Astaxanthin attenuates the increase in mitochondrial respiration during the activation of hepatic stellate cells

Yuan

Molecular Therapy - Nucleic Acids

et al. 2019

Recently, emerging evidence shows that dysregulation of circadian genes is closely associated with liver fibrosis. However, how dysregulation of circadian genes promotes liver fibrosis is unknown. In this study, we show that neuronal PAS domain protein 2 (NPAS2), one of the core circadian molecules that has been shown to promote hepatocarcinoma cell proliferation, significantly contributed to liver fibrogenesis. NPAS2 is upregulated in hepatic stellate cells (HSCs) after fibrogenic injury, which subsequently contributes to the activation of HSCs. Mechanistically, NPAS2 plays a profibrotic role via direct transcriptional activation of hairy and enhancer of split 1 (Hes1), a critical transcriptor of Notch signaling for the fibrogenesis process, in HSCs. Our findings demonstrate that NPAS2 plays a critical role in liver fibrosis through direct transcriptional activation of Hes1, indicating that NPAS2 may serve as an important therapeutic target to reverse the progression of liver fibrosis.

Section: Resultsmentioning

confidence: 99%

Section: Overexpression Of Npas2 In Hscs Is Mainly Mediated By Downregulation Of Mir-19b-3pmentioning

confidence: 99%

NPAS2 Contributes to Liver Fibrosis by Direct Transcriptional Activation of Hes1 in Hepatic Stellate Cells

Yuan

Molecular Therapy - Nucleic Acids

et al. 2019

“…The hepatic first-pass effect of drugs can be initially evaluated by the liver microsomes metabolic system invitro. 25 As shown in Figure 2C, the metabolism of PAE was extremely rapid in the liver microsomes metabolism system (liver microsomes + NADPH), and the metabolic residual content at 30 min was only 20.97% ± 2.99%. The metabolism of PAE in the blank liver microsomes (without NADPH) was significantly lower than that in the liver microsomes metabolic system.…”

Section: Stability Of Pae In Simulated Biological Samplesmentioning

confidence: 88%

<p>Primary Studies on Construction and Evaluation of Ion-Sensitive in situ Gel Loaded with Paeonol-Solid Lipid Nanoparticles for Intranasal Drug Delivery</p>

Sun¹,

Xie²,

Wang³

et al. 2020

IJN

Background: Paeonol (PAE) is a potential central neuroprotective agent with poor water solubility and rapid metabolism in vivo. The key to improve the clinical application of PAE in the treatment of neurodegenerative diseases is to improve the brain delivery of it. The purpose of this study was to construct a paeonol-solid lipid nanoparticles-in situ gel (PAE-SLNs-ISG) drug delivery system based on nose-brain transport pathway. Materials and Methods: In this study, the stability of PAE in simulated biological samples was studied firstly in order to clarify the reasons for low oral bioavailability. Paeonol-solid lipid nanoparticles (PAE-SLNs) were prepared by high-temperature emulsification-low-temperature curing combined with ultrasound. The PAE-SLNs-ISG drug delivery system was constructed, and related formulation optimization, preparation characterization, cell evaluation and in vivo evaluation were performed. Results: The metabolic mechanism of PAE incubated in the liver microsomes metabolic system was in accordance with the first-order kinetics, and the half-life was 0.23 h. PAE-SLNs were polyhedral or spherical particles with good dispersion and the particle size was 166.79 nm ± 2.92 nm. PAE-SLNs-ISG solution was a Newtonian fluid with a viscosity of 44.36 mPa • S ± 2.89 mPa • S. The viscosity of PAE-SLNs-ISG gel was 1542.19 mPa • S ± 19.30 mPa • S, and the rheological evaluation showed that the gel was a non-Newtonian pseudoplastic fluid with shear thinning, thixotropy and yield value. The release mechanism of PAE from PAE-SLNs was drug diffusion; the release mechanism of PAE from PAE-SLNs-ISG was a synergistic effect of skeleton erosion and drug diffusion. The cell viabilities of PAE-SLNs and PAE-SLNs-ISG in the concentration range of 0.001 µg/mL to 10 µg/mL were higher than 90%, showing a low level of cytotoxicity. The geometric mean fluorescent intensities of RPMI 2650 cells incubated with fluorescein isothiocyanate-solid lipid nanoparticles (FITC-SLNs) for 1 h, 4 h and 6 h were 1841 ± 24, 2261 ± 27 and 2757 ± 22, respectively. Cyanine7 NHS ester-solid lipid nanoparticles-in situ gel (Cy7-SLNs-ISG) accumulated effectively in the brain area after administration through the olfactory area, and the fluorescence response was observed in olfactory bulb, cerebellum and striatum. Conclusion: SLNs-ISG nose-brain drug delivery system can effectively deliver SLNs to brain regions, and it is a potentially effective strategy to realize the brain region delivery of PAE.

“…17 Moreover, increasing evidence has demonstrated that AST inhibits ATP depletion to maintain the energy supply to the cells. 13,14 Our previous studies also suggested that AST attenuated SE-induced cognitive dysfunction through inhibited oxidative stress, neuroinflammation, and neuronal apoptosis in rat brains. 18 However, there are no studies have investigated whether AST influences neuroinflammation by regulating the ATP-P2X7R signal in SE.…”

Section: Introductionmentioning

confidence: 93%

“…Most studies have reported that AST inhibits reactive oxygen species production, maintains the structural integrity of mitochondria, suppresses the inflammatory signaling pathway, and attenuates cellular dysfunction. [14][15][16] Similarly, a recent study indicated that AST reverses the damage to hippocampal neurons in neonatal rats exposed to maternal seizure, which may contribute to the reduction of oxidative stress. 17 Moreover, increasing evidence has demonstrated that AST inhibits ATP depletion to maintain the energy supply to the cells.…”

Section: Introductionmentioning

confidence: 93%

<p>Astaxanthin Attenuates Neuroinflammation in Status Epilepticus Rats by Regulating the ATP-P2X7R Signal</p>

Wang

Deng

Xie

et al. 2020

DDDT

Background: As a life-threatening neurological emergency, status epilepticus (SE) is often refractory to available treatment. Current studies have shown a causal role of neuroinflammation in patients with lower seizure thresholds and driving seizures. The ATP-gated purinergic P2X7 receptor (P2X7R) is mainly expressed on the microglia, which function as gatekeepers of inflammation. Although emerging evidence has demonstrated significant anti-inflammatory effects of astaxanthin (AST) in SE, the associated mechanism remains unclear. Therefore, this study aimed to clarify the effects of AST on P2X7R-related inflammation in SE. Methods: SE was induced in rats using lithium-pilocarpine, and AST was administered 1 h after SE induction. Rat microglia were treated with lipopolysaccharide (LPS), AST, ATP, 2,3-O-4-benzoyl-4-benzoyl-ATP (BzATP) and oxidized ATP (oxATP). The Morris water maze, immunohistochemistry, and Nissl staining were performed in rats. Expressions of P2X7R and inflammatory cytokines (such as cycloxygenase-2 (Cox-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α)) were detected using real-time polymerase chain reaction (RT-PCR) and Western blot (WB) both in rats and microglia. ATP concentration in the microglia was evaluated using ELISA. Results: The AST alleviated hippocampal injury and improved cognitive dysfunction induced by SE. AST also effectively inhibited inflammation and downregulated P2X7R expression in both rat brain and microglia. The results also showed that AST reduced the extracellular ATP levels and that P2X7R expression could be increased by extracellular ATP. In addition, BzATP upregulates the expression of P2X7R and inflammatory factors in microglia. Conversely, it downregulates the expression of P2X7R and inflammatory factors. Conclusion: Our study suggests that AST attenuated ATP-P2X7R mediated inflammation in SE.