The Regulatory Mechanism of Hypoxia-inducible Factor 1 and its Clinical Significance.

Hypoxia-inducible factor (HIF) is a nuclear protein that plays a crucial role in oxygen homeostasis through its transcriptional activity and thousands of target gene profiles. Through transcriptional and post-transcriptional regulation, the downstream target genes of HIF can trigger multiple pathological responses in the body, including energy metabolism, cytopenia, and angiogenesis. There are three distinct subtypes of HIF: HIF-1, HIF-2, and HIF-3. HIF-1 is a significant regulator of the cellular response to hypoxia, and the balance between its production and degradation is critical for this response. As hypoxia is linked to several disorders, understanding HIF can open up novel avenues for the treatment of many diseases. This review describes the regulatory mechanisms of HIF-1 synthesis and degradation and the clinical significance of the hypoxia-inducible factor pathway in lung injury, kidney disease, hematologic disorders, and inflammation-related diseases.

The study of neuroprotective effect of ferulic acid based on cell metabolomics.

Ferulic acid (FA), a naturally derived phenolic compound, has antioxidant and antidepressant-like effects. It is still a challenge to study its mechanism due to the complexity of the pathophysiology of depression. In this study, ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) was used to perform metabolomics studies based on biochemical changes in differentiated rat pheochromocytoma (PC12) cells treated with corticosterone-induced neurological damage after FA treatment. A total of 31 metabolites were identified as potential biomarkers for corticosterone-induced PC12 cells injury. Among them, 24 metabolites were regulated after FA treatment. Pathway analysis revealed that these metabolites were mainly involved in the amino acid metabolism, energy metabolism and glycerophospholipid metabolism. In addition, based on the results of metabolomics, three cell signaling pathways related to glutamate were discovered. To further study the interactions between FA and major targets in three signaling pathways, a molecular docking method was employed. The results showed that FA had the strongest binding power with protein kinase B (AKT). Furthermore, the result of mRNA changes analyzed by quantitative real time RT-PCR indicated that AKT and protein kinase A (PKA) in the signaling pathway were up regulated after treatment with FA compared with model group. This study shows that strategies based on cell metabolomics associated with molecular docking and molecular biology is a helpful tool to elucidate the neuroprotective mechanism of FA.

Comparative analysis of the compatibility effects of Danggui-Sini Decoction on a blood stasis syndrome rat model using untargeted metabolomics.

Danggui-Sini Decoction (DSD) is one of the most widely used traditional Chinese medicine formulae (TCMF) for treating various diseases caused by cold coagulation and blood stasis due to its effect of nourishing blood to warm meridians in clinical use. However, studies of the mechanism of how it dispels blood stasis and its compatible regularity are challenging because of the complex pathophysiology of blood stasis syndrome (BSS) and the complexity of DSD, with multiple active ingredients acting on different targets. Observing variations of endogenous metabolites in rats with BSS after administering DSD may further our understanding of the mechanism of BSS and the compatible regularity of DSD. In this study, to understand the pathogenesis of BSS and assess the compatibility effects of DSD, an ultra-performance liquid chromatography quadrupole-time of flight mass spectrometry-based untargeted metabolomics approach was used. Serum metabolic profiles in rats with BSS that was induced by an ice water bath associated with subcutaneous injection of epinephrine hydrochloride were compared with the intervention groups which were administered with DSD or its compatibility. Using pattern recognition analysis, a clear separation between the BSS model and control group was observed; DSD and its compatibility intervention groups were clustered closer toward the control than the model group, which corroborates results of hemorheology studies. In addition, 20 metabolites were considered as potential biomarkers associated with the development of BSS. Nine metabolites were regulated by DSD in intervening blood stasis, they were considered to be correlated with the effect of nourishing blood to warm meridians. Additionally, the results suggested that the intervention effect of DSD on BSS may involve regulating four pathways, namely, arachidonic acid metabolism, glycerophospholipid metabolism, bile acid biosynthesis, and pyruvate metabolism. Moreover, each functional unit (monarch, minister, and assistant) in DSD regulates different metabolites and metabolic pathways to achieve different effects on dispelling blood stasis; however, their intervention efficacies are inferior to the holistic formula, which may be due to the synergism of the bioactive ingredients in seven herbs of DSD. This study demonstrated that metabolomics is a powerful tool for evaluating the efficacy and compatibility effects of traditional Chinese medicine (TCM).

Investigation of the hepatoprotective effect of Corydalis saxicola Bunting on carbon tetrachloride-induced liver fibrosis in rats by 1H-NMR-based metabonomics and network pharmacology approaches.

Liver fibrosis is a common consequence of chronic liver diseases resulting from multiple etiologies. Furthermore, prolonged unresolved liver fibrosis may gradually progress to cirrhosis, and eventually evolve into hepatocellular carcinoma (HCC). Corydalis saxicola Bunting (CS), a type of traditional Chinese folk medicine, has been reported to have hepatoprotective effects on the liver. However, the exact mechanism of how it cures liver fibrosis requires further elucidation. In this work, an integrated approach combining proton nuclear magnetic resonance (1H-NMR)-based metabonomics and network pharmacology was adopted to elucidate the anti-fibrosis mechanism of CS. Metabonomic study of serum biochemical changes by carbon tetrachloride (CCl4)-induced liver fibrosis in rats after CS treatment were performed using 1H-NMR analysis. Metabolic profiling by means of partial least squares-discriminate analysis (PLS-DA) indicated that the metabolic perturbation caused by CCl4 was reduced after CS treatment. As a result, lipids, leucine, alanine, acetate, O-acetyl-glycoprotein and creatine were significantly restored after CS treatment, which regulated valine, leucine and isoleucine metabolism; arginine and proline metabolism; lipid metabolism and pyruvate metabolism. Additionally, 157 potential targets of CS and 265 targets of liver fibrosis were identified by means of network pharmacology. Subsequently, 5 target proteins, which are the intersection of potential CS targets and liver fibrosis targets, indicated that CS has potential anti-fibrosis effects through regulating alanine aminotransferase (ALT) activity, the farnesoid X receptor (FXR), cyclooxygenase-2 (COX-2), matrix metalloproteinase-1 (MMP-1) and angiotensinogen. Chelerythrine and sanguinarine were the potential active compounds in CS for treating liver fibrosis through regulating ALT activity. This study is the first report to study the anti-fibrosis effects of CS on the basis of combining a metabonomics and network pharmacology approaches, and it may be a potentially powerful tool to study the efficacy and mechanisms of traditional Chinese folk medicines.

High expression of forkhead box protein C2 is related to poor prognosis in human gliomas.

BACKGROUND: Increasing evidence has indicated that high Forkhead box protein C2 (FOXC2) level is closely associated with the development, progression, and poor prognosis of a variety of tumors. However, the relationship between FOXC2 and the progression of human gliomas remains to be clarified. The aim of present study was to assess FOXC2 expression and to explore its contribution in human gliomas. MATERIALS AND METHODS: Realtime quantitative PCR was performed to examine FOXC2 expression in 85 pairs of fresh frozen glioma tissues and corresponding non-neoplastic brain tissues. Associations of FOXC2 expression with clinicopathological factors and prognosis of glioma patients were statistically analyzed. RESULTS: The relative mRNA expression of FOXC2 was significantly higher in glioma tissues than the corresponding non-neoplastic brain tissues (p<0.001). In addition, high FOXC2 expression was significantly associated with advanced pathological grade (P=0.005) and the low Karnofsky performance score (KPS) (p=0.003), correlating with poor survival (p<0.001). Furthermore, multivariate Cox regression analysis showed that high FOXC2 expression was an independent predictor of overall survival (p=0.006). CONCLUSIONS: FOXC2 may act as an oncogenic gene and represent a potential regulator of aggressive development and a candidate prognostic marker in human gliomas.