Peroxynitrite imaging in ferroptosis-mediated drug-induced liver injury with a near-infrared fluorescence probe.

BACKGROUND: Over-consumption of drugs can result in drug-induced liver damage (DILI), which can worsen liver failure. Numerous studies have shown the significant role ferroptosis plays in the pathophysiology of DILI, which is typified by a marked imbalance between the generation and breakdown of lipid reactive oxygen species (ROS). The content of peroxynitrite (ONOO-) rapidly increased during this process and was thought to be a significant marker of early liver injury. Therefore, the construction of fluorescence probe for the detection and imaging of ONOO- holds immense importance in the early diagnosis and treatment of ferroptosis-mediated DILI. RESULTS: We designed a probe DILI-ONOO based on the ICT mechanism for the purpose of measuring and visualizing ONOO- in ferroptosis-mediated DILI processes and associated studies. This probe exhibited significant fluorescence changes with good sensitivity, selectivity, and can image exogenous and endogenous ONOO- in cells with low cytotoxicity. Using this probe, we were able to show changes in ONOO- content in ferroptosis-mediated DILI cells and mice models induced by the intervention of acetaminophen (APAP) and isoniazid (INH). By measuring the concentration of ferroptosis-related indicators in mice liver tissue, we were able to validate the role of ferroptosis in DILI. It is worth mentioning that compared to existing alanine transaminase (ALT) and aspartate aminotransferase (AST) detection methods, this probe can achieve early identification of DILI prior to serious liver injury. SIGNIFICANCE: This work has significant reference value in researching the relationship between ferroptosis and DILI and visualizing research. The results indicate a strong correlation between the progression of DILI and ferroptosis. Additionally, the use of DILI-ONOO shows promise in investigating the DILI process and assessing the effectiveness of medications in treating DILI.

Association between estimated pulse wave velocity and in-hospital mortality of patients with acute kidney injury: a retrospective cohort analysis of the MIMIC-IV database.

BACKGROUND: Estimated pulse wave velocity (ePWV) has been found to be an independent predictor of cardiovascular mortality and kidney injury, which can be estimated noninvasively. This study aimed to investigate the association between ePWV and in-hospital mortality in critically ill patients with acute kidney injury (AKI). METHODS: This study included 5960 patients with AKI from the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. The low and high ePWV groups were compared using a Kaplan-Meier survival curve to evaluate the differences in survival status. Cox proportional hazards models were used to explore the association between ePWV and in-hospital mortality in critically ill patients with AKI. To further examine the dose-response relationship, we used a restricted cubic spline (RCS) model. Stratification analyses were conducted to investigate the effect of ePWV on hospital mortality across various subgroups. RESULTS: Survival analysis indicated that patients with high ePWV had a lower survival rate than those with low ePWV. Following adjustment, high ePWV demonstrated a statistically significant association with an increased risk of in-hospital mortality among AKI patients (HR = 1.53, 95% CI = 1.36-1.71, p < 0.001). Analysis using the RCS model confirmed a linear increase in the risk of hospital mortality as the ePWV values increased (P for nonlinearity = 0.602). CONCLUSIONS: A high ePWV was significantly associated with an increased risk of in-hospital mortality among patients with AKI. Furthermore, ePWV was an independent predictor of in-hospital mortality in critically ill patients with AKI.

Oxidative Stress and 4-hydroxy-2-nonenal (4-HNE): Implications in the Pathogenesis and Treatment of Aging-related Diseases.

Oxidative stress plays an important role in the development of aging-related diseases by accelerating the lipid peroxidation of polyunsaturated fatty acids in the cell membrane, resulting in the production of aldehydes, such as malondialdehyde and 4-hydroxy-2-nonenal (4-HNE) and other toxic substances. The compound 4-HNE forms adducts with DNA or proteins, disrupting many cell signaling pathways including the regulation of apoptosis signal transduction pathways. The binding of proteins to 4-HNE (4-HNE-protein) acts as an important marker of lipid peroxidation, and its increasing concentration in brain tissues and fluids because of aging, ultimately gives rise to some hallmark disorders, such as neurodegenerative diseases (Alzheimer's and Parkinson's diseases), ophthalmic diseases (dry eye, macular degeneration), hearing loss, and cancer. This review aims to describe the physiological origin of 4-HNE, elucidate its toxicity in aging-related diseases, and discuss the detoxifying effect of aldehyde dehydrogenase and glutathione in 4-HNE-driven aging-related diseases.

Identifying PIF1 as a Potential Target of Wenxia Changfu Formula in Promoting Lung Cancer Cell Apoptosis: Bioinformatics Analysis and Biological Evidence.

Lung cancer remains the leading cause of cancer-related deaths worldwide. Traditional Chinese medicine (TCM) is a valuable resource of active natural products and plays an important role in cancer treatment with the advantages of high efficiency and safety. Wenxia Changfu formula (WCF) is modified from Dahuang Fuzi decoction from Han Dynasty and has been used for treating lung cancer in China. Our previous research showed that WCF had an antitumor effect in vivo and in vitro, while the mechanism has not been well illustrated. In this study, the effect of WCF on the proliferative ability in three lung cancer cells and one noncancerous human cell line was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. WCF suppressed A549, H460, and PC-9 cell viability in a dose-dependent manner, with no inhibition of noncancerous MRC-5 cells after 48 h treatment with WCF (0-50 mg/mL). Furthermore, we screened for genes in A549 cells using four WCF-treated samples and four control samples on a gene expression profile microarray. 21 genes were significantly downregulated by WCF, which may potentially play an important role in the proliferation of A549 cells. High-content screening evaluated whether silencing the 21 genes affected A549 cell growth. The results showed that PIF1 knockdown exhibited the most potent inhibition of cell proliferation compared with the other genes. Downregulation of PIF1 increased A549 cell apoptosis and the activity of caspase 3/7. Besides, RT-PCR showed that the expression levels of PIF1 mRNA decreased significantly in A549, H460, and PC-9 cells after WCF treatment. In conclusion, the present observations indicate that WCF may inhibit lung cancer cell proliferation by promoting apoptosis via regulating the expression of PIF1.

Coix lacryma-jobi Seed Oil Reduces Fat Accumulation in Nonalcoholic Fatty Liver Disease by Inhibiting the Activation of the p-AMPK/SePP1/apoER2 Pathway.

The lipid metabolism disorder is the key role of Nonalcoholic fatty liver disease (NAFLD). Selenoprotein P plays an important role in the pathological process of lipid accumulation. Coix lacryma-jboi seed oil (CLSO) is an active component extracted from Coix lacryma-jobi seed (CLS) which has been found to be effective of reducing blood fat and antioxidative. But the effect and mechanism of CLSO on NAFLD are not clear. The aim of this study was to explore the therapeutic effect and mechanism of CLSO in the treatment of NAFLD. Our result showed that CLSO decreased the liver/body weight ratio, lowered the total cholesterol (TC) and triacylglycerol (TG), and elevated the high density lipoprotein (HDL) in serum. CLSO reduced the lipid deposition in the liver of NAFLD rats. In addition, CLSO could bring down the abnormal expression of superoxide dismutase (SOD) and malondialdehyde (MDA). Moreover, CLSO significantly declined the liver apolipoprotein E (apoE), apolipoprotein E receptor (apoER) and selenoprotein P 1 (SePP1) expression. In vivo, CLSO decreased the lipid droplets and TG level, reduced the protein expression of SePP1, apoER, phosphor-adenosine 5'-monophosphate (AMP)-activated protein kinase (p-AMPK) in the cytoplasm of HepG2 cells induced by oleic acid and palmitic acid (OP). At the same time, lipid accumulation was observed in the Sepp1 high expression cells induced by endoplasmic reticulum (ER) activator tunicamycin (Tm). CLSO could identically reduce the protein expression of SePP1, apoER, p-AMPK in the cytoplasm of HepG2 cells induced by Tm. This result not only proved the CLSO had therapeutic effect on NAFLD, but also confirmed its mechanism associated with degrading the phosphorylation of adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) which led to the decrease of the expression SePP1/apoER2 in order to reduce lipid accumulation. The study suggests CLSO has great medicinal value in treating NAFLD besides its edibility.

Levodopa affects spike and local field synchronisation in the pedunculopontine nucleus of a rat model of Parkinson's disease.

The pedunculopontine nucleus (PPN) undergoes significant anatomic and electrophysiological alterations in Parkinson's disease (PD), severely impacting locomotion. However, the effect of 6-hydroxydopamine (6-OHDA) lesion and levodopa (L-DOPA) therapy on the relationships between spike activities and local field potential (LFP) within the PPN is not well-understood. Synchronisation between the spike activity of individual neurones and LFP of neuronal ensembles is a crucial problem in the pathogenesis of PD. In this study, LFP signals and spikes in the PPN of rats in control, lesioned, and L-DOPA groups were recorded synchronously with a multi-unit electrical signal acquisition system and analysed for their coherence value, spike-field coherence, and phase-lock relationship. The spike-LFP relationship in the PPN was markedly increased in specific frequency bands because of the 6-OHDA lesion but differed depending on the animal locomotion state and neuronal type. L-DOPA had a limited therapeutic effect on the 6-OHDA-induced increase in the coherence value. Our study demonstrates that the PPN spike-LFP relationship is involved in the pathogenesis of PD and is critical for the effects of L-DOPA, providing a basis for the clinical treatment of refractory PD symptoms.

An Overview of Lipid Metabolism and Nonalcoholic Fatty Liver Disease.

The occurrence of nonalcoholic fatty liver disease (NAFLD) is associated with major abnormalities of hepatic lipid metabolism. We propose that lipid abnormalities directly or indirectly contribute to NAFLD, especially fatty acid accumulation, arachidonic acid metabolic disturbance, and ceramide overload. The effects of lipid intake and accumulation on NAFLD and NAFLD treatment are explained with theoretical and experimental details. Overall, these findings provide further understanding of lipid metabolism in NAFLD and may lead to novel therapies.