White crystalline powder
(2R)-2-[(2R,3R,3aR,6S,7S,9bR)-6-(2-Carboxyethyl)-2-hydroxy-7-isopropenyl-3a,6,9b-trimethyl-2,3,3a,4,6,7,8,9b-octahydro-1H-cyclopenta[a]naphthalen-3-yl]-6-methyl-5-methyleneheptanoic acid/1H-Benz[e]indene-6-propanoic acid, 3-[(1R)-1-carboxy-5-methyl-4-methylenehexyl]-2,3,3a,4,6,7,8,9b-octahydro-2-hydroxy-3a,6,9b-trimethyl-7-(1-methylethenyl)-, (2R,3R,3aR,6S,7S,9bR)-
Poricoic acid A, isolated from Poria cocos, possesses anti-tumor activity. Poricoic acid A enhances melatonin inhibition of AKI-to-CKD transition by regulating Gas6/AxlNFκB/Nrf2 axis.
664.0±55.0 °C at 760 mmHg
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provides coniferyl ferulate(CAS#:137551-38-3) MSDS, density, melting point, boiling point, structure, formula, molecular weight etc. Articles of coniferyl ferulate are included as well.>> amp version: coniferyl ferulate
Renal ischemia-reperfusion injury (IRI) is a complex syndrome, which causes chronic kidney disease (CKD) after recovery from IRI-mediated acute kidney injury (AKI). There is no single therapy that could effectively prevent the renal injury after ischemia. In this study, the effects of melatonin or poricoic acid A (PAA) and their combination were investigated in protecting against AKI-to-CKD transition in rats and hypoxia/reoxygenation (H/R)-induced injury in cultured renal NRK-52E cells. Melatonin and PAA significantly reduced the magnitude of rise in serum creatinine and urea levels in IRI rats at days 3 and 14. Our results further showed that treatment with melatonin and PAA ameliorated renal fibrosis and podocyte injury by attenuating oxidative stress and inflammation via regulation of nuclear factor-kappa B (NF-κB) and nuclear factor-erythroid-2-related factor 2 (Nrf2) pathways in IRI rats. Melatonin and PAA protected against AKI-to-CKD transition by regulating growth arrest-specific 6 (Gas6)/AxlNFκB/Nrf2 signaling cascade. Melatonin and PAA initiallyupregulated Gas6/Axl signaling to reduce oxidative stress and inflammation in AKI and subsequently downregulated Gas6/Axl signaling to attenuate renal fibrosis and progression to CKD. Melatonin and PAA inhibited expression of extracellular matrix proteins. Poricoic acid A enhances melatonin-mediated inhibition of AKI-to-CKD transition by the regulating Gas6/AxlNFκB/Nrf2 signaling cascade. Notably, our study first identified Axl as a promising therapeutic target for prevention of AKI-to-CKD transition.
Acute kidney injury; Chronic kidney disease; Gas6/Axl; Inflammation and oxidative stress; Melatonin; Poria cocos; Poricoic acid A.
Poricoic Acid A Enhances Melatonin Inhibition of AKI-to-CKD Transition by Regulating Gas6/AxlNFκB/Nrf2 Axis
Dan-Qian Chen 1 , Ya-Long Feng 1 , Lin Chen 1 , Jing-Ru Liu 1 , Ming Wang 1 , Nosratola D Vaziri 2 , Ying-Yong Zhao 3
Background: N-methyl-D-aspartate (NMDA) receptor is a tetrameric protein complex composed of glycine-linked NR1 subunits and glutamate-linked NR2 subunits. There are four NR2 subunits (A-D) that differ in development, anatomy, and function profiles. They play various roles in normal and neuropathologic conditions. Specific agonists, antagonists, and modulators of subunits for selective NMDA receptors may be precious mediational tools and potent agents for treating diseases. The objective of this study was to determine the effect of poricoic acid A on NMDA receptor known to mediate excitatory synaptic transmission factors and cause changes in synaptic strength. Inhibitory effect of poricoic acid A on NR1a combined with NR2A, NR2B, NR2C, or NR2D receptor was evaluated.
Methods: Glutamate-mediated currents for each NR1a and NR2 subunits were investigated using two-electrode voltage-clamp techniques. Molecular modeling and molecular dynamics simulation studies were carried out with Autodock Tools. Poricoic acid A and NMDA receptor protein complex were examined with Ligplot and Pymol docking program. Ligplot shows binding activity at the protein and the ligand.
Results: The inhibitory effect of poricoic acid A on glutamate-induced inward current in a concentration-dependent manner that was reversible. Half inhibitory concentrations of glutamate on NR1a/NR2A, NR1a/NR2B, NR1a/NR2C, and NR1a/NR2D receptors were 9.6 ± 1.2, 5.7 ± 0.4, 46.1 ± 21.5, and 21.5 ± 8.2 μM, respectively. This corresponded to the order of inhibitory effect of oocyte expressing NR1a and NR2s subunit of NR1a/NR2B > NR1a/NR2A > NR1a/NR2C > NR1a/NR2D.
Conclusions: Taken together, these results indicate that poricoic acid A can modulate the expression of NMDA receptor. In addition, the regulation of excitatory ligand-gating ion channel by poricoic acid A may have pharmaceutical functions on excitatory synaptic transmission of neuronal system.
Excitatory synaptic transmission; NMDA receptors; Poricoic acid A; Subunit specificity; Triterpenoid.
Subunit-specific Effects of Poricoic Acid A on NMDA Receptors
Jaeeun Lee 1 , Chaelin Kim 1 , Hye Duck Yeom 1 , Khoa V A Nguyen 1 , Sanung Eom 1 , Shinhui Lee 1 , Ji-Hye Jung 2 , Jeong-Ho Lee 3 , Sung Hyun Kim 2 , Il-Kwang Kim 4 , Jun-Ho Lee 5
Background: Acute kidney injury (AKI) is one of the major risk factors for progression to chronic kidney disease (CKD) and renal fibrosis. However, effective therapies remain poorly understood. Here, we examined the renoprotective effects of melatonin and poricoic acid A (PAA) isolated from the surface layer of Poria cocos, and investigated the effects of combined therapy on the interaction of TGF-β/Smad and Wnt/β-catenin in a rat model of renal ischemia-reperfusion injury (IRI) and hypoxia/reoxygenation (H/R) or TGF-β1-induced HK-2 cells.
Methods: Western blot and immunohistochemical staining were used to examine protein expression, while qRT-PCR was used to examine mRNA expression. Coimmunoprecipitation, chromatin immunoprecipitation, RNA interference, and luciferase reporter gene analysis were employed to explore the mechanisms of PAA and melatonin’s renoprotective effects.
Results: PAA and combined therapy exhibited renoprotective and antifibrotic effects, but the underlying mechanisms were different during AKI-to-CKD continuum. Melatonin suppressed Smad-dependent and Smad-independent pathways, while PAA selectively inhibited Smad3 phosphorylation through distrupting the interactions of Smad3 with TGFβRI and SARA. Further studies demonstrated that the inhibitory effects of melatonin and PAA were partially depended on Smad3, especially PAA. Melatonin and PAA also inhibited the Wnt/β-catenin pathway and its profibrotic downstream targets, and PAA performed better. We further determined that IRI induced a nuclear Smad3/β-catenin complex, while melatonin and PAA disturbed the interaction of Smad3 and β-catenin, and supplementing with PAA could enhance the inhibitory effects of melatonin on the TGF-β/Smad and Wnt/β-catenin pathways.
Conclusions: Combined melatonin and PAA provides a promising therapeutic strategy to treat renal fibrosis during the AKI-to-CKD continuum.
TGF-β/Smad; Wnt/β-catenin; melatonin; poricoic acid A; renal fibrosis; renal ischemia-reperfusion injury.
Combined Melatonin and Poricoic Acid A Inhibits Renal Fibrosis Through Modulating the Interaction of Smad3 and β-Catenin Pathway in AKI-to-CKD Continuum
Dan-Qian Chen 1 , Gang Cao 2 , Hui Zhao 1 , Lin Chen 1 , Tian Yang 1 , Ming Wang 1 , Nosratola D Vaziri 3 , Yan Guo 4 , Ying-Yong Zhao 5
2019 Aug 14