Dr. Rachid Skouta's Research Group

Assessing the Antioxidant Properties of Larrea tridentata Extract as a Potential Molecular Therapy against Oxidative Stress

Oxidative stress has been linked to neurodegenerative diseases such as Huntington’s, Parkinson’s, Alzheimer’s and amyotrophic lateral sclerosis diseases. Larrea tridentata (LT) also known as Creosote Bush is an evergreen shrub found in the Chihuahuan desert which has been used medicinally by Native American tribes in southwestern North America and the Amerindians of South America. However, studies of the antioxidant capacity of the crude extract of LT towards the discovery of novel molecular therapies bearing antioxidants and drug-like properties are lacking. In this study, we assessed the antioxidant properties of Larrea tridentata, collected specifically from the Chihuahuan desert in the region of El Paso del Norte, TX, USA. LT phytochemicals were obtained from three different extracts (ethanol; ethanol: water (60:40) and water). Then the extracts were evaluated in eight different assays (DPPH, ABTS, superoxide; FRAP activity, nitric oxide, phenolic content, UV visible absorption and cytotoxicity in non-cancerous HS27 cells). The three extracts were not affecting the HS27 cells at concentrations up to 120 μg/mL. Among the three extracts, we found that the mixture of ethanol: water (60:40) LT extract has the most efficient antioxidant properties (IC 50 (DPPH at 30 min) = 111.7 ± 3.8 μg/mL; IC 50 (ABTS) = 8.49 ± 2.28 μg/mL; IC 50 (superoxide) = 0.43 ± 0.17 μg/mL; IC 50 (NO) = 230.4 ± 130.4 μg/mL; and the highest phenolic content was estimated to 212.46 ± 7.05 mg GAE/L). In addition, there was a strong correlation between phenolic content and the free-radical scavenging activity assays. HPLC-MS study identified nine compounds from the LT-ethanol: water extract including Justicidin B and Beta peltain have been previously reported as secondary metabolites of Larrea tridentata.


Skouta, R.; Morán-Santibañez, K.; Valenzuela, C.; Vasquez, A.; Fenelon, K. (2018) Assessing the Antioxidant Properties of Larrea tridentata Extract as a Potential Molecular Therapy against Oxidative Stress., Molecules

Neuroprotective effect of antioxidant compounds

Neurodegenerative diseases affect millions of individuals worldwide. It has been estimated that the number of patients affected by neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), traumatic brain injury (TBI), stroke and amyotrophic lateral sclerosis (ALS) will increase over time, due to the growing size of the elderly population (Willis, 2015). Currently AD affect 5.3 million people in the US and ~44 million people worldwide; PD affect 1.0 million people in the US and 7-10 million people worldwide; HD affect 30,000 people in the US and 100,000 people worldwide; TBI affect 1.4 million people in the US and 5.3 million people worldwide; Stroke affect 795,000 people in the US and 15.0 million people worldwide and finally ALS affect 12,000-30,000 people in the US and 450,000 people worldwide. Although a number of FDA approved drugs for these diseases have been used, they have been shown to produce diverse side effects and yield relatively modest benefits. Therefore, to surpass these limitations of current therapeutics, extensive research and development are underway to find drugs that are effective with less or no undesirable side effects.


Shimada, K.; Skouta, R.; Kaplan, A.; Yang, W.; Hayano, M.; Dixon, S.; Brown, L.; Valenzuela, C.; Wolpaw, A.; Stockwell, B. (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis., Nature Chemistry Biology

Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis

Apoptosis is one type of programmed cell death. Increasingly, non-apoptotic cell death is recognized as being genetically con- trolled, or ‘regulated’. However, the full extent and diversity of alternative cell death mechanisms remain uncharted. Here we surveyed the landscape of pharmacologically accessible cell death mechanisms. In an examination of 56 caspase-independent lethal compounds, modulatory profiling showed that 10 compounds induced three different types of regulated non-apoptotic cell death. Optimization of one of those ten resulted in the discovery of FIN56, a specific inducer of ferroptosis. Ferroptosis has been found to occur when the lipid-repair enzyme GPX4 is inhibited. FIN56 promoted degradation of GPX4. FIN56 also bound to and activated squalene synthase, an enzyme involved in isoprenoid biosynthesis, independent of GPX4 degradation. These discoveries show that dysregulation of lipid metabolism is associated with ferroptosis. This systematic approach is a means to discover and characterize novel cell death phenotypes.


Shimada, K.; Skouta, R.; Kaplan, A.; Yang, W.; Hayano, M.; Dixon, S.; Brown, L.; Valenzuela, C.; Wolpaw, A.; Stockwell, B. (2016) Global survey of cell death mechanisms reveals metabolic regulation of ferroptosis., Nature Chemistry Biology

ER Protein Processing Under Oxidative Stress: Implications and Prevention

Elevated levels of mitochondrial nitrosative stress have been associated with the pathogenesis of both Parkinson's and Alzheimer's diseases. The mechanism involves catalytic poisoning of the endoplasmic reticulum (ER)-resident oxidoreductase chaperone, protein disulfide isomerase (PDI), and the subsequent accumulation of ER-processed substrate proteins. Using a model system to mimic mitochondrial oxidative and nitrosative stress, we demonstrate a PDI-independent mechanism whereby reactive oxygen species (ROS) compromise regeneration rates of disulfide bond-containing ER-processed proteins. Under ROS-duress, the secretion-destined traffic adopts disulfide-exposed structures making the protein flux retrotranslocation biased. We also demonstrate that ROS-compromised protein maturation rates can be rescued by the polyphenol ellagic acid (EA). Our results are significant in that they reveal an additional mechanism which could promote neurodegenerative disorders. Furthermore, our data reveal that EA possesses therapeutic potential as a lead prophylactic agent against oxidative/nitrosative stress-related neurodegenerative diseases.


Khalil, M.; Valenzuela, C.; Sisniega, D.; Skouta, R.; Narayan, M. (2016) ER Protein Processing Under Oxidative Stress: Implications and Prevention., Cell Biochemistry and Biophysics