Review
Cell Biology
Robert J. Pignolo, Maurizio Pacifici
Summary: Metabolic derivatives of vitamin A, known as retinoids, regulate tissue and organ functions prenatally and postnatally. Studies showed that chondrogenic cell differentiation and cartilage maturation require the absence of retinoid signaling and repression function by unliganded RARs. Synthetic retinoid agonists could be potential pharmacological agents to inhibit heterotopic ossification.
Review
Physiology
Anqun Chen, Yu Liu, Yu Lu, Kyung Lee, John Cijiang He
Summary: Retinoic acid (RA) has dual effects in kidney disease, providing renal protection while also potentially inducing podocyte injury and apoptosis, highlighting the need to target specific RA-mediated pathways for effective therapeutic treatments.
AMERICAN JOURNAL OF PHYSIOLOGY-RENAL PHYSIOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Zhengrong Yang, Donald D. Muccio, Nathalia Melo, Venkatram R. Atigadda, Matthew B. Renfrow
Summary: Differential scanning calorimetry and differential scanning fluorimetry were used to measure the thermal stability of human retinoid X receptor-alpha ligand binding domain (RXRa LBD) homodimer in the absence or presence of rexinoid and coactivator peptide, GRIP-1. The study found that binding of rexinoid and GRIP-1 significantly affected the stability and unfolding enthalpy of the homodimer, consistent with previous structural studies.
Review
Medicine, Research & Experimental
Mingyan Shao, Linghui Lu, Qian Wang, Lin Ma, Xue Tian, Changxiang Li, Chun Li, Dongqing Guo, Qiyan Wang, Wei Wang, Yong Wang
Summary: RXRs play a crucial role in heart development and energy metabolism. While they are promising targets for treating cardiovascular diseases, their use is limited by toxicity. Further understanding of the mechanisms of RXRs in cardiovascular disease can aid in the rational design of more selective drugs.
BIOMEDICINE & PHARMACOTHERAPY
(2021)
Article
Biochemistry & Molecular Biology
Nathalia Melo, Olga V. Belyaeva, Wilhelm K. Berger, Laszlo Halasz, Jianshi Yu, Nagesh Pilli, Zhengrong Yang, Alla V. Klyuyeva, Craig A. Elmets, Venkatram Atigadda, Donald D. Muccio, Maureen A. Kane, Laszlo Nagy, Natalia Y. Kedishvili, Matthew B. Renfrow
Summary: This study investigated the mechanism of action of two next-generation rexinoids, UAB110 and UAB111. The results showed that UAB110 and UAB111 were more potent in enhancing ATRA signaling compared to UAB30 and Targretin. These rexinoids achieved activation through different molecular responses to ligand binding.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Biochemistry & Molecular Biology
Baixue Li, Shi-Ying Cai, James L. Boyer
Summary: Retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activated by retinoids, play crucial roles in various biological processes such as embryo development, homeostasis, cell proliferation, differentiation and death. In liver physiology, RAR/RXR heterodimers regulate lipid and bile acid synthesis and metabolism, cholesterol transport in macrophages, and fibrogenesis in hepatic stellate cells. Specific genes carrying out these functions are regulated by RAR/RXR in liver cells, providing a mechanistic understanding of their roles in liver physiology. Still, detailed signaling mechanisms of RAR/RXR in regulating liver gene expression remain to be fully elucidated in future studies.
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
(2021)
Review
Biochemistry & Molecular Biology
Roberta Lattanzi, Rossella Miele
Summary: The prokineticin family is a group of secreted peptides classified as chemokines based on their structure and functions. Prokineticins bind with high affinity to two G protein-coupled receptors and play important roles in various physiological functions. Dysregulation of the system leads to inflammatory processes associated with many pathological conditions. The use of PKR antagonists can reduce the upregulation of PK2/PKRs triggered by inflammatory processes, suggesting a potential strategy for treating inflammatory/neuroinflammatory diseases.
CURRENT ISSUES IN MOLECULAR BIOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Mohamed R. Abdelaal, Sameh H. Soror, Mohamed R. Elnagar, Hesham Haffez
Summary: The study found that synthetic retinoids, particularly EC19, exhibited potent antiproliferative and cytotoxic effects on cancer cell lines such as HepG2, Caco-2, and MCF-7. These compounds significantly affected cell cycle progression and gene expression, with a notable impact on inducing apoptosis, cell cycle arrest, and inhibition of metastasis.
Article
Chemistry, Medicinal
Viktoria M. S. Kjaer, Loukas Ieremias, Viktorija Daugvilaite, Michael Luckmann, Thomas M. Frimurer, Trond Ulven, Mette M. Rosenkilde, Jon Vabeno
Summary: The research found that the agonist activity of the G protein-coupled receptor GPR183/EBI2 is influenced by the substitution pattern of one of the two distal phenyl rings, acting as a molecular efficacy-switch.
Article
Chemistry, Medicinal
Su Hui Yang, Daulat Bikram Khadka, Jinhe Han, Soon-Young Na, Minsang Shin, Don-Kyu Kim, Byung-Chul Oh, Eun Young Kim, Hueng-Sik Choi, Won-Jea Cho
Summary: ERR gamma is an orphan nuclear receptor similar to estrogen receptors, but its endogenous ligand is unknown. Only stilbene and flavonol molecules have been found to modulate its transcriptional activity, but without selectivity. Therefore, virtual screening identified a novel ERR gamma inverse agonist, pyrazolamide 7, and its optimized derivative, pyrazolamide 19, showed potent and selective inverse agonistic activity towards ERR gamma. Pyrazolamide 19 exhibited strong affinity towards ERR gamma and inhibited the expression of hepcidin, fibrinogen, and gluconeogenic genes, suggesting potential antimicrobial, anti-coagulant, and antidiabetic activities.
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Hee-Kyung Park, Lan Phuong Nguyen, Thai Uy Nguyen, Minyeong Cho, Huong Thi Nguyen, Sunghoon Hurh, Hong-Rae Kim, Jae Young Seong, Cheol Soon Lee, Byung-Joo Ham, Jong-Ik Hwang
Summary: CXCL12 is an essential chemokine for organ development and homeostasis, and its receptor CXCR4 is widely expressed on target cells. Multiple splice variants of CXCR4 have been identified, and these variants have different expression patterns and cellular functions. The variants may also interact with each other during cellular responses to CXCL12. Therefore, further investigation of the functional roles of CXCR4 variants could contribute to the development of novel drug interventions.
Article
Chemistry, Medicinal
Francisco O. Battiti, Saheem A. Zaidi, Vsevolod Katritch, Amy Hauck Newman, Alessandro Bonifazi
Summary: This study investigates the role of regio- and stereochemistry in cyclic aliphatic linkers tethering pharmacophores targeting dopamine D-2 and D-3 receptors, introducing potent and selective agonists while modulating subtype selectivity in a stereospecific manner. The findings demonstrate a novel approach to modulate dopaminergic ligand pharmacology and introduce a new class of optically active cyclic linkers that can be utilized in expanding bitopic drug design towards other GPCRs. Extensive molecular docking studies support the pharmacological observations presented in the study.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Medicinal
Fabao Zhao, Unai Atxabal, Sofia Mariottini, Feng Yi, James S. Lotti, Nirvan Rouzbeh, Na Liu, Lennart Bunch, Kasper B. Hansen, Rasmus P. Clausen
Summary: The design and synthesis of (R)-3-(5-furanyl)carboxamido-2-aminopropanoic acid analogues as agonists at the glycine binding site in the GluN1 subunit of NMDA receptors were described. These novel analogues show variable potencies and agonist efficacies among different NMDA receptor subtypes, providing new opportunities for the development of therapeutic agents that can modulate specific NMDA receptor subtypes.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Biochemical Research Methods
Jooseong Oh, Hyi-Thaek Ceong, Dokyun Na, Chungoo Park
Summary: In this study, a machine learning model was developed to identify GPCR agonists and antagonists. The model showed high accuracy in classifying ligands and can be applied in virtual screening for potential GPCR-binding agonists and antagonists.
BMC BIOINFORMATICS
(2022)
Article
Chemistry, Analytical
Xiaojun Qin, Wenhua Li, Xingye Yang, Zhao Ma, Dong Liang, Xiongfeng Luo, Xinxin Chen, Shilong Hu, Lupei Du, Lijuan Chai, Minyong Li
Summary: The novel fluorescent agonists based on photoinduced electron transfer (PeT) exhibit efficient binding affinity with alpha(1)-adrenergic receptors (alpha(1)-ARs) and can be used to selectively image and trace the dynamic process of alpha(1)-AR internalization in living cells. Additionally, a bioluminescence resonance energy transfer binding assay with these new probes has been well-established and applied as a powerful tool for alpha(1)-AR-associated study during drug discovery.
ANALYTICAL CHEMISTRY
(2021)
Editorial Material
Oncology
Hinrich Gronemeyer
INTERNATIONAL JOURNAL OF CANCER
(2022)
Review
Oncology
Yasenya Kasikci, Hinrich Gronemeyer
Summary: Cancer genetics and genomics have provided insights into tumor development and heterogeneity. However, current cancer research may overlook complexity and individual diversity. A systems approach that reconstructs altered information networks and identifies key regulators is suggested. Individualized strategies are favored, as interindividual variability within patient cohorts is too high to extract common polygenic network information. A multinational and multidisciplinary effort is needed to develop dynamic regulatory networks and propose targeted therapies based on altered information transfer in individual cancers.
INTERNATIONAL JOURNAL OF CANCER
(2022)
Article
Chemistry, Medicinal
Melanie Schneider, Vanessa Delfosse, Muriel Gelin, Marina Grimaldi, Meritxell Granell, Laurene Heriaud, Jean-Luc Pons, Martin Cohen Gonsaud, Patrick Balaguer, William Bourguet, Gilles Labesse
Summary: By determining the crystal structure of dabrafenib bound to PXR and analyzing its mode of binding to both PXR and its primary target, B-Raf-V600E, new compounds with nanomolar activity against B-Raf and no detectable affinity for PXR were derived. The crystal structure of B-Raf in complex with the lead compound revealed a subdomain swapping of the activation loop with potentially important functional implications for prolonged inhibition of B-Raf-V600E.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Immacolata Maietta, Amparo Martinez-Perez, Rosana Alvarez, Angel R. De Lera, Africa Gonzalez-Fernandez, Rosana Simon-Vazquez
Summary: Epigenetic modifications play a crucial role in the proliferation, drug resistance, and metastasis of pancreatic ductal adenocarcinoma (PDAC). In this study, researchers tested the effects of different epigenetic enzyme inhibitors and a drug that restores p53 function on PDAC cell lines. The results showed that inhibiting certain enzymes or combining drugs with gemcitabine can significantly reduce cell viability and potentially serve as a new treatment strategy for PDAC. RNA-Seq analysis also identified potential biomarkers for synergy.
Article
Endocrinology & Metabolism
Albane le Maire, Martial Rey, Valerie Vivat, Laura Guee, Pauline Blanc, Christian Malosse, Julia Chamot-Rooke, Pierre Germain, William Bourguet
Summary: This study identified two RXR variants, one completely disabled for ligand binding while maintaining other functions intact and another that selectively impairs interaction with natural rexinoids but not with some synthetic ligands. The study also suggested a possible involvement of fatty acids in the weak interaction of RXRs with corepressors.
JOURNAL OF MOLECULAR ENDOCRINOLOGY
(2022)
Article
Plant Sciences
Aurea Rivas, Marta Castineira, Rosana Alvarez, Belen Vaz, Angel R. de Lera
Summary: The stereoselective synthesis of C40-all-trans- carotenoids with the formal hexahydrobenzofuran skeletons aurochrome, auroxanthin, and equinenone-5'8'-epoxide is reported. The synthesis is based on a one-pot or stepwise double Horner-Wadsworth-Emmons (HWE) reaction of a terminal enantiopure C15-5,6-epoxycyclohexadienylphosphonate and a central C10-trienedial. The ring expansion of the epoxycyclohexadienylphosphonate, generated by a Stille cross-coupling reaction, to the hexahydrobenzofuran skeleton was promoted by the reaction conditions of the HWE reaction prior to double-bond formation.
JOURNAL OF NATURAL PRODUCTS
(2022)
Article
Chemistry, Organic
Patricia Garcia-Dominguez, Angel R. de Lera
Summary: This study successfully synthesized several constitutional isomers of macrolactam and ruled out alternative structures of the original one through spectroscopic data comparison.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Chemistry, Organic
Patricia Garcia-Dominguez, Paula Lorenzo, Rosana Alvarez, Angel R. . de Lera
Summary: The total synthesis of the suggested structure of (-)-novofumigatamide was achieved, but the NMR data did not match that of the natural product. Further synthetic efforts were made to assemble alternative structures, but none of them matched the natural product. This highlights the challenges in identifying the structure of natural products.
JOURNAL OF ORGANIC CHEMISTRY
(2022)
Article
Cell Biology
A. Huyghe, G. Furlan, J. Schroeder, E. Cascales, A. Trajkova, M. Ruel, F. Studer, M. Larcombe, Y. Bo Yang Sun, F. Mugnier, L. De Matteo, A. Baygin, J. Wang, Y. Yu, N. Rama, B. Gibert, J. Kielbassa, L. Tonon, P. Wajda, N. Gadot, M. Brevet, M. Siouda, P. Mulligan, R. Dante, P. Liu, H. Gronemeyer, M. Mendoza-Parra, J. M. Polo, F. Lavial
Summary: Coordinated changes of cellular plasticity and identity are critical for pluripotent reprogramming and oncogenic transformation. This study provides insights into the partitioned control of cellular plasticity and identity for both regenerative and cancer biology.
NATURE CELL BIOLOGY
(2022)
Review
Biochemistry & Molecular Biology
Claudio Martinez, Patricia Garcia-Dominguez, Rosana Alvarez, Angel R. de Lera
Summary: This article introduces the natural products containing 2,5-dioxopiperazine generated by head-to-tail cyclization of peptides, with a focus on tryptophan-derived derivatives that allow for further structural diversification. The more complex dimeric bispyrrolidinoindoline epi(poly)thiodioxopiperazines and their derivatives are also discussed. The article covers the isolation, structural characterization, biological activities, putative biogenetic routes, and synthetic efforts related to these compounds, as well as the evaluation of structurally simple analogs.
Article
Multidisciplinary Sciences
Jakub Gruszczyk, Loic Grandvuillemin, Josephine Lai-Kee-Him, Matteo Paloni, Christos G. Savva, Pierre Germain, Marina Grimaldi, Abdelhay Boulahtouf, Hok-Sau Kwong, Julien Bous, Aurelie Ancelin, Cherine Bechara, Alessandro Barducci, Patrick Balaguer, William Bourguet
Summary: This study reveals the structure of AHR, providing mechanistic insights into ligand-binding promiscuity and selectivity.
NATURE COMMUNICATIONS
(2022)
Review
Biochemistry & Molecular Biology
Torsten Bohn, Angel R. de Lera, Jean-Francois Landrier, Harald Carlsen, Daniel Merk, Tilman Todt, Jenny Renaut, Ralph Ruehl
Summary: Carotenoids are abundant lipophilic plant metabolites that have potential health benefits for humans, including reduced mortality. They can impact oxidative stress and inflammation through interactions with transcription factors. The article describes both old and new metabolic pathways of carotenoids and their bioactive derivatives, as well as the techniques and tools needed to comprehensively study this topic.
Article
Toxicology
Albert Braeuning, Patrick Balaguer, William Bourguet, Jordi Carreras-Puigvert, Katreece Feiertag, Jorke H. Kamstra, Dries Knapen, Dajana Lichtenstein, Philip Marx-Stoelting, Jonne Rietdijk, Kristin Schubert, Ola Spjuth, Evelyn Stinckens, Kathrin Thedieck, Rik van den Boom, Lucia Vergauwen, Martin von Bergen, Neele Wewer, Daniel Zalko
Summary: In the past, the focus of analyzing the endocrine disrupting properties of chemicals was mainly on estrogenic or androgenic properties, as well as steroidogenesis and thyroid signaling. However, more recent attention has been given to the disruption of energy metabolism and related signaling pathways by exogenous substances known as metabolism-disrupting chemicals (MDCs). This paper provides an overview of the efforts within the EU-funded Partnership for the Assessment of Risks of Chemicals (PARC) to develop novel in vitro methods for detecting endocrine metabolic disruptors and improving the toxicological toolbox.
FRONTIERS IN TOXICOLOGY
(2023)
Article
Endocrinology & Metabolism
Xiao-Min Ren, Richard C. Chang, Yikai Huang, Angelica Amorim Amato, Coralie Carivenc, Marina Grimaldi, Yun Kuo, Patrick Balaguer, William Bourguet, Bruce Blumberg
Summary: 2,4-Di-tert-butylphenol (2,4-DTBP) is a commercial antioxidant and toxic natural secondary metabolite detected in humans. This study demonstrates that 2,4-DTBP and related compounds act as obesogens and endocrine disruptors by activating nuclear receptors. The findings suggest the importance of developing safer antioxidants that do not interact with crucial nuclear receptors to avoid adverse effects on human development and physiology.
Review
Biochemistry & Molecular Biology
Patricia Garcia-Dominguez, Andrea Areal, Rosana Alvarez, Angel R. de Lera
Summary: This article covers the research progress of 2,5-dioxopiperazine-containing natural products up to the end of 2021, with a focus on those derived from tryptophan. These products exhibit diverse structures and are constructed by polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) assembly lines. Recent studies have successfully synthesized these natural products through the mining of microbial genome sequences and competition between heterologous expression and synthetic campaigns, allowing for the investigation of their biological activities and biosynthetic pathways.
NATURAL PRODUCT REPORTS
(2022)