Chronic kidney disease (CKD) is problem that has become one of the major issues affecting public health. Extensive clinical data suggests that the prevalence of hyperlipidemia in CKD patients is significantly higher than in the general population. Lipid metabolism disorders can damage the renal parenchyma and promote the occurrence of cardiovascular disease (CVD). Cyanate is a uremic toxin that has attracted widespread attention in recent years. Usually, 0.8% of the molar concentration of urea is converted into cyanate, while myeloperoxidase (MPO) catalyzes the oxidation of thiocyanate to produce cyanate at the site of inflammation during smoking, inflammation, or exposure to environmental pollution. One of the important physiological functions of cyanate is protein carbonylation, a non-enzymatic post-translational protein modification. Carbamylation reactions on proteins are capable of irreversibly changing protein structure and function, resulting in pathologic molecular and cellular responses. In addition, recent studies have shown that cyanate can directly damage vascular tissue by producing large amounts of reactive oxygen species (ROS). Oxidative stress leads to the disorder of liver lipid metabolism, which is also an important mechanism leading to cirrhosis and liver fibrosis. However, the influence of cyanate on liver has remained unclear. In this research, we explored the effects of cyanate on the oxidative stress injury and abnormal lipid metabolism in mice and HL-7702 cells. In results, cyanate induced hyperlipidemia and oxidative stress by influencing the content of total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), superoxide dismutase (SOD), catalase (CAT) in liver. Cyanate inhibited NF-E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and the phosphorylation of adenosine 5′monophosphate-activated protein kinase (AMPK), activated the mTOR pathway. Oxidative stress on the cells reduced significantly by treating with TBHQ, an antioxidant, which is also an activator of Nrf2. The activity of Nrf2 was rehabilitated and phosphorylation of mTOR decreased. In conclusion, cyanate could induce oxidative stress damage and lipid deposition by inhibiting Nrf2/HO-1 pathway, which was rescued by inhibitor of Nrf2.

The urea cycle (UC) removes the excess nitrogen and ammonia generated by nitrogen-containing compound composites or protein breakdown in the human body. Research has shown that changes in UC enzymes are not only related to tumorigenesis and tumor development but also associated with poor survival in hepatocellular, breast, and colorectal cancers (CRC), etc. Cytoplasmic ornithine, the intermediate product of the urea cycle, is a specific substrate for ornithine decarboxylase (ODC, also known as ODC1) for the production of putrescine and is required for tumor growth. Polyamines (spermidine, spermine, and their precursor putrescine) play central roles in more than half of the steps of colorectal tumorigenesis. Given the close connection between polyamines and cancer, the regulation of polyamine metabolic pathways has attracted attention regarding the mechanisms of action of chemical drugs used to prevent CRC, as the drug most widely used for treating type 2 diabetes (T2D), metformin (Met) exhibits antitumor activity against a variety of cancer cells, with a vaguely defined mechanism. In addition, the influence of metformin on the UC and putrescine generation in colorectal cancer has remained unclear. In our study, we investigated the effect of metformin on the UC and putrescine generation of CRC in vivo and in vitro and elucidated the underlying mechanisms. In nude mice bearing HCT116 tumor xenografts, the administration of metformin inhibited tumor growth without affecting body weight. In addition, metformin treatment increased the expression of monophosphate (AMP)-activated protein kinase (AMPK) and p53 in both HCT116 xenografts and colorectal cancer cell lines and decreased the expression of the urea cycle enzymes, including carbamoyl phosphate synthase 1 (CPS1), arginase 1 (ARG1), ornithine trans-carbamylase (OTC), and ODC. The putrescine levels in both HCT116 xenografts and HCT116 cells decreased after metformin treatment. These results demonstrate that metformin inhibited CRC cell proliferation via activating AMPK/p53 and that there was an association between metformin, urea cycle inhibition and a reduction in putrescine generation.

Gastric cancer (GC) in adolescents and young adults (AYA; 15–39 years) is rare but clinically distinct. Contemporary global estimates and temporal drivers – particularly age–period–cohort (APC) effects and socioeconomic differentials – remain unclear. We conducted a secondary analysis using data from the Global Burden of Disease 2021 database and quantified the incidence, mortality, and disability-adjusted life years of AYA GC across 204 countries and territories from 1990 to 2021. Age-standardized rates and estimated annual percentage changes (EAPCs) were calculated using log-linear regression. APC models were used to describe age-, period-, and cohort-related patterns. Disease burden was stratified by Socio-demographic Index (SDI), and Global Burden of Disease (GBD)-attributed deaths related to diets high in sodium and smoking were examined within the GBD comparative risk assessment framework. From 1990 to 2021, the global AYA GC burden declined substantially, yet disparities by sex, SDI, and cohort persisted. Globally, the age-standardized incidence rate of AYA GC decreased from 2.45 per 1,00,000 population in 1990 to 1.41 per 1,00,000 population in 2021, with an EAPC of −2.04% (95% confidence interval [CI]: −2.21 to −1.88). Deaths declined from 38.15 × 10 ³ to 24.27 × 10 ³ , with an EAPC of −2.75% (95% CI: −2.94 to −2.57). The age-standardized disability-adjusted life year rate decreased from 99.73 to 46.64 per 1,00,000 population, with an EAPC of −2.54% (95% CI: −2.63 to −2.46). Males consistently had higher burdens than females. Incidence was positively correlated with SDI over time ( r = 0.2393, P < .001), whereas mortality was negatively correlated with SDI in the 2021 cross-sectional analysis ( r = −0.3092, P < .001). APC analysis showed a positive age effect peaking at 35 to 39 years and a net drift of −2.18% per year. Within the GBD comparative risk assessment framework, the GBD-attributed proportion of AYA GC deaths related to diets high in sodium was approximately 15% in East Asia in 2021, while the GBD-attributed proportion related to smoking exceeded 10% in parts of Central and Eastern Europe.