Yue Zhao

Background:: Both Salvianolate Injection and warfarin are widely prescribed in patients with cardiovascular diseases, but the interaction between them is unknown and needs to be investigated. Objective:: This research aims to study the effects and mechanism of Salvianolate Injection on the pharmacodynamics and pharmacokinetics of warfarin in rats. Methods:: Male Wistar rats were intraperitoneally injected Salvianolate Injection (18 mg/kg) with or without oral administration of warfarin (0.2 mg/kg). A coagulation analyzer evaluated prothrombin time (PT) and activated partial thromboplastin time (APTT). International normalized ratio (INR) was calculated based on PT. UPLC-MS/MS combined with a chiral column was used to separate and measure the plasma concentration of R-warfarin and S-warfarin. Agilent SB-C18 column (1.8 μm, 2.1 mm × 50 mm) was used for separation, column temperature at 20°C. The isocratic mobile phase was acetonitrile-aqueous ammonium acetate (5 mM, pH 4) at a flow rate of 0.2 mL/min and 11.5 min for each injection. Pharmacokinetic parameters were calculated using DAS 2.0 software. Results:: Salvianolate Injection increased PT and INR (p < 0.05), while APTT was unaffected (p > 0.05). Compared with the warfarin group, the co-administration of Salvianolate Injection and singledose warfarin enlarged PT and INR (p < 0.05). Similar increases in pharmacokinetic parameters of R-warfarin and S-warfarin, including Cmax, AUC0-t, AUC0-∞, t1/2, and CL/F (p < 0.05), were observed in the co-administration group. A steady-state study of warfarin indicated that PT and INR in the coadministration group are longer than those in the warfarin group (p < 0.05). On days 7th and 8th of warfarin treatment (two and three days after Salvianolate Injection treatment), the plasma concentration of R-warfarin increased by 47.22% and 50.16% (p < 0.05), and plasma concentration of Swarfarin increased by 32.39% and 45.99% (p < 0.05), respectively. Conclusion:: Salvianolate Injection exhibits an anticoagulation effect in rats. Salvianolate Injection can enhance the anticoagulant effect of warfarin by slowing metabolism and increasing the concentration of both enantiomers. These results suggest that the combination of Salvianolate Injection and warfarin should be avoided or closely monitored in case of increasing bleeding risk.

Safflower Yellow for injection (SYI) is a medicine made from the herbal plant safflower (Carthami Flos). SYI’s clinical indication is used for the treatment against grade I, II, and III stable angi...

Pathological cardiac hypertrophy is a process characterized by significant disturbance of protein turnover. Cullin-associated and Neddylation-dissociated 1 (CAND1) acts as a coordinator to modulate substrate protein degradation by promoting the formation of specific cullin-based ubiquitin ligase 3 complex in response to the accumulation of specific proteins, which thereby maintains the normal protein homeostasis. However, whether CAND1 titrates the degradation of hypertrophic related proteins and manipulates cardiac hypertrophy remains unknown. In this study, we found that the protein level of CAND1 was increased in the heart tissues from heart failure (HF) patients and TAC mice. CAND1-KO+/- aggravated TAC-induced cardiac hypertrophic phenotypes; in contrast, CAND1-Tg attenuated the maladaptive cardiac remodeling. At the protein level, CAND1 overexpression downregulated, whereas CAND1-KO+/- or knockdown upregulated the expression of calcineurin, a critical pro-hypertrophic protein at both in vivo and in vitro conditions. Mechanistically, CAND1 overexpression favored, whilst CAND1 knockdown blocked the assembly of Cul1/atrogin1/calcineurin complex, an E3 that renders the ubiquitination and degradation of calcineurin. It turned out that calcineurin ubiquitination was suppressed by CAND1 knockdown, but enhanced by CAND1 overexpression. In addition, overexpression of truncated calcineurin that cannot be recognized by atrogin1 abrogated the antihypertrophic effects of CAND1. Notably, CAND1 deficiency-induced hypertrophic phenotypes were partially rescued by knockdown of calcineurin, and application of exogenous CAND1 prevented TAC-induced cardiac hypertrophy and heart failure. In conclusion, CAND1 exerts a protective effect against cardiac hypertrophy and heart failure partially by inducing the degradation of calcineurin. CAND1 represents a novel, promising therapeutic target for cardiac hypertrophy and heart failure. Keywords: CAND1; heart failure; calcineurin; ubiquitination; cullin1

Cardiac ischemia–reperfusion (I/R) injury is a pathological process resulting in cardiomyocyte death. The present study aims to evaluate the role of the long noncoding RNA Cardiac Injury-Related Bclaf1-Inhibiting LncRNA (lncCIRBIL) on cardiac I/R injury and delineate its mechanism of action. The level of lncCIRBIL is reduced in I/R hearts. Cardiomyocyte-specific transgenic overexpression of lncCIRBIL reduces infarct area following I/R injury. Knockout of lncCIRBIL in mice exacerbates cardiac I/R injury. Qualitatively, the same results are observed in vitro. LncCIRBIL directly binds to BCL2-associated transcription factor 1 (Bclaf1), to inhibit its nuclear translocation. Cardiomyocyte-specific transgenic overexpression of Bclaf1 worsens, while partial knockout of Bclaf1 mitigates cardiac I/R injury. Meanwhile, partial knockout of Bclaf1 abrogates the detrimental effects of lncCIRBIL knockout on cardiac I/R injury. Collectively, the protective effect of lncCIRBIL on I/R injury is accomplished by inhibiting the nuclear translocation of Bclaf1. LncCIRBIL and Bclaf1 are potential therapeutic targets for ischemic cardiac disease.