Maria Dolores Moya Garzon

All Publications

• The role of somatosensory innervation of adipose tissues. Nature Wang, Y., Leung, V. H., Zhang, Y., Nudell, V. S., Loud, M., Servin-Vences, M. R., Yang, D., Wang, K., Moya-Garzon, M. D., Li, V. L., Long, J. Z., Patapoutian, A., Ye, L. 2022

  Abstract

  Adipose tissues communicate with the central nervous system to maintain whole-body energy homeostasis. The mainstream view is that circulating hormones secreted by the fat convey the metabolic state to the brain, which integrates peripheral information and regulates adipocyte function through noradrenergic sympathetic output1. Moreover, somatosensory neurons of the dorsal root ganglia innervate adipose tissue2. However, the lack of genetic tools to selectively target these neurons has limited understanding of their physiological importance. Here we developed viral, genetic and imaging strategies to manipulate sensory nerves in an organ-specific manner in mice. This enabled us to visualize the entire axonal projection of dorsal root ganglia from the soma to subcutaneous adipocytes, establishing the anatomical underpinnings of adipose sensory innervation. Functionally, selective sensory ablation in adipose tissue enhanced the lipogenic and thermogenetic transcriptional programs, resulting in an enlarged fat pad, enrichment of beige adipocytes and elevated body temperature under thermoneutral conditions. The sensory-ablation-induced phenotypes required intact sympathetic function. We postulate that beige-fat-innervating sensory neurons modulate adipocyte function by acting as a brake on the sympathetic system. These results reveal an important role of the innervation by dorsal root ganglia of adipose tissues, and could enable future studies to examine the role of sensory innervation of disparate interoceptive systems.

  View details for DOI 10.1038/s41586-022-05137-7

  View details for PubMedID 36045288

• New salicylic acid derivatives, double inhibitors of glycolate oxidase and lactate dehydrogenase, as effective agents decreasing oxalate production EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY Moya-Garzon, M., Rodriguez-Rodriguez, B., Martin-Higueras, C., Franco-Montalban, F., Fernandes, M. X., Gomez-Vidal, J. A., Pey, A. L., Salido, E., Diaz-Gavilan, M. 2022; 237: 114396

  Abstract

  The synthesis and biological evaluation of double glycolate oxidase/lactate dehydrogenase inhibitors containing a salicylic acid moiety is described. The target compounds are obtained in an easily scalable two-step synthetic procedure. These compounds showed low micromolar IC50 values against the two key enzymes in the metabolism of glyoxylate. Mechanistically they behave as noncompetitive inhibitors against both enzymes and this fact is supported by docking studies. The biological evaluation also includes in vitro and in vivo assays in hyperoxaluric mice. The compounds are active against the three types of primary hyperoxalurias. Also, possible causes of adverse effects, such as cyclooxygenase inhibition or renal toxicity, have been studied and discarded. Altogether, this makes this chemotype with drug-like structure a good candidate for the treatment of primary hyperoxalurias.

  View details for DOI 10.1016/j.ejmech.2022.114396

  View details for Web of Science ID 000804173500004

  View details for PubMedID 35500475

• Small Molecule-Based Enzyme Inhibitors in the Treatment of Primary Hyperoxalurias JOURNAL OF PERSONALIZED MEDICINE Dolores Moya-Garzon, M., Antonio Gomez-Vidal, J., Alejo-Armijo, A., Altarejos, J., Roberto Rodriguez-Madoz, J., Xavier Fernandes, M., Salido, E., Salido, S., Diaz-Gavilan, M. 2021; 11 (2)

  Abstract

  Primary hyperoxalurias (PHs) are a group of inherited alterations of the hepatic glyoxylate metabolism. PHs classification based on gene mutations parallel a variety of enzymatic defects, and all involve the harmful accumulation of calcium oxalate crystals that produce systemic damage. These geographically widespread rare diseases have a deep impact in the life quality of the patients. Until recently, treatments were limited to palliative measures and kidney/liver transplants in the most severe forms. Efforts made to develop pharmacological treatments succeeded with the biotechnological agent lumasiran, a siRNA product against glycolate oxidase, which has become the first effective therapy to treat PH1. However, small molecule drugs have classically been preferred since they benefit from experience and have better pharmacological properties. The development of small molecule inhibitors designed against key enzymes of glyoxylate metabolism is on the focus of research. Enzyme inhibitors are successful and widely used in several diseases and their pharmacokinetic advantages are well known. In PHs, effective enzymatic targets have been determined and characterized for drug design and interesting inhibitory activities have been achieved both in vitro and in vivo. This review describes the most recent advances towards the development of small molecule enzyme inhibitors in the treatment of PHs, introducing the multi-target approach as a more effective and safe therapeutic option.

  View details for DOI 10.3390/jpm11020074

  View details for Web of Science ID 000622701200001

  View details for PubMedID 33513899

  View details for PubMedCentralID PMC7912158

• Salicylic Acid Derivatives Inhibit Oxalate Production in Mouse Hepatocytes with Primary Hyperoxaluria Type 1 JOURNAL OF MEDICINAL CHEMISTRY Dolores Moya-Garzon, M., Martin Higueras, C., Penalver, P., Romera, M., Fernandes, M. X., Franco-Montalban, F., Gomez-Vidal, J. A., Salido, E., Diaz-Gavilan, M. 2018; 61 (16): 7144-7167

  Abstract

  Primary hyperoxaluria type 1 (PH1) is a rare life-threatening genetic disease related to glyoxylate metabolism and characterized by accumulation of calcium oxalate crystals. Current therapies involve hepatic and/or renal transplantation, procedures that have significant morbidity and mortality and require long-term immunosuppression. Thus, a pharmacological treatment is urgently needed. We introduce here an unprecedented activity of salicylic acid derivatives as agents capable of decreasing oxalate output in hyperoxaluric hepatocytes at the low micromolar range, which means a potential use in the treatment of PH1. Though correlation of this phenotypic activity with glycolate oxidase (GO) inhibition is still to be verified, most of the salicylic acids described here are GO inhibitors with IC50 values down to 3 μM. Binding mode of salicylic acids inside GO has been studied using in silico methods, and preliminary structure-activity relationships have been established. The drug-like structure and ease of synthesis of our compounds make them promising hits for structural optimization.

  View details for DOI 10.1021/acs.jmedchem.8b00399

  View details for Web of Science ID 000442960800013

  View details for PubMedID 30028141

• Development of a Cannabinoid-Based Photoaffinity Probe to Determine the Delta(8/9)-Tetrahydrocannabinol Protein Interaction Landscape in Neuroblastoma Cells CANNABIS AND CANNABINOID RESEARCH Soethoudt, M., Alachouzos, G., van Rooden, E. J., Moya-Garzon, M., van den Berg, R. N., Heitman, L. H., van der Stelt, M. 2018; 3 (1): 136-151

  Abstract

  Introduction: Δ9-Tetrahydrocannabinol (THC), the principle psychoactive ingredient in Cannabis, is widely used for its therapeutic effects in a large variety of diseases, but it also has numerous neurological side effects. The cannabinoid receptors (CBRs) are responsible to a large extent for these, but not all biological responses are mediated via the CBRs. Objectives: The identification of additional target proteins of THC to enable a better understanding of the (adverse) physiological effects of THC. Methods: In this study, a chemical proteomics approach using a two-step photoaffinity probe is applied to identify potential proteins that may interact with THC. Results: Photoaffinity probe 1, containing a diazirine as a photocrosslinker, and a terminal alkyne as a ligation handle, was synthesized in 14 steps. It demonstrated high affinity for both CBRs. Subsequently, two-step photoaffinity labeling in neuroblastoma cells led to identification of four potential novel protein targets of THC. The identification of these putative protein hits is a first step towards a better understanding of the protein interaction profile of THC, which could ultimately lead to the development of novel therapeutics based on THC.

  View details for DOI 10.1089/can.2018.0003

  View details for Web of Science ID 000616128300015

  View details for PubMedID 29992186

  View details for PubMedCentralID PMC6038054