This study aimed to use metabolomic methods to explore how Holothuria leucospilota polysaccharides (HLP) improved metabolism disorders in the liver of Goto-Kakizaki (GK) rats with spontaneous type 2 diabetes. The results showed that HLP effectively improved the metabolic disorder. Based on KEGG functional analysis, five key biomarkers associated with bile acid metabolism were detected and screened ( P < 0.05). The results of serum total bile acid levels and liver damage in diabetic rats further showed the regulatory effects of HLP on bile acid metabolism. The results of bile acid-related gene expression in the liver showed that HLP inhibited liver farnesoid X Receptor - small heterodimer partner (FXR-SHP) signalling and increased the expression of bile acid synthesis genes ( P < 0.05). Our results explored the underlying mechanisms by which HLP accelerated cholesterol consumption to anti-hypercholesterolemia and anti-diabetic by inhibiting liver FXR-SHP signaling. HLP's effect on bile acid regulation provides insights into treating T2DM.
Objectives Rifampin (RIF), isoniazid (INH) and pyrazinamide (PZA) are essential components of the short-term first-line anti-tuberculosis (anti-TB) chemotherapy regimen and can cause hepatotoxicity. However, the mechanism of anti-TB drug-induced hepatotoxicity (ATDH) is currently unclear. We investigate the relevant contributions to liver injury and the pathway of the above-mentioned drugs administered alone or in combination.Methods UPLC-Q-TOF/MS-based metabolomics, bile acids (BAs) analysis and FXR/SHP detection were used to evaluate the toxicity of these drugs and clarify the underlying metabolism-related pathway.Results In C57BL/6 mice administered the corrected clinical doses, RIF, INH and PZA could induced hepatotoxicity; with less toxicity in the combination therapy than RIF. The pathological biochemistry, BAs concentration and metabolically regulated FXR/SHP gene expression analyzes in mice were consistent with the metabolomics results. FXR played a role in the hepatotoxicity of anti-tuberculosis drugs in the obeticholic acid treated and FXR-/- mice. Additionally, the purine and lipid metabolic pathways were involved in ATDH.Conclusion ATDH was involved in bile acids and lipid and purine metabolism. The BAs metabolic pathway involvement in mice was validated in TB patients. The noninvasive metabolomics approach is more systemic than routine toxicity evaluation and can be used to assess compound toxicity and the underlying mechanism.
The ischemic strokes seriously threaten human health with high incidence and disability rates. Cerebral embolism and impaired brain function are the two major clinical features of this disease. Therefore, rapid restoration of cerebral blood supply and synchronous improvement of impaired neurological function is the key to treating strokes. Herein, based on the microenvironment of cerebral thrombosis and pathological characteristics of damaged neurons, we constructed a shear force and reactive oxygen species (ROS) dual-responsive system (UK@Fuc/CDPC-PTPCS) for sequential targeted delivery of thrombolytic agent urokinase (UK) and neuroprotective drug cytosolic choline (CDPC). Results proved that after intravenous administration, UK@Fuc/CDPC-PTPCS can quickly locate to cerebral thrombosis site via the active recognition capability of fucoidan (Fuc) to P-selectin overexpressed on activated platelets. Subsequently, the sharply increased blood shear force separated the core-shell structure by breaking the host-guest interaction of β-cyclodextrin (β-CD), so the UK loaded in the shell was first released to rapid thrombolysis and then restored cerebral blood supply. Afterward, the stroke homing peptide (SHp) modified CDPC-PTPCS core actively recognized ischemic damaged neuronal cells. Then high intracellular ROS triggered CDPC release at specific sites to exert neuroprotective effects. This study offered a new therapeutic strategy for ischemic stroke.
危险品化学品经营许可证（带存储）