Review
Medicine, Research & Experimental
Yanfang Zhang, Liangcai Gao, Bingyi Yao, Shengbo Huang, Yuanjin Zhang, Jie Liu, Zongjun Liu, Xin Wang
Summary: Epoxyeicosatrienoic acids (EETs) play a crucial role in heart function and their metabolic pathway serves as an important target for drug development and prevention of cardiotoxicity, showing promising prospects for cardiovascular disease treatment.
Article
Pharmacology & Pharmacy
Iwona Baranowska, Olga Gawrys, Agnieszka Walkowska, Krzysztof H. Olszynski, Ludek Cervenka, John R. Falck, Adeniyi M. Adebesin, John D. Imig, Elzbieta Kompanowska-Jezierska
Summary: Numerous studies have shown that metabolites of arachidonic acid, specifically epoxyeicosatrienoic acids (EETs) and 20-Hydroxyeicosatetraenoic acid (20-HETE), play important roles in blood pressure regulation, vascular tone, and renal function control. In this study, the researchers tested the effectiveness of EET-A and AAA in treating spontaneously hypertensive rats (SHR) and found that the combination treatment not only reduced blood pressure but also increased nitric oxide levels.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Physiology
Agnieszka Walkowska, Ludek Cervenka, John D. Imig, John R. Falck, Janusz Sadowski, Elzbieta Kompanowska-Jezierska
Summary: The study demonstrated that in spontaneously hypertensive rats, both EET-A and AAA induced renal vasodilation but did not show additive effects. Both agents have a definite therapeutic potential for hypertension and deserve further experimental and clinical testing for novel antihypertensive therapy.
FRONTIERS IN PHYSIOLOGY
(2021)
Article
Clinical Neurology
Ranran Han, Jieru Wan, Xiaoning Han, Honglei Ren, John R. Falck, Sailu Munnuri, Zeng-Jin Yang, Raymond C. Koehler
Summary: Recent research has found that 20-HETE participates in acute brain injury induced by intracerebral hemorrhage (ICH) by activating ferroptosis pathways, providing a potential target for treatment. Inhibition of 20-HETE can reduce neuronal death and lipid peroxidation levels, showing a neuroprotective effect after ICH.
FRONTIERS IN NEUROLOGY
(2021)
Article
Biochemistry & Molecular Biology
Oleksii Skorokhod, Vincenzo Triglione, Valentina Barrera, Giovanna Di Nardo, Elena Valente, Daniela Ulliers, Evelin Schwarzer, Gianfranco Gilardi
Summary: Malaria is a parasitic infection that can become life-threatening due to imbalanced immune responses. The phagocytosis of malarial pigment hemozoin (HZ) and HZ-containing Plasmodium parasites by monocytes leads to their dysfunction. This dysfunction is caused by the bioactive lipoperoxidation products 4-hydroxynonenal (4-HNE) and hydroxyeicosatetraenoic acids (HETEs). The conjugation of 4-HNE with CYP4F11 inhibits the omega-hydroxylation of 15-HETE, resulting in monocyte dysfunction and immune suppression in malaria.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Review
Pharmacology & Pharmacy
Mohammed A. W. ElKhatib, Fadumo Ahmed Isse, Ayman O. S. El-Kadi
Summary: The incidence of heart failure (HF) is preceded by cardiac hypertrophy (CH). Arachidonic acid (AA) metabolism is modulated during cardiac hypertrophy. Studies have shown that AA metabolites mediated by cytochrome P450 (CYP) play a role in the pathogenesis of cardiac hypertrophy. Inflammation has been found to affect the expression of CYPs and their metabolites in the heart. Pro-inflammatory metabolites such as HETEs are implicated in cardiac hypertrophy, while anti-inflammatory EETs have cardioprotective properties. This review highlights the impact of inflammation on CYP-derived AA metabolites and cardiac hypertrophy, and discusses potential anti-inflammatory strategies for the treatment of cardiac hypertrophy and heart failure.
DRUG METABOLISM REVIEWS
(2023)
Article
Cell Biology
Yongping Chen, Haotian Yang, Tianyuan Yang, Haiyang Zhang, Yuan Zhao, Lin Li, Honggang Fan
Summary: The study showed that low-dose alcohol can alleviate acute stress-induced renal dysfunction and histological damage, suppress oxidative stress and inflammation, as well as reduce apoptosis. The protective effects are achieved through inhibiting the CYP4A/20-HETE and LTB4/BLT1 pathways, but not the COX/PGE(2) pathway.
OXIDATIVE MEDICINE AND CELLULAR LONGEVITY
(2021)
Article
Pharmacology & Pharmacy
Yanfang Zhang, Yuanjin Zhang, Jie Liu, Yuan Xu, Bingyi Yao, Xin Wang
Summary: CYP2J2 deficiency leads to a decrease in EETs levels in plasma, exacerbating myocarditis, myocardial hypertrophy, and fibrosis, and inhibiting the mitochondrial energy metabolism signal network. With increasing age, the levels of 11,12-EET and 14,15-EET in plasma of KO rats decrease significantly, and heart injury becomes more severe. However, after CYP2J deletion, the heart initiates a self-protection mechanism by upregulating mechanism factors and mitochondrial fusion factors, but this protective effect disappears with aging.
TOXICOLOGY AND APPLIED PHARMACOLOGY
(2023)
Review
Biochemistry & Molecular Biology
Zeqi Shi, Zuowen He, Dao Wen Wang
Summary: Inflammation plays a crucial role in various systemic illnesses, and EETs have been found to have anti-inflammatory effects, reducing inflammation and remodeling of blood vessels. EETs also play important roles in other pathological conditions. Manipulating the AA-CYP450-EETs-sEH pathway has shown potential in alleviating inflammatory diseases, highlighting the importance of this research field.
Article
Pharmacology & Pharmacy
Samar H. Gerges, Ahmad H. Alammari, Mahmoud A. El-Ghiaty, Fadumo A. Isse, Ayman O. S. El-Kadi
Summary: This study found significant sex- and enantiospecific differences in the formation levels of different HETEs in all organs of male and female rats. The majority of HETEs, especially midchain HETEs and 20-HETE, showed significantly higher formation rates in male organs. In the liver, the R enantiomer of several HETEs showed a higher formation rate than the corresponding S enantiomer, while the brain and small intestine demonstrated a higher abundance of the S enantiomer. 19(S)-HETE was more abundant than 19(R)-HETE in all organs except the kidney.
CANADIAN JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY
(2023)
Article
Biochemistry & Molecular Biology
Lina A. Dahabiyeh, Muhammad Mujammami, Reem H. AlMalki, Tawfiq Arafat, Hicham Benabdelkamel, Assim A. Alfadda, Anas M. Abdel Rahman
Summary: This study used mass spectrometry-based lipid profiling to investigate the changes in lipid metabolism in the serum of healthy individuals after taking a single dose of metformin. The results showed significant alterations in lipid species involved in arachidonic acid metabolism, steroid hormone biosynthesis, and glycerophospholipid metabolism. These findings provide insights into the pleiotropic effects of metformin in various diseases.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Huaming Tang, Yuanli Kuang, Wan Wu, Bing Peng, Qianmei Fu
Summary: Recent studies have shown that quercetin, the main active component of saffron, inhibits breast carcinoma (BC) progression by down-regulating CYP3A4 to decrease the metabolization of AA to EETs, thereby blocking the nuclear translocation of p-Stat3 and impeding BC development.
MOLECULAR MEDICINE
(2023)
Review
Physiology
Jinsheng Lai, Chen Chen
Summary: Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid produced by cytochrome P450 (CYP) epoxygenases, with beneficial effects against inflammation, fibrosis, and apoptosis in cardiovascular diseases. Studies have shown that increasing EET levels can protect against cardiovascular diseases such as hypertension, myocardial infarction, and heart failure. Therefore, upregulation of EETs may be a potential therapeutic strategy for cardiovascular diseases.
FRONTIERS IN PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Kathleen Lukaszewicz, John R. R. Falck, Julian Lombard
Summary: In Dahl salt-sensitive rats, impaired vascular relaxation can be restored by restoring physiological levels of angiotensin II, inhibiting 20-HETE production, or introducing a normally functioning renin allele. However, chronically low angiotensin II levels in SS rats were found to upregulate cytochrome P450-4A and increase the production of the vasoconstrictor 20-HETE. The renin-angiotensin system and the CYP4A/20-HETE pathway both contribute to vascular dysfunction in the Dahl SS rat, but they are independent of each other.
Article
Endocrinology & Metabolism
Rachel Njeim, Kawthar Braych, Hilda E. Ghadieh, Nadim S. Azar, William S. Azar, Batoul Dia, Angelo Leone, Francesco Cappello, Hala Kfoury, Frederic Harb, Abdo R. Jurjus, Assaad A. Eid, Fuad N. Ziyadeh
Summary: Diabetes is associated with reduced bioavailability of epoxyeicosatrienoic acid (EET) and increased expression of glomerular vascular endothelial growth factor A (VEGF-A). This study investigated the protective effects of a soluble epoxide hydrolase inhibitor (AUDA) on diabetic kidney disease and the role of VEGF-A signaling pathway in diabetes-induced glomerular injury. The downregulation of CYP2C11-derived EET formation was linked to the activation of the VEGF-A pathway. Inhibiting VEGF-A attenuated glomerular injury by reducing reactive oxygen species production. These findings highlight the mechanistic link between CYP2C11-derived EETs, VEGF-A, and Nox4.
Article
Chemistry, Medicinal
Hamdah M. Al Nebaihi, Rami Al Batran, John R. Ussher, Zaid H. Maayah, Ayman O. S. El-Kadi, Dion R. Brocks
JOURNAL OF PHARMACEUTICAL SCIENCES
(2020)
Article
Cardiac & Cardiovascular Systems
Nikole J. Byrne, Nobutoshi Matsumura, Zaid H. Maayah, Mourad Ferdaoussi, Shingo Takahara, Ahmed M. Darwesh, Jody L. Levasseur, James Won Suk Jahng, Dyonne Vos, Nirmal Parajuli, Ayman O. S. El-Kadi, Branko Braam, Martin E. Young, Subodh Verma, Peter E. Light, Gary Sweeney, John M. Seubert, Jason R. B. Dyck
CIRCULATION-HEART FAILURE
(2020)
Review
Cell Biology
Zaid H. Maayah, Shingo Takahara, Mourad Ferdaoussi, Jason R. B. Dyck
INFLAMMATION RESEARCH
(2020)
Article
Immunology
Zaid H. Maayah, Mourad Ferdaoussi, Shingo Takahara, Shubham Soni, Jason R. B. Dyck
Summary: The study suggests that empagliflozin has a positive impact on acute sepsis-induced renal injury, improving survival and reducing inflammation. By reducing systemic and renal inflammation, empagliflozin has the potential to decrease mortality rates in patients with acute septic renal injury.
INFLAMMOPHARMACOLOGY
(2021)
Review
Toxicology
Zaid H. Maayah, Shingo Takahara, Jason R. B. Dyck
Summary: Doxorubicin (DOX) is a potent anti-neoplastic antibiotic that may cause cardiotoxicity, but reducing NLRP3 inflammasome activity can alleviate this effect. Therefore, novel pharmacological targets that target NLRP3 may be able to mitigate DOX-induced cardiotoxicity without compromising its anti-tumor activity.
ARCHIVES OF TOXICOLOGY
(2021)
Article
Cardiac & Cardiovascular Systems
Shingo Takahara, Mourad Ferdaoussi, Nikola Srnic, Zaid H. Maayah, Shubham Soni, Anna K. Migglautsch, Rolf Breinbauer, Erin E. Kershaw, Jason R. B. Dyck
Summary: Inhibition of adipocyte ATGL alleviates cardiac remodeling induced by chronic beta-adrenergic stimulation by reducing galectin-3 secretion from adipose tissue. This suggests that targeting lipolysis in adipocytes may be a potential therapeutic approach for heart failure patients with activated sympathetic nervous systems. Further investigation is warranted to explore the involvement of galectin-3 in the mechanisms linking excessive adipose tissue lipolysis to cardiac pathologies.
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
(2021)
Review
Cardiac & Cardiovascular Systems
Shingo Takahara, Shubham Soni, Zaid H. Maayah, Mourad Ferdaoussi, Jason R. B. Dyck
Summary: When circulating glucose levels are depleted, the heart may rely on ketone bodies as an alternative energy source, which can also suppress inflammation. Therefore, increasing circulating ketones may be beneficial for the treatment of heart failure.
CARDIOVASCULAR RESEARCH
(2022)
Article
Cardiac & Cardiovascular Systems
Koenraad Philippaert, Subha Kalyaanamoorthy, Mohammad Fatehi, Wentong Long, Shubham Soni, Nikole J. Byrne, Amy Barr, Jyoti Singh, Jordan Wong, Taylor Palechuk, Chloe Schneider, Ahmed M. Darwesh, Zaid H. Maayah, John M. Seubert, Khaled Barakat, Jason R. B. Dyck, Peter E. Light
Summary: SGLT2 inhibitors have cardioprotective effects against heart failure by inhibiting the late component of the cardiac sodium channel current.
Article
Biochemistry & Molecular Biology
Zaid H. Maayah, Abrar S. Alam, Shingo Takahara, Shubham Soni, Mourad Ferdaoussi, Nobutoshi Matsumura, Beshay N. Zordoky, David D. Eisenstat, Jason R. B. Dyck
Summary: DOX is an effective anticancer agent but can cause cardiotoxic effects. Co-treatment with RES can attenuate cardiac injury by reducing systemic inflammation.
Article
Cardiac & Cardiovascular Systems
Shingo Takahara, Shubham Soni, Kiran Phaterpekar, Ty T. Kim, Zaid H. Maayah, Jody L. Levasseur, Heidi L. Silver, Darren H. Freed, Mourad Ferdaoussi, Jason R. B. Dyck
Summary: Recent evidence suggests that chronic supplementation of exogenous ketones is beneficial for the failing heart, improving cardiac function and reducing cardiac pathology. Further investigations are needed to understand the underlying mechanisms.
Article
Biochemistry & Molecular Biology
Shubham Soni, Matthew D. Martens, Shingo Takahara, Heidi L. Silver, Zaid H. Maayah, John R. Ussher, Mourad Ferdaoussi, Jason R. B. Dyck
Summary: The study found that exogenous beta-hydroxybutyrate attenuates the inflammatory response and organ dysfunction in sepsis. Oral administration of beta-hydroxybutyrate for three days prior to lipopolysaccharide injection significantly protected mice against systemic inflammation and mitigated cardiac, renal, and liver dysfunction. These protective effects were independent of changes to enzymes involved in ketone metabolism.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2022)
Review
Biochemistry & Molecular Biology
Tahseen S. Sayed, Zaid H. Maayah, Heba A. Zeidan, Abdelali Agouni, Hesham M. Korashy
Summary: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcriptional factor with diverse physiological and pathological roles. It has been found that environmental pollutants can increase the risk of diseases such as diabetes and obesity by activating AhR. Current research focuses on understanding the mechanisms of AhR in insulin secretion and glucose homeostasis, involving pathways such as gluconeogenesis, hypoxia-inducible factor, oxidative stress, and inflammation.
CELLULAR & MOLECULAR BIOLOGY LETTERS
(2022)
Article
Chemistry, Medicinal
Hevna Dhulkifle, Tahseen S. Sayed, Hanan H. Abunada, Sara M. Abulola, Ali Alhoshani, Hesham M. Korashy, Zaid H. Maayah
Summary: Patients with sepsis are at high risk of morbidity and mortality due to multiple organ injuries caused by pathological inflammation. Acute renal injury is a significant contributor to sepsis morbidity and mortality. 6-formylindolo(3,2-b)carbazole (FICZ) has shown potential protective effects against sepsis-induced renal injury through the activation of AhR/Nrf2.
CHEMICAL RESEARCH IN TOXICOLOGY
(2023)
Article
Pharmacology & Pharmacy
Zaid H. H. Maayah, Mourad Ferdaoussi, Abrar Alam, Shingo Takahara, Heidi Silver, Shubham Soni, Matthew D. D. Martens, Dean T. T. Eurich, Jason R. B. Dyck
Summary: The study demonstrates that CBD can improve cardiac function and reduce renal injury induced by cytokine storm, by reducing inflammation levels both systemically and renally. This suggests a potential repurposing of CBD to reduce morbidity in patients with cytokine storm, especially in severe infections such as sepsis.
CANNABIS AND CANNABINOID RESEARCH
(2022)
Article
Cardiac & Cardiovascular Systems
Shingo Takahara, Shubham Soni, Kiran Phaterpekar, Ty T. Kim, Zaid H. Maayah, Jody L. Levasseur, Heidi L. Silver, Darren H. Freed, Mourad Ferdaoussi, Jason R. B. Dyck
Summary: Recent evidence has shown that ketone bodies, especially BHB, benefit the failing heart by serving as an alternative energy source and possessing anti-inflammatory and anti-oxidative properties. Chronic supplementation of ketones improved cardiac function in mice with established heart failure, reducing cardiomyocyte hypertrophy and fibrosis. These findings suggest that ketone therapy may be a potential treatment option for heart failure.