Optimal Strategy for HIFU-Based Renal Sympathetic Denervation in Canines.

Background: The association between the treatment efficacy and safety of high-intensity focused ultrasound (HIFU)-based renal sympathetic denervation (RDN) and the acoustic energy dose applied has not been fully studied and may provide important understanding of the mechanism that led to failure of the WAVE IV trial. The objective of this study was to externally deliver different HIFU doses to canines for RDN treatment and to investigate the optimal energy dose for HIFU-based RDN. Methods: Thirty canines were divided into five RDN groups according to dose of acoustic energy applied, and a sham control group that consisted of four canines was used for comparisons. All animals in the RDN groups underwent the RDN procedure with different acoustic energy doses, while in the sham control group, renal arteries were harvested without being subjected to acoustic energy delivery and were imaged using color Doppler flow imaging (CDFI). Blood pressure (BP) was recorded, and blood samples were collected before the RDN procedure and at 28 days after the RDN procedure. Histological examinations and measurement of renal tissue norepinephrine concentration were performed in all retrieved samples. Results: Suppression of BP was significant in the 300 W (15.17/8.33 ± 1.47/1.21 mmHg), 250 W (14.67/9.33 ± 1.21/1.37 mmHg), and 200 W (13.17/9.17 ± 2.32/1.84 mmHg) groups. Semiquantitative histological assessment of periarterial nerves around the kidney revealed that target nerves in the 300 W (9.77 ± 0.63), 250 W (9.42 ± 0.67), and 200 W (9.58 ± 0.54) groups had the highest nerve injury scores, followed by the 150 W group (5.29 ± 0.62). Furthermore, decreased renal tissue norepinephrine concentration, together with decreased expression of tyrosine hydroxylase in the 300, 250, and 200 W groups demonstrated effective sympathetic depression following sufficient acoustic energy deposition. However, the renal artery injury score in the 300 W group (0.93 ± 0.13) was significantly higher than in the other groups (p < 0.001). Conclusion: This study provides evidence that RDN effectiveness is based on the energy dose delivered and that 200-250 W is effective and safe in normal-sized canines.

Indole-3-carbinol inhibits lipid deposition and promotes autophagy in hyperlipidemia zebrafish larvae.

Indole-3-carbinol (I3C) is extracted from cruciferous vegetables and is well known for its anti-cancer, antioxidant and anti-inflammatory effects. This study investigated the protective effect of I3C in hyperlipidemia zebrafish larvae and early life stage toxicity of I3C on zebrafish embryos/larvae. Zebrafish larvae were fed with 4% high-cholesterol diet (HCD) and treated with I3C 2.5µmol/L and 5µmol/L for two weeks. Confocal image analysis, oil Red O staining were used to analysis vascular lipid accumulation and western blotting was used to evaluate possible mechanics. In addition, zebrafish embryos were treated with I3C for 96 h to assess the general toxicity and cardiotoxicity. We found that lipid deposition on vasculature was dose-dependently decreased in the I3C treated groups as compared with control group (47%, 23%, p<0.01). Moreover, we demonstrated that I3C inhibited lipid deposition by inducing autophagy, as identified by the enhancement of LC3-II, beclin-1, hVps34 and m-cathepsin D as well as by the reduction of P62, Bcl-2, Akt, p- Akt, mTOR, and p- mTOR in HCD fed zebrafish larvae (p<0.05). In summary, I3C shows protective effects on hyperlipidemia zebrafish larvae and maybe a promising multitarget drug in the prevention and protection against atherosclerotic.