Heavy metals and elderly kidney health: A multidimensional study through Enviro-target Mendelian Randomization.

Chronic Kidney Disease (CKD), closely linked to environmental factors, poses a significant public health challenge. This study, based on 529 triple-repeated measures from key national environmental pollution area and multiple gene-related public databases, employs various epidemiological and bioinformatics models to assess the impact of combined heavy metal exposure (Chromium [Cr], Cadmium [Cd], and Lead [Pb]) on early renal injury and CKD in the elderly. Introducing the novel Enviro-Target Mendelian Randomization method, our research explores the causal relationship between metals and CKD. The findings indicate a positive correlation between increased levels of metal and renal injury, with combined exposure caused renal damage more significantly than individual exposure. The study reveals that metals primarily influence CKD development through oxidative stress and metal ion resistance pathways, focusing on three related genes (SOD2, MPO, NQO1) and a transcription factor (NFE2L2). Metals were found to regulate oxidative stress levels in the body by increasing the expression of SOD2, MPO, NQO1, and decreasing NFE2L2, leading to CKD onset. Our research establishes a new causal inference framework linking environmental pollutants-pathways-genes-CKD, assessing the impact and mechanisms of metal exposure on CKD. Future studies with more extensive in vitro evidence and larger population are needed to validate.

Fructose-Bisphosphate Aldolase A Regulates Hypoxic Adaptation in Hepatocellular Carcinoma and Involved with Tumor Malignancy.

BACKGROUND: Hypoxia is an important factor in malignant tumors, and glycolysis is a major metabolic contributor in their development. Glycolytic enzymes have gained increasing attention as potential therapeutic targets because they are associated with cancer-specific metabolism. Fructose-bisphosphate aldolase A (ALDOA), a key glycolytic enzyme, reportedly is associated with hepatocellular carcinoma (HCC). However, its role in pathogenesis and its clinical significance in HCC remain largely unknown. AIM: To explore the increased expression of ALDOA in HCC in correlation with tumor malignancy, and to investigate the potential regulatory role ALDOA plays in HCC progression through its regulation in hypoxia adaptation. METHODS AND RESULTS: To better understand ALDOA and its correlation with clinicopathological features of HCC, we analyzed 100 HCC clinical specimens using immunohistochemistry analysis. The results show that the ALDOA expression level is significantly higher in advanced HCC and in HCC with venous invasion. Using in vitro knockdown assays, we showed that higher ALDOA expression was positively associated with cell proliferation, cell cycle, apoptosis, and invasion under both normoxic and hypoxic conditions. Evidence shows that the underlying mechanism is due to the regulatory function of ALDOA in glycolysis, the cell cycle, matrix metalloproteinase-mediated extracellular matrix degradation, and epithelial-mesenchymal transformation. CONCLUSIONS: Data indicated that ALDOA is significantly upregulated in HCC tissue and is closely related to HCC malignancy. ALDOA is likely to regulate HCC progression by regulating HCC tumor cell proliferation, apoptosis, and invasion in both normoxic and hypoxic condition.

Triptolide prolonged allogeneic islet graft survival in chemically induced and spontaneously diabetic mice without impairment of islet function.

BACKGROUND: Triptolide (TPT) is a diterpenoid triepoxide extracted from the Chinese herb Tripterygium wilfordii Hook. F. It exhibits potent immunosuppressive and anti-inflammatory properties. This study was undertaken to investigate its effects on prolongation of islet allograft survival in rodents. Additionally, we investigated whether TPT would be toxic to islet function in vivo. METHODS: We transplanted BALB/c islets to either chemically induced diabetic C57BL/6 mice or spontaneously diabetic nonobese diabetic (NOD) mice. TPT was injected within 2 weeks or continuously, until rejection, in the two combinations. Then, we evaluated the toxicity of TPT on islet function by daily injection to naive BALB/c or diabetic BALB/c that was cured by syngeneic islet transplantation under the kidney capsule. Mice injected with cyclosporine A (CsA) or vehicle served as controls. Intraperitoneal glucose tolerance tests (IPGTTs) performed at 4 and 8 weeks in the naive BALB/c group, and at 2, 4, 6, and 8 weeks in the syngeneic transplanted group. RESULTS: The medium survival time of islets allograft from TPT treated C57BL/6 and NOD recipients were 28.5 days (range 24-30 days, n=10) and 33.0 days (range 15-47 days, n=6), respectively, and they were significantly different from those of the vehicle treated controls, which were 14.0 days (range 13-16 days, n=6) and 5.0 days (range 4-10 days, n=6), respectively (all P<0.0001). The IPGTT demonstrated that there was no difference between the TPT treated and vehicle treated groups, either in the normal or syngeneic transplanted islet BALB/c mice. However, CsA injection impaired islet function in both normal and syngeneic transplanted mice as early as 4 weeks. CONCLUSION: TPT prolonged islets allograft survival in a chemically induced diabetic or an autoimmune diabetic murine model without impairment of islet function.

Severe acute pancreatitis in the elderly: etiology and clinical characteristics.

AIM: To investigate the etiology and clinical characteristics of severe acute pancreatitis (SAP) in elderly patients (> or = 60 years of age). METHODS: We reviewed retrospectively all the SAP cases treated in Xuanwu Hospital in Beijing between 2000 and 2007. RESULTS: In 169 patients with SAP, 94 were elderly and 16 died. Biliary and idiopathic etiologies were the first two causes that accounted for over 90% of SAP in the elderly. Biliary, hyperlipemic and alcoholic etiologies were the first three causes in the young. The proportion of co-morbidity of cholelithiasis, biliary infection, hypertension and coronary heart disease in the aged was significantly higher than that in their young partners. The scores of APACHE II and Ranson were also significantly higher in the elderly except the CT score. Organ failures were more common in the elderly, but the local pancreatic complications were not different between the two groups. Mortality of the aged was correlated with the severity of SAP, multiple co-morbidity and incidence of multiple organ dysfunction syndrome (MODS). MODS was the main cause of death. CONCLUSION: The etiology of SAP in the elderly is quite different from that in the young. Biliary and unknown factors are main causes in the aged. The elderly are subject to major organ failures but there is no difference in the occurrence of local pancreatic complications between the elderly and the young. It is crucial to monitor and improve the functions of major organs so as to prevent MODS in the aged with SAP.