| Description: |
Nordihydroguaiaretic acid(NDGA), an inhibitor of lipoxygenase, also inhibits cytochrome P-450-mediated monooxygenase activity in rat epidermal and hepatic microsomes. NDGA has anti-inflammatory, antimutagen and/or anticarcinogen activities. NDGA protects hippocampal neurons against amyloid β-peptide toxicity, and attenuates free radical and calcium accumulation, it can interupt a neurodegenerative pathway relevant to the pathophysiology of Alzheimer's disease. NDGA protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice. NDGA-crosslinking of decellularized valvular matrix is a promising approach for preparation of heart valve tissue engineering scaffolds. |
| Targets: |
ROS | SREBP-1 | PPARγ | AMPK | Beta Amyloid | P-gp | NADPH-oxidase |
| In vitro: |
| Brain research, 1994, 654(1):171-176. | | Nordihydroguaiaretic acid protects hippocampal neurons against amyloid β-peptide toxicity, and attenuates free radical and calcium accumulation.[Reference: WebLink] | Recent findings indicate that amyloid β-peptide (Aβ) can be neurotoxic by a mechanism involving an increase in the concentration of intracellular free Ca2+ ([Ca2+]i) and the generation of free radicals.
METHODS AND RESULTS:
In the present study, the lipoxygenase inhibitor/antioxidant Nordihydroguaiaretic acid (NDGA) protected cultured rat hippocampal neurons against the toxicity of Aβ in a concentration-dependent manner. Measurements of cellular oxidation (using the oxidation-sensitive dye 2,7-dichlorofluorescin) and intracellular free Ca2+ levels (using the Ca2+ indicator dye fura-2), showed that NDGA suppressed Aβ-induced accumulation of reactive oxygen species (ROS) and Ca2+; Ca2+ responses to glutamate were also suppressed by NDGA. NDGA prevented neuronal injury and accumulation of ROS induced by iron, indicating a role for NDGA as an antioxidant in NDGA-mediated neuroprotection. Another lipoxygenase inhibitor (AA861) also protected against Aβ and iron toxicity whereas the the 5-lipoxygenase-activating protein inhibitor L655,238 and the cyclooxygenase inhibitor indomethacin were ineffective.
CONCLUSIONS:
These findings suggest that NDGA can interupt a neurodegenerative pathway relevant to the pathophysiology of Alzheimer's disease. | | Drug Metabolism and Disposition ,1991,19(3):620-4. | | Nordihydroguaiaretic acid, an inhibitor of lipoxygenase, also inhibits cytochrome P-450-mediated monooxygenase activity in rat epidermal and hepatic microsomes.[Reference: WebLink] | Nordihydroguaiaretic acid (NDGA), a plant lignan and phenolic antioxidant, is a known lipoxygenase inhibitor.
METHODS AND RESULTS:
In this study, we investigated the effect of NDGA on rat epidermal and hepatic monooxygenase activity and its interaction with rat hepatic microsomal cytochrome P-450. The addition of NDGA to epidermal microsomes prepared from control and 3-methylcholanthrene (3-MC)-pretreated rats and hepatic microsomal preparations from control, 3-MC-pretreated, and phenobarbital (PB)-pretreated rats resulted in a concentration-dependent inhibition of aryl hydrocarbon hydroxylase (AHH) and 7-ethoxyresorufin O-deethylase (ERD) activities. The 50% inhibitory dose for NDGA ranged from 4.1 x 10(-5) to 13.1 x 10(-5) M for AHH and ERD activities in these microsomal preparations. The addition of NDGA to hepatic microsomes prepared from PB-pretreated rats resulted in spectral changes characterized by absorbance maxima at 380 nm and minima at 414 nm, typical of type I binding difference spectra. It also showed time- and concentration-dependent inhibition of the binding of carbon monoxide to dithionite or NADPH-reduced cytochrome P-450.
CONCLUSIONS:
We speculate that perhaps hydroxyl groups present in NDGA play an important role in inhibiting the monooxygenase activity and suggest that NDGA may have potential as an antimutagen and/or anticarcinogen. Furthermore, caution must be exercised in elucidating the role of lipoxygenase in metabolic pathways based solely on the criterion of inhibition by NDGA. | | Journal of Materials Science: Materials in Medicine, 2010, 21(2):473-480. | | Crosslinking effect of Nordihydroguaiaretic acid (NDGA) on decellularized heart valve scaffold for tissue engineering.[Reference: WebLink] | Decellularized heart valve scaffolds possess many desirable properties in valvular tissue engineering. However, their current applications were limited by short durability, easily structural dysfunction and immunological competence. Although crosslinking with chemical reagents, such as glutaraldehyde (GA), will enhance the mechanical properties, the low long-term stability and cytotoxicity of the scaffolds remains potential problem. Nordihydroguaiaretic acid (NDGA) is a bioactive natural product which is able to crosslink collagen and was proven to be effective in preparation of scaffold for tendon tissue engineering.
METHODS AND RESULTS:
In this paper, NDGA crosslinked decellularized heart valve scaffolds demonstrated higher tensile strength, enzymatic hydrolysis resistance and store stability than the non-crosslinked ones. Its mechanical properties and cytocompability were superior to that of GA-crosslinked heart valve matrix. Below the concentration of 10 μg/ml, NDGA has no visible cytotoxic effect on both endothelial cells (EC) and valvular interstitial cells (VIC) and its cytotoxicity is much less than that of GA. The LC50 (50% lethal concentration) of NDGA on ECs and VICs are 32.6 μg/ml and 47.5 μg/ml, respectively, while those of GA are almost 30 times higher than NDGA ( P < 0.05). ECs can attach to and maintain normal morphology on the surface of NDGA-crosslinked valvular scaffolds but not GA-crosslinked ones.
CONCLUSIONS:
This study demonstrated that NDGA-crosslinking of decellularized valvular matrix is a promising approach for preparation of heart valve tissue engineering scaffolds. |
|
| In vivo: |
| Biochemical & Biophysical Research Communications, 2010, 401(1):92-97. | | Nordihydroguaiaretic acid protects against high-fat diet-induced fatty liver by activating AMP-activated protein kinase in obese mice.[Reference: WebLink] | Nonalcoholic fatty liver disease, one of the most common causes of chronic liver disease, is strongly associated with metabolic syndrome. Nordihydroguaiaretic acid (NDGA) has been reported to inhibit lipoprotein lipase; however, the effect of NDGA on hepatic lipid metabolism remains unclear.
METHODS AND RESULTS:
We evaluated body weight, adiposity, liver histology, and hepatic triglyceride content in high-fat diet (HFD)-fed C57BL/6J mice treated with NDGA. In addition, we characterized the underlying mechanism of NDGA’s effects in HepG2 hepatocytes by Western blot and RT-PCR analysis. NDGA (100 or 200 mg/kg/day) reduced weight gain, fat pad mass, and hepatic triglyceride accumulation, and improved serum lipid parameters in mice fed a HFD for 8 weeks. NDGA significantly increased AMP-activated protein kinase (AMPK) phosphorylation in the liver and in HepG2 hepatocytes. NDGA downregulated the level of mature SREBP-1 and its target genes (acetyl-CoA carboxylase and fatty acid synthase), but, it upregulated expression of genes involved in fatty acid oxidation, such as peroxisome proliferator-activated receptor (PPAR)α, PPARγ coactivator-1, carnitine palmitoyl transferase-1, and uncoupling protein-2. The specific AMPK inhibitor compound C attenuated the effects of NDGA on expression of lipid metabolism-related proteins in HepG2 hepatocytes.
CONCLUSIONS:
The beneficial effects of NDGA on HFD-induced hepatic triglyceride accumulation are mediated through AMPK signaling pathways, suggesting a potential target for preventing NAFLD. |
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