.05) , and the Nrf2 protein expression level in the 0.125, 0.25, 0.5 mmol/L LaCl(3) treatment group was significantly decreased (P<0.05) . Conclusion: Lanthanum may increase the level of ROS in cells by down regulating the expression of Nrf2, thus activating MMP9 to reduce the expression level of intercellular tight junction proteins occludin and ZO-1.
Rats ; Animals ; Matrix Metalloproteinase 9/metabolism* ; NF-E2-Related Factor 2/metabolism* ; Tight Junction Proteins/metabolism* ; Occludin/pharmacology* ; Choroid Plexus/metabolism* ; Reactive Oxygen Species/metabolism* ; Lanthanum/pharmacology* ; Epithelial Cells ; Zonula Occludens-1 Protein/metabolism* ; Phosphoproteins/pharmacology*

OBJECTIVEThe present study was undertaken to evaluate the subchronic toxicity of lanthanum and to determine the no observed adverse effect level (NOAEL), which is a critical factor in the establishment of an acceptable dietary intake (ADI).

METHODSIn accordance with the Organization for Economic Co-operation and Development (OECD) testing guidelines, lanthanum nitrate was administered once daily by gavage to Sprague-Dawley (SD) rats at dose levels of 0, 1.5, 6.0, 24.0, and 144.0 mg/kg body weight (BW) per day for 90 days, followed by a recovery period of 4 weeks in the 144.0 mg/kg BW per day and normal control groups. Outcome parameters were mortality, clinical symptoms, body and organ weights, serum chemistry, and food consumption, as well as ophthalmic, urinary, hematologic, and histopathologic indicators. The benchmark dose (BMD) approach was applied to estimate a point of departure for the hazard risk assessment of lanthanum.

RESULTSSignificant decreases were found in the 144.0 mg/kg BW group in the growth index, including body weight, organ weights, and food consumption. This study suggests that the NOAEL of lanthanum nitrate is 24.0 mg/kg BW per day. Importantly, the 95% lower confidence value of the benchmark dose (BMDL) was estimated as 9.4 mg/kg BW per day in females and 19.3 mg/kg BW per day in males.

CONCLUSIONThe present subchronic oral exposure toxicity study may provide scientific data for the risk assessment of lanthanum and other rare earth elements (REEs).

Animals ; Blood Chemical Analysis ; Body Weight ; Dose-Response Relationship, Drug ; Drug Administration Schedule ; Female ; Lanthanum ; administration & dosage ; toxicity ; Male ; No-Observed-Adverse-Effect Level ; Rats ; Rats, Sprague-Dawley ; Specific Pathogen-Free Organisms ; Toxicity Tests, Subchronic ; Urinalysis

Background: Hyperphosphatemia is a risk factor associated with mortality in patients on maintenance hemodialysis. Gut absorption of phosphate is the major source. Recent studies indicated that the intestinal flora of uremic patients changed a lot compared with the healthy population, and phosphorus is an essential element of bacterial survival and reproduction. The purpose of this study was to explore the role of intestinal microbiota in phosphorus metabolism. Methods: A prospective self-control study was performed from October 2015 to January 2016. Microbial DNA was isolated from the stools of 20 healthy controls and 21 maintenance hemodialysis patients. Fourteen out of the 21 patients were treated with lanthanum carbonate for 12 weeks. Thus, stools were also collected before and after the treatment. The bacterial composition was analyzed based on 16S ribosomal RNA pyrosequencing. Bioinformatics tools, including sequence alignment, abundance profiling, and taxonomic diversity, were used in microbiome data analyses. Correlations between genera and the serum phosphorus were detected with Pearson's correlation. For visualization of the internal interactions and further measurement of the microbial community, SparCC was used to calculate the Spearman correlation coefficient with the corresponding P value between each two genera. Results: Thirteen genera closely correlated with serum phosphorus and the correlation coefficient was above 0.4 (P < 0.05). We also found that 58 bacterial operational taxonomic units (OTUs) were significantly different and more decreased OTUs were identified and seven genera (P < 0.05) were obviously reduced after using the phosphate binder. Meanwhile, the microbial richness and diversity presented downward trend in hemodialysis patients compared with healthy controls and more downward trend after phosphorus reduction. The co-occurrence network of genera revealed that the network complexity of hemodialysis patients was significantly higher than that of controls, whereas treatment with lanthanum carbonate reduced the network complexity. Conclusions Gut flora related to phosphorus metabolism in hemodialysis patients, and improving intestinal microbiota may regulate the absorption of phosphate in the intestine. The use of phosphate binder lanthanum carbonate leads to a tendency of decreasing microbial diversity and lower network complexity.
Child ; Female ; Gastrointestinal Microbiome ; drug effects ; physiology ; Humans ; Lanthanum ; therapeutic use ; Male ; Middle Aged ; Phosphorus ; metabolism ; Prospective Studies ; Renal Dialysis ; Risk Factors ; Uremia ; drug therapy ; metabolism ; microbiology

The effect of lanthanum carbonate on abdominal aortic calcification (AAC) in the elderly maintenance hemodialysis (MHD) patients was investigated. Fifty-four cases subjected to routine MHD complicated with skin pruritus admitted to our hospital were selected and randomly divided into case group (n=28) and control group (n=26). The control group was given routine MHD alone. The case group was given lanthanum carbonate additionally on the basis of routine MHD. The changes of itching degrees at first and third month, and serum calcium, phosphorus, calcium-phosphorus products, intact parathyroid hormone (iPTH) levels and AAC scores at third month after treatments were compared between the two groups. The correlation between calcium-phosphorus products and AAC scores was also analyzed. There was no significant difference in the baseline of blood urea nitrogen (BUN), serum creatinine (Scr), uric acid, albumin, hemoglobin, C reactive protein (CRP), low density lipoprotein (LDL), high density lipoprotein (HDL), triglyceride, total cholesterol between case group and control group (P>0.05 for all). There was also no significant difference in the baseline itching scores between the case group and the control group (P>0.05). At 1st and 3rd month after treatment, the itching scores in the case group were 14.2 ± 3.2 and 10.5 ± 2.3, respectively, which were significantly lower than the baseline and those in the control group (P<0.05 for all). At 1st and 3rd month after treatment, the itching scores in the control group were 23.6 ± 5.9 and 24.8 ± 6.3, respectively, which were significantly higher than the baseline (P<0.05). There was no significant difference in the baseline of serum calcium, phosphorus, calcium-phosphorus products, iPTH levels between the case group and control group (P>0.05). At 3rd month after treatment, serum phosphorus, calcium-phosphorus products and iPTH levels in the case group were decreased significantly as compared with the baseline (P<0.05), and the serum calcium, phosphorus, calcium-phosphorus products, and iPTH levels were statistically decreased as compared with those in the control group (P<0.05). The AAC scores showed statistically significant difference between the case group and the control group (P<0.05). The serum phosphorus and AAC scores showed a positive correlation in both two groups. It was suggested that the administration of lanthanum carbonate in the elderly MHD patients can effectively relieve itching, and simultaneously reduce serum phosphorus and iPTH levels, resulting in the attenuation of vascular calcification.
Aged ; Aged, 80 and over ; Case-Control Studies ; Female ; Humans ; Lanthanum ; administration & dosage ; therapeutic use ; Male ; Middle Aged ; Parathyroid Hormone ; analysis ; Phosphates ; blood ; Pruritus ; blood ; drug therapy ; etiology ; Renal Dialysis ; adverse effects ; methods ; Treatment Outcome ; Vascular Calcification ; blood ; drug therapy

Wnk kinase maintains cell volume, regulating various transporters such as sodium-chloride cotransporter, potassium-chloride cotransporter, and sodium-potassium-chloride cotransporter 1 (NKCC1) through the phosphorylation of oxidative stress responsive kinase 1 (OSR1) and STE20/SPS1-related proline/alanine-rich kinase (SPAK). However, the activating mechanism of Wnk kinase in specific tissues and specific conditions is broadly unclear. In the present study, we used a human salivary gland (HSG) cell line as a model and showed that Ca2+ may have a role in regulating Wnk kinase in the HSG cell line. Through this study, we found that the HSG cell line expressed molecules participating in the WNK-OSR1-NKCC pathway, such as Wnk1, Wnk4, OSR1, SPAK, and NKCC1. The HSG cell line showed an intracellular Ca2+ concentration ([Ca2+]i) increase in response to hypotonic stimulation, and the response was synchronized with the phosphorylation of OSR1. Interestingly, when we inhibited the hypotonically induced [Ca2+]i increase with nonspecific Ca2+ channel blockers such as 2-aminoethoxydiphenyl borate, gadolinium, and lanthanum, the phosphorylated OSR1 level was also diminished. Moreover, a cyclopiazonic acid-induced passive [Ca2+]i elevation was evoked by the phosphorylation of OSR1, and the amount of phosphorylated OSR1 decreased when the cells were treated with BAPTA, a Ca2+ chelator. Finally, through that process, NKCC1 activity also decreased to maintain the cell volume in the HSG cell line. These results indicate that Ca2+ may regulate the WNK-OSR1 pathway and NKCC1 activity in the HSG cell line. This is the first demonstration that indicates upstream Ca2+ regulation of the WNK-OSR1 pathway in intact cells.
Cell Line* ; Cell Size ; Gadolinium ; Humans ; Lanthanum ; Oxidative Stress ; Phosphorylation ; Phosphotransferases ; Salivary Glands* ; Sodium Chloride Symporters ; Sodium-Potassium-Chloride Symporters

OBJECTIVETo investigate the regulatory effects of lanthanum chloride (LaCl3) on the activation of nuclear factor kappa B inhibitor (IκB) kinase beta (IKKβ) induced by tumor necrosis factor alpha (TNF-α).

METHODS(1) Hela cells were cultured routinely in vitro. One portion of cells were collected and divided into TNF-α group (cultured with serum-free RMPI 1640 medium containing 20 ng/mL TNF-α for 30 min), low-dose LaCl3 + TNF-α group, moderate-dose LaCl3 + TNF-α group, high-dose LaCl3 + TNF-α group, LaCl3 group (cultured with serum-free RMPI 1640 medium containing 100 µmol/L LaCl3 for 30 min), and control group (cultured with serum-free RMPI 1640 medium for 30 min) according to the random number table. Cells in low-dose LaCl3 + TNF-α group, moderate-dose LaCl3 + TNF-α group, high-dose LaCl3 + TNF-α group were first cultured with serum-free RMPI 1640 medium containing 5, 25, 100 µmol/L LaCl3 for 4 h, and then stimulated with serum-free RMPI 1640 medium containing 20 ng/mL TNF-α for 30 min. There were 3 samples in each group. Cells were collected for detection of intracellular location of NF-κB/p65 protein by immunofluorescence staining. (2) Another portion of cells were collected and divided into TNF-α group, low-dose LaCl3 + TNF-α group, moderate-dose LaCl3 + TNF-α group, high-dose LaCl3 + TNF-α group, and control group with the same treatment as above. There were 3 samples in each group. The protein levels of NF-κB/p65 in nuclei, and the protein levels of IκBα, phosphorylated IκBα (p-IκBα) as well as IKKβ and phosphorylated IKKβ (p-IKKβ) in cytoplasm were determined by Western blotting. The binding activity between NF-κB/p65 in the nuclear and target gene was determined by NF-κB/p65 transcription factor kit (denoted as absorption value). Data were processed with analysis of variance or LSD-t test.

RESULTS(1) High expression of NF-κB/p65 was observed in cytoplasm of control group. High expression of NF-κB/p65 was observed in nuclei of TNF-α group. The expression of NF-κB/p65 in cytoplasm of LaCl3 group was lower than that of control group. In groups treated with LaCl3 and TNF-α, NF-κB/p65 expression levels in nuclei and cytoplasm were decreased along with the increase in the concentration of LaCl3, which were all lower than those in TNF-α group. (2) There was certain amount of NF-κB/p65 protein expressed in nuclei of control group. The expression of NF-κB/p65 protein in nuclei of TNF-α group was higher than that of control group. In groups treated with LaCl3 and TNF-α, the expressions of NF-κB/p65 protein in nuclei were decreased along with an increase in the concentration of LaCl3. The level of IκBα in TNF-α group was significantly decreased but that of p-IκBα increased as compared with those in control group. Along with the increase in the concentration of LaCl3, the levels of IκBα gradually increased and the levels of p-IκBα gradually decreased in groups treated with LaCl3 and TNF-α. There were no statistical differences in expression levels of IKKβ among the 5 groups. The expression of p-IKKβ could be hardly observed in control group, but it was obviously increased in TNF-α group. The expression levels of p-IKKβ in groups treated with LaCl3 and TNF-α were gradually decreased along with the increase in the concentration of LaCl3. The absorption value in TNF-α group was 0.39 ± 0.03, which was higher than that in control group (0, t = -7.23, P<0.01). The absorption values in low-dose LaCl3 +TNF-α group, moderate-dose LaCl3 + TNF-α group, and high-dose LaCl3 +TNF-α group were respectively 0.17 ± 0.03, 0.15 ± 0.03, and 0, which were obviously lower than that in TNF-α group (with t values respectively -6.54, -5.92, -7.23, P values all below 0.01).

CONCLUSIONSLaCl3 can block the activation of NF-κB signaling pathway by blocking the phosphorylation of IKKβ of Hela cells.

Culture Media ; HeLa Cells ; Humans ; I-kappa B Kinase ; metabolism ; I-kappa B Proteins ; metabolism ; Lanthanum ; pharmacology ; NF-KappaB Inhibitor alpha ; Signal Transduction ; drug effects ; Transcription Factor RelA ; metabolism ; Tumor Necrosis Factor-alpha ; pharmacology

In order to investigate the effects of pyrolysis conditions on bio-oil production from biomass in molten salt, experiments of biomass pyrolysis were carried out in a self-designed reactor in which the molten salt ZnCl2-KCl (with mole ratio 7/6) was selected as heat carrier, catalyst and dispersion agent. The effects of metal salt added into ZnCl2-KCl and biomass material on biomass pyrolysis were discussed, and the main compositions of bio-oil were determined by GC-MS. Metal salt added into molten salt could affect pyrolysis production yields remarkably. Lanthanon salt could enhance bio-oil yield and decrease water content in bio-oil, when mole fraction of 5.0% LaCl3 was added, bio-oil yield could reach up to 32.0%, and water content of bio-oil could reduce to 61.5%. The bio-oil and char yields were higher when rice straw was pyrolysed, while gas yield was higher when rice husk was used. Metal salts showed great selectivity on compositions of bio-oil. LiCl and FeCl2 promoted biomass to pyrolyse into smaller molecular weight compounds. CrCl3, CaCl2 and LaCl3 could restrain second pyrolysis of bio-oil. The research provided a scientific reference for production of bio-oil from biomass pyrolysis in molten salt.
Biofuels ; analysis ; Bioreactors ; microbiology ; Catalysis ; Chlorides ; chemistry ; Lanthanum ; chemistry ; Lipids ; biosynthesis ; Oryza ; metabolism ; Plant Stems ; metabolism ; Potassium Chloride ; chemistry ; Salts ; chemistry ; Zinc Compounds ; chemistry

OBJECTIVETo study the characteristics of the growth and periplocin accumulation of the adventitious roots of Periploca sepium, and on this basis, study the effect of Ag+ and La3+ elicitors on the growth and periplocin accumulation of the adventitious roots.

METHODThe adventitious roots were sampled every four days, and the dry weight and the contents of the periplocin were measured. The curves of the growth and periplocin accumulation of the roots were plotted. The Ag+ and La3+ elicitors with different concentrations were added to the medium when the adventitious roots grew in the stable phase to study the optimal concentration which was good to synthesize the periplocin. Besides, the optimal concentration of Ag+ and La3+ elicitors was added to the different growth phases to study the effect of the elicitors on the growth and periplocin synthesis of adventitious roots.

RESULTThe characteristics of the growth of adventitious roots of P. sepium showed a typical growth S-Curve, which displayed a half-coupling relationship with the metabolism of periplocin. The optimal concentrations of Ag+ and La3+ elicitors were both 0.05 mmol L(-1). Besides, it was the best period for the Ag+ and La3+ elicitors to elicit the synthesis of periplocin when in the terminally exponential phase.

CONCLUSIONThe growth of adventitious roots and the accumulation of periplocin show a half-coupling relationship. Besides, the concentration and additive time of Ag and La3+ elicitors obviously influences the growth of adventitious roots and synthesis of periplocin.

Drugs, Chinese Herbal ; analysis ; metabolism ; Lanthanum ; metabolism ; Periploca ; chemistry ; growth & development ; metabolism ; Plant Roots ; chemistry ; growth & development ; metabolism ; Saponins ; analysis ; metabolism ; Silver ; metabolism

OBJECTIVETo study influence of lanthanum chloride (LaCl(3)) on the expression of immediate early genes (IEGs) including c-jun, early growth response gene 1 (Egr1) and activity-regulated cytoskeletal gene (Arc) in the hippocampus of rats, and discuss the mechanism of LaCl(3) undermining learning and memory capability.

METHODSForty female Wistar adult rats were divided into control group, low LaCl(3)-contaminated group (0.25%), medium LaCl(3)-contaminated group (0.50%), and high LaCl(3)-contaminated group (1.00%) by randomized design. Each group had ten female rats along with five male rats and mated by the ratio of 2:1. The amounts of pups in the above four groups were 80, 83, 78 and 75 separately. The pups in respective group were La-dyed by lactation, and then the pups in LaCl(3)-contaminated groups drank 0.25%, 0.50% and 1.00% LaCl(3) separately for one month. Learning and memory capability of pups were measured in jumping stairs experiment. Hippocampal lanthanum content was determined by inductively coupled plasma mass spectrometry (ICP-MS). Hippocampal c-jun, Egr1 and Arc mRNA expression was detected by RT-PCR, and corresponding protein expression was measured by Western blotting method.

RESULTSIn the jumping stairs experiment, pups in 0.25%, 0.50% and 1.00% LaCl(3)-contaminated groups respectively made (1.75 ± 0.71), (2.38 ± 0.92) and (3.00 ± 0.76) mistakes; significantly higher than control group (1.25 ± 0.46) (q values were 4.386, 6.793, P < 0.05). However, the incubation period of 0.25%, 0.50% and 1.00% LaCl(3)-contaminated groups were (174.13 ± 33.72), (139.25 ± 45.83) and (75.50 ± 18.56) respectively, which were all significantly lower than that of control group (206.75 ± 20.47) (q values were 2.958, 6.121, 11.902, P < 0.05). Hippocampal c-jun mRNA expression were (0.89 ± 0.08), (0.77 ± 0.12), (0.58 ± 0.14) and (0.29 ± 0.10); while the c-jun protein expression were (0.72 ± 0.13), (0.64 ± 0.11), (0.43 ± 0.11) and (0.31 ± 0.14), and the Egr1 mRNA expression were (0.78 ± 0.09), (0.61 ± 0.13), (0.53 ± 0.10) and (0.22 ± 0.08), Egr1 protein expression were (0.65 ± 0.18), (0.40 ± 0.15), (0.32 ± 0.13) and (0.14 ± 0.09) in 0.25%, 0.50% and 1.00% LaCl(3)-contaminated groups; and all of which presented a dose-effect relationship that the correlation coefficients of these parameters with dose were -0.900 (t = 11.309, P = 0.000), -0.969 (t = 7.058, P = 0.000), -0.898 (t = 11.179, P = 0.000) and -0.962 (t = 6.739, P = 0.000).

CONCLUSIONLaCl(3) undermines the learning and memory capability of rats, which is possibly related to lower expression of c-jun and Egr1 gene and protein induced by lanthanum in hippocampus.

Animals ; Early Growth Response Protein 1 ; metabolism ; Female ; Gene Expression ; Genes, Immediate-Early ; drug effects ; genetics ; Hippocampus ; drug effects ; metabolism ; Lanthanum ; pharmacology ; Learning ; drug effects ; Male ; Memory ; drug effects ; Proto-Oncogene Proteins c-jun ; metabolism ; Rats ; Rats, Wistar