Article
Pharmacology & Pharmacy
Stefania Sgroi, Elisa Romeo, Paolo Di Fruscia, Pier Francesca Porceddu, Debora Russo, Natalia Realini, Ennio Albanesi, Tiziano Bandiera, Fabio Bertozzi, Angelo Reggiani
Summary: Inhibiting NAAA may be a promising pharmacological strategy to modulate the inflammatory aspect of multiple sclerosis and manage disease progression.
PHARMACOLOGICAL RESEARCH
(2021)
Article
Pharmacology & Pharmacy
Francesca Palese, Silvia Pontis, Natalia Realini, Alexa Torrens, Faizy Ahmed, Francesca Assogna, Clelia Pellicano, Paola Bossu, Gianfranco Spalletta, Kim Green, Daniele Piomelli
Summary: This study reveals the important role of NAAA-regulated PEA signaling in the survival of dopamine neurons and the development of Parkinson's disease symptoms. Deletion of the Naaa gene or inhibition of NAAA activity can significantly reduce neuron death and alleviate Parkinson's symptoms. Additionally, elevated NAAA expression is observed in the postmortem brain cortex and premortem blood-derived exosomes of Parkinson's disease patients. These findings suggest that NAAA could be a potential target for neuroprotective intervention.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Chemistry, Medicinal
Michael S. Malamas, Spiro Pavlopoulos, Shakiru O. Alapafuja, Shrouq Farah, Alexander Zvonok, Khadijah A. Mohammad, Jay West, Nicholas Thomas Perry, Dimitrios N. Pelekoudas, Girija Rajarshi, Christina Shields, Honrao Chandrashekhar, Jodi Wood, Alexandros Makriyannis
Summary: N-Acylethanolamines, particularly the palmitoylethanolamide hydrolyzed by NAAA, have been studied for their role in inflammation, pain, and drug addiction. Through synthesis and structure-activity relationship studies, potent inhibitors for hNAAA have been developed with high selectivity against other enzymes. These inhibitors have been identified as pharmacological tools for investigating the role of NAAA in various physiological processes.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Kazuhito Tsuboi, Tatsuya Tai, Ryouhei Yamashita, Hanif Ali, Takashi Watanabe, Toru Uyama, Yoko Okamoto, Keisuke Kitakaze, Yasuhiro Takenouchi, Shinji Go, Iffat Ara Sonia Rahman, Hitoshi Houchi, Tamotsu Tanaka, Yasuo Okamoto, Akira Tokumura, Junko Matsuda, Natsuo Ueda
Summary: This study demonstrates the ability of acid ceramidase (AC) to hydrolyze N-acylethanolamines (NAEs) and suggests its physiological role as a third NAE hydrolase.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS
(2021)
Article
Pharmacology & Pharmacy
Yuhang Li, Yitian Li, Sennan Xu, Yue Chen, Pan Zhou, Ting Hu, Hua Li, Ying Liu, Yaping Xu, Jie Ren, Yan Qiu, Canzhong Lu
Summary: This study found that N-acylethanolamine acid amidase (NAAA) is upregulated in psoriasis patients and mouse models. The upregulated NAAA contributes to psoriasis progression by enhancing dendritic cell maturation. NAAA expressed in dendritic cells plays a critical role in the development of psoriasis. This study also revealed that NAAA degrades a molecule called PEA and reduces the production of IL10, which promotes the maturation of dendritic cells and thus the development of psoriasis.
PHARMACOLOGICAL RESEARCH
(2022)
Article
Immunology
Da Huang, Jiayu Shen, Lingyun Zhai, Huanhuan Chen, Jing Fei, Xiaoqing Zhu, Jianwei Zhou
Summary: Through bioinformatics approaches, NAAA was found to be aberrantly expressed in various malignant tumors and its overexpression was associated with poor prognosis. NAAA was involved in cell cycle and immune regulation-related signaling pathways, correlated with tumor microenvironment and immune cell infiltration, and could serve as a potential target for cancer immunotherapy.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Pharmacology & Pharmacy
Xiaohua Xie, Yitian Li, Sennan Xu, Pan Zhou, Longhe Yang, Yaping Xu, Yan Qiu, Yungang Yang, Yuhang Li
Summary: NAAA is a lysosomal enzyme responsible for the hydrolysis of FAEs. This study generated NAAA-deficient mice and found that the deletion of NAAA increased the levels of PEA and AEA in bone marrow and macrophages, and elevated AEA levels in lungs. Unexpectedly, genetic blockade of NAAA showed moderately effective anti-inflammatory effects in acute lung injury, but poor analgesic effects in hyperalgesia and mechanical allodynia models. These phenotypes were associated with the absence of NAAA in non-BM cells. Overall, the study suggests that genetic blockade of NAAA regulates FAEs metabolism and inflammatory responses in a cell-specific manner.
FRONTIERS IN PHARMACOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Agnese Gagliardi, Roberto Molinaro, Massimo Fresta, Andrea Duranti, Donato Cosco
Summary: In this study, polymeric nanoparticles were used to encapsulate the NAAA inhibitor URB866, improving its physical stability. The nanoparticles demonstrated time- and temperature-dependent stability and a greater ability to retain the compound. The nanoparticles also enhanced the photostability of URB866 and displayed better antioxidant properties on various cell lines at a certain concentration.
Article
Endocrinology & Metabolism
Wei Gao, Kornelius Schmidt, Soren Enge, Clemens Kirschbaum
Summary: The study measured hair endocannabinoid and N-acylethanolamine levels over a period of two and a half years in 100 female participants, with strong test-retest associations found and no correlations observed between perceived stress and the measured substances. The findings support the idea that endocannabinoids and N-acylethanolamines in hair are stable trait biomarkers over time.
PSYCHONEUROENDOCRINOLOGY
(2021)
Article
Clinical Neurology
Mauro Congiu, Laura Micheli, Michele Santoni, Claudia Sagheddu, Anna Lisa Muntoni, Alexandros Makriyannis, Michael S. Malamas, Carla Ghelardini, Lorenzo Di Cesare Mannelli, Marco Pistis
Summary: The study showed that NAAA inhibition with the novel brain permeable NAAA inhibitor AM11095 can enhance the analgesic effects of morphine, delay the development of tolerance to morphine, and reduce neuroinflammation in the spinal cord.
Article
Biochemistry & Molecular Biology
Andrea Ghidini, Laura Scalvini, Francesca Palese, Alessio Lodola, Marco Mor, Daniele Piomelli
Summary: The catalytic efficiency of NAAA is strictly dependent on the length of the fatty acyl chain in both saturated and monounsaturated FAEs, with a wider tolerance for modifications of the polar heads. This relationship is reflective of the relative stability of enzyme-substrate complexes in molecular dynamics simulations.
JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
(2021)
Article
Pharmacology & Pharmacy
Yitian Li, Pan Zhou, Ting Hu, Jie Ren, Yaping Xu, Yan Qiu, Canzhong Lu, Yuhang Li
Summary: TBI induced an increase in PEA levels, preventing BBB disruption, but NAAA facilitated PEA degradation through neutrophils, weakening the BBB protective effects and exacerbating tissue injury.
EUROPEAN JOURNAL OF PHARMACOLOGY
(2021)
Article
Neurosciences
Yannick Fotio, Roberto Ciccocioppo, Daniele Piomelli
Summary: The study found that NAAA inhibitors can reduce voluntary alcohol intake without affecting water, food, or saccharin consumption. Additionally, NAAA inhibitors also attenuate voluntary alcohol self-administration.
PSYCHOPHARMACOLOGY
(2021)
Article
Multidisciplinary Sciences
Melissa Simard, Andrea Tremblay, Sophie Morin, Genevieve Rioux, Nicolas Flamand, Roxane Pouliot
Summary: This study aims to characterize the endocannabinoid system and evaluate the effects of n-3-derived NAEs on psoriatic keratinocytes. The study found that n-3 polyunsaturated fatty acids can alter the levels of related lipid mediators, reduce keratinocyte proliferation, and alleviate the inflammatory features of psoriasis.
SCIENTIFIC REPORTS
(2023)
Article
Clinical Neurology
Pauline Bottemanne, Owein Guillemot-Legris, Adrien Paquot, Julien Masquelier, Michael Malamas, Alexandros Makriyannis, Mireille Alhouayek, Giulio G. Muccioli
Summary: The study reveals that NAAA inhibition significantly reduces pathological changes in a multiple sclerosis model, while FAAH inhibition is less effective, and simultaneous inhibition of NAAA and FAAH does not provide additional benefits.
Article
Anesthesiology
Wisam Toma, Martial Caillaud, Nipa H. Patel, Tammy H. Tran, Giulia Donvito, Jane Roberts, Deniz Bagdas, Asti Jackson, Aron Lichtman, David A. Gewirtz, Alexandros Makriyannis, Michael S. Malamas, M. Imad Damaj
Summary: The study shows that paclitaxel reduces PEA levels in the spinal cord, while exogenous administration of PEA partially alleviates PIPN. Additionally, targeting NAAA enzyme with specific compound AM9053 can reverse and prevent PIPN. These findings suggest that selective NAAA inhibitors could be promising future therapeutics for the treatment and prevention of PIPN.
EUROPEAN JOURNAL OF PAIN
(2021)
Article
Nursing
Adriana V. Gaitan, JodiAnne T. Wood, Yingpeng Liu, Lipin Ji, Spyros P. Nikas, Alexandros Makriyannis, Carol J. Lammi-Keefe
Summary: This study found correlations between maternal dietary intake of long-chain polyunsaturated fatty acids and the concentrations of fatty acids and derived endocannabinoids in human milk. The inadequate intake of docosahexaenoic acid by participants was highlighted as a concern for infant development.
JOURNAL OF HUMAN LACTATION
(2021)
Article
Biochemistry & Molecular Biology
Basma G. Eid, Thikryat Neamatallah, Abeer Hanafy, Hany M. El-Bassossy, Lenah Binmahfouz, Hibah M. Aldawsari, Atif Hasan, Gamal Abd El-Aziz, Kiran Vemuri, Alexandros Makriyannis
Summary: The study investigated the effects of two neutral CB1 receptor antagonists, AM6545 and AM4113, on nephropathy associated with MetS in rats. Both compounds showed renal protective effects by inhibiting elevated proteinuria and albumin excretion rate, alleviating swelling and inflammatory cells infiltration in kidney structures, and preventing urine uric acid increase, collagen deposition, and elevated expression of TGF beta 1 in MetS animals. AM6545 and AM4113 interfered with TGF beta 1-mediated renal inflammation and fibrosis through peripheral action.
Article
Neurosciences
Despina Kokona, Dimitris Spyridakos, Manolis Tzatzarakis, Sofia Papadogkonaki, Eirini Filidou, Konstantinos Arvanitidis, George Kolios, Manjunath Lamani, Alexandros Makriyannis, Michael S. Malamas, Kyriaki Thermos
Summary: The endocannabinoid 2-AG has shown neuroprotective effects against excitotoxicity in the retina by activating CB1 and CB2 receptors as well as the PI3K/Akt signaling pathway. Inhibition of its metabolic enzymes, such as ABHD6 and MAGL, also provides partial neuroprotection against excitotoxicity in the retina.
Article
Chemistry, Medicinal
Thanh C. Ho, Marcus A. Tius, Spyros P. Nikas, Ngan K. Tran, Fei Tong, Han Zhou, Nikolai Zvonok, Alexandros Makriyannis
Summary: The novel oxa-adamantyl cannabinoids are identified as high affinity ligands for CB1 and CB2 cannabinoid receptors, showing potential as potent CB1 receptor agonists. Their synthesis is convenient, amenable to scale up, and suitable for large-scale preparation.
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2021)
Article
Chemistry, Medicinal
Shan Jiang, Christos Iliopoulos-Tsoutsouvas, Fei Tong, Christina A. Brust, Catherine M. Keenan, Jimit Girish Raghav, Tian Hua, Simiao Wu, Jo-Hao Ho, Yiran Wu, Travis W. Grim, Nikolai Zvonok, Ganesh A. Thakur, Zhi-Jie Liu, Keith A. Sharkey, Laura M. Bohn, Spyros P. Nikas, Alexandros Makriyannis
Summary: Novel cannabinergic probes have been developed to stabilize cannabinoid receptors through tight binding interactions, exhibiting high binding affinity and potent agonist activity. A key ligand, 27a, displays exceptional megagonist properties, acting centrally and peripherally, distinguishing it from previously reported megagonists.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Shrouq I. Farah, Samantha Hilston, Ngan Tran, Nikolai Zvonok, Alexandros Makriyannis
Summary: The interaction profiles of 2-AG, 1-AG, and 3-AG with endocannabinoid enzymes and CB1 receptor show differences in affinity and potency. The stereochemistry is crucial for the MGL enzyme, with 3-AG being the best substrate and 1-AG demonstrating the worst substrate profile. Both 1-AG and 3-AG are efficiently hydrolyzed by hABHD6 without preference.
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
(2022)
Article
Neurosciences
Jenny L. Wilkerson, Lauren B. Alberti, Ganesh A. Thakur, Alexandros Makriyannis, Erin D. Milligan
Summary: CB2R agonists can impact the expression of TRPV1 in the spinal cord and DRG, critical for combating allodynia.
Article
Pharmacology & Pharmacy
Barbara Romano, Ester Pagano, Fabio A. Iannotti, Fabiana Piscitelli, Vincenzo Brancaleone, Giuseppe Lucariello, Maria Francesca Nani, Ferdinando Fiorino, Rosa Sparaco, Giovanna Vanacore, Federica Di Tella, Donatella Cicia, Ruggero Lionetti, Alexandros Makriyannis, Michael Malamas, Marcello De Luca, Giovanni Aprea, Maria D'Armiento, Raffaele Capasso, Bernardo Sbarro, Tommaso Venneri, Vincenzo Di Marzo, Francesca Borrelli, Angelo A. Izzo
Summary: The research shows the functional importance of N-acyl ethanolamine acid amidase (NAAA) in colorectal cancer (CRC) progression, with its inhibition counteracting tumor growth and affecting the composition of tumor secretome. NAAA is proposed as a valid drug target for the treatment of CRC growth and development.
BRITISH JOURNAL OF PHARMACOLOGY
(2022)
Article
Chemistry, Medicinal
Ioannis P. Papanastasiou, Markos-Orestis Georgiadis, Christos Iliopoulos-Tsoutsouvas, Carol A. Paronis, Christina A. Brust, Ngan K. Tran, Lipin Ji, Xiaoyu Ma, JodiAnne T. Wood, Nikolai Zvonok, Fei Tong, Laura M. Bohn, Spyros P. Nikas, Alexandros Makriyannis
Summary: This study merged the features of nabilone and AM2389 and optimized the C3 side chain. Among the nabilone analogs, AM8936 exhibited balanced and potent agonist activity on the CB1 receptor, making it a potential candidate for further development.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Multidisciplinary Sciences
Arman A. Sadybekov, Anastasiia Sadybekov, Yongfeng Liu, Christos Iliopoulos-Tsoutsouvas, Xi-Ping Huang, Julie Pickett, Blake Houser, Nilkanth Patel, Ngan K. Tran, Fei Tong, Nikolai Zvonok, Manish K. Jain, Olena Savych, Dmytro S. Radchenko, Spyros P. Nikas, Nicos A. Petasis, Yurii S. Moroz, Bryan L. Roth, Alexandros Makriyannis, Vsevolod Katritch
Summary: Structure-based virtual ligand screening using V-SYNTHES method is effective in rapidly identifying high-scoring compounds from a large chemical space, with experimental results demonstrating successful hit rates and potencies. This approach shows promise for lead discovery and is easily scalable for use with diverse docking algorithms.
Article
Anesthesiology
Xiaoyan Lin, Zhili Xu, Lawrence Carey, Julian Romero, Alexandros Makriyannis, Cecilia J. Hillard, Elizabeth Ruggiero, Marilyn Dockum, George Houk, Ken Mackie, Phillip J. Albrecht, Frank L. Rice, Andrea G. Hohmann
Summary: This study investigated the cell types expressing CB2 receptor and found that CB2 expressed in previously unrecognized populations of skin cells may serve as a potential target for suppressing chemotherapy-induced neuropathic pain.
Article
Multidisciplinary Sciences
Othman Benchama, Sergiy Tyukhtenko, Michael S. Malamas, Mark K. Williams, Alexandros Makriyannis, Hava Karsenty Avraham
Summary: This study found that the use of MAGL inhibitor AM9928 can effectively block the adhesion and migration of TNBC cells, reduce the secretion of pro-inflammatory factors by cells, and inhibit the activation of HBMECs and cytokine secretion caused by TNBC. Animal experiments showed that AM9928 can inhibit the growth of mammary tumors in the mammary fat pads and reduce the permeability changes of the blood brain barrier, thus reducing the metastasis of TNBC in the brain. These findings suggest that MAGL inhibitors have the potential to be a novel strategy for TNBC treatment.
SCIENTIFIC REPORTS
(2022)
Correction
Chemistry, Medicinal
Thanh C. Ho, Joseph J. Mullins, Marcus A. Tius, Spyros P. Nikas, Ngan K. Tran, Fei Tong, Nicolai Zvonok, Alexandros Makriyannis
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(2022)
Article
Cell Biology
Suthakar Ganapathy, Jian Liu, Tianqi Yu, Rui Xiong, Qiang Zhang, Alexandros Makriyannis, Changyan Chen
Summary: Hexavalent chromium (Cr(VI)) pollution is a serious environmental and health concern. This study reveals the role of protein kinase C (PKC) in Cr(VI)-induced carcinogenesis and drug resistance, and suggests that PKC can be a potential biomarker for early detection of health damages and a therapeutic target for developing new treatments for diseases caused by Cr(VI).