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BACKGROUND: Lanthanum carbonate is widely used to manage serum phosphate and calcium levels in end-stage kidney disease (ESKD) patients, yet comprehensive long-term safety data are lacking. This study leverages the FDA Adverse Event Reporting System (FAERS) to assess the extended safety profile of lanthanum carbonate. RESEARCH DESIGN AND METHODS: We analyzed FAERS data (2004-2022) to study the association between lanthanum carbonate and adverse events (AEs). Using MedDRA v25.0, we identified risk signals through System Organ Classes (SOCs) and Preferred Terms (PTs). Disproportionality analyzes quantified lanthanum carbonate-associated AE signals. RESULTS: Among 3,284 reports, 2,466 were primary suspected AEs linked to lanthanum carbonate. Males reported AEs more frequently than females. Patients aged over 64 represented the majority. Median onset time for lanthanum carbonate-related AEs was 146 days. Gastrointestinal disorders were prevalent. We identified 16 new signals, including stress, abnormal hepatic function, cholelithiasis, bile duct stone, gastric cancer, and adenocarcinoma gastric. Stress was notable, particularly in male patients over 65 and those with lower weight. CONCLUSIONS: This study affirms lanthanum carbonate's long-term safety for reducing elevated blood phosphorus levels. While gastrointestinal disorders were common, attention must focus on emerging AEs, particularly stress, especially in elderly patients.
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BACKGROUND: Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron-sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. METHODS: We generated neuron-specific Isca1 knockout rat (Isca1flox/flox -NeuN-Cre) using CRISPR-Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. RESULTS: This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. CONCLUSIONS: This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.
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Proteínas Hierro-Azufre , Enfermedades Mitocondriales , Ratas , Humanos , Animales , Síndrome , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Proteínas Hierro-Azufre/química , Proteínas Hierro-Azufre/genética , Proteínas Hierro-Azufre/metabolismo , Mitocondrias/genética , Mitocondrias/metabolismo , Mitocondrias/patología , Neuronas/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismoRESUMEN
AIMS: Multiple mitochondrial dysfunction (MMD) can lead to complex damage of mitochondrial structure and function, which then lead to the serious damage of various metabolic pathways including cerebral abnormalities. However, the effects of MMD on heart, a highly mitochondria-dependent tissue, are still unclear. In this study, we use iron-sulfur cluster assembly 1 (Isca1), which has been shown to cause MMD syndromes type 5 (MMDS5), to verify the above scientific question. MAIN METHODS: We generated myocardium-specific Isca1 knockout rat (Isca1flox/flox/α-MHC-Cre) using CRISPR-Cas9 technology. Echocardiography, magnetic resonance imaging (MRI), histopathological examinations and molecular markers detection demonstrated phenotypic characteristics of our model. Immunoprecipitation, immunofluorescence co-location, mitochondrial activity, ATP generation and iron ions detection were used to verify the molecular mechanism. KEY FINDINGS: This study was the first to verify the effects of Isca1 deficiency on cardiac development in vivo, that is cardiomyocytes suffer from mitochondria damage and iron metabolism disorder, which leads to myocardial oncosis and eventually heart failure and body death in rat. Furthermore, forward and reverse validation experiments demonstrated that six-transmembrane epithelial antigen of prostate 3 (STEAP3), a new interacting molecule for ISCA1, plays an important role in iron metabolism and energy generation impairment induced by ISCA1 deficiency. SIGNIFICANCE: This result provides theoretical basis for understanding of MMDS pathogenesis, especially on heart development and the pathological process of heart diseases, and finally provides new clues for searching clinical therapeutic targets of MMDS.
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Cardiomiopatías , Trastornos del Metabolismo del Hierro , Animales , Cardiomiopatías/genética , Cardiomiopatías/metabolismo , Trastornos del Metabolismo del Hierro/metabolismo , Masculino , Mitocondrias/genética , Mitocondrias/metabolismo , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , RatasRESUMEN
Background: Multiple mitochondrial dysfunction syndromes (MMDS) presents as complex mitochondrial damage, thus impairing a variety of metabolic pathways. Heart dysplasia has been reported in MMDS patients; however, the specific clinical symptoms and pathogenesis remain unclear. More urgently, there is a lack of an animal model to aid research. Therefore, we selected a reported MMDS causal gene, Isca1, and established an animal model of MMDS complicated with cardiac dysplasia. Methods: The myocardium-specific Isca1 knockout heterozygote (Isca1 HET) rat was obtained by crossing the Isca1 conditional knockout (Isca1 cKO) rat with the α myosin heavy chain Cre (α-MHC-Cre) rat. Cardiac development characteristics were determined by ECG, blood pressure measurement, echocardiography and histopathological analysis. The responsiveness to pathological stimuli were observed through adriamycin treatment. Mitochondria and metabolism disorder were determined by activity analysis of mitochondrial respiratory chain complex and ATP production in myocardium. Results: ISCA1 expression in myocardium exhibited a semizygous effect. Isca1 HET rats exhibited dilated cardiomyopathy characteristics, including thin-walled ventricles, larger chambers, cardiac dysfunction and myocardium fibrosis. Downregulated ISCA1 led to deteriorating cardiac pathological processes at the global and organizational levels. Meanwhile, HET rats exhibited typical MMDS characteristics, including damaged mitochondrial morphology and enzyme activity for mitochondrial respiratory chain complexes â , â ¡ and â £, and impaired ATP production. Conclusion: We have established a rat model of MMDS complicated with cardiomyopathy, it can also be used as model of myocardial energy metabolism dysfunction and mitochondrial cardiomyopathy. This model can be applied to the study of the mechanism of energy metabolism in cardiovascular diseases, as well as research and development of drugs.
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Cardiomiopatías , Proteínas Hierro-Azufre , Enfermedades Mitocondriales , Animales , Cardiomiopatías/genética , Humanos , Proteínas Hierro-Azufre/genética , Mitocondrias/genética , Enfermedades Mitocondriales/genética , Proteínas Mitocondriales/genética , Miocardio/metabolismo , Ratas , SíndromeRESUMEN
Environmental issues pose huge threats to public health, particularly the damage caused by fine particulate matter (PM2.5). However, the mechanisms of injury require further investigation and medical materials that can protect the lungs from PM2.5 are needed. We have found that Colla corii asini, a traditional Chinese medicine that has long been used to treat various ailments, is a good candidate to serve this purpose. To understand the mechanisms of PM2.5-induced lung toxicity and the protective effects of Colla corii asini, we established a rat model of lung injury via intratracheal instillation of artificial PM2.5 (aPM2.5). Our results demonstrated that Colla corii asini significantly protected against lung function decline and pathologic changes. Inflammation was ameliorated by suppression of Arg-1 to adjust the disturbed metabolic pathways induced by aPM2.5, such as arginine and nitrogen metabolism and aminoacyl-tRNA biosynthesis, for 11 weeks. Our work found that metabolomics was a useful tool that contributed to further understanding of PM2.5-induced respiratory system damage and provided useful information for further pharmacological research on Colla corii asini, which may be valuable for therapeutic intervention.
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Gelatina/farmacología , Lesión Pulmonar/prevención & control , Pulmón/patología , Medicina Tradicional China , Material Particulado/toxicidad , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Citocinas/inmunología , Modelos Animales de Enfermedad , Gelatina/administración & dosificación , Pulmón/efectos de los fármacos , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/patología , Masculino , Metabolómica , Ratas , Ratas Sprague-DawleyRESUMEN
A reversed-phase high-performance liquid chromatographic method has been developed to quantitatively determine matrine in liquid crystal nanoparticles. The chromatographic method is carried out using an isocratic system. The mobile phase was composed of methanol-PBS(pH6.8)-triethylamine (50 : 50 : 0.1%) with a flow rate of 1 mL/min with SPD-20A UV/vis detector and the detection wavelength was at 220 nm. The linearity of matrine is in the range of 1.6 to 200.0 µ g/mL. The regression equation is y = 10706x - 2959 (R (2) = 1.0). The average recovery is 101.7%; RSD = 2.22% (n = 9). This method provides a simple and accurate strategy to determine matrine in liquid crystalline nanoparticle.