Author: Bittencourt, Clarissa A ; Martin, Renan P ; Arata, Júlia G ; Branquinho, Jéssica ; Pesquero, João B ; Neves, Raquel L ; Araújo, Ronaldo C ; Icimoto, Marcelo Y

OBJECTIVE AND DESIGNKinin B1 receptor (B1R) has a key role in adipocytes to protect against obesity and glycemic metabolism, thus becoming a potential target for regulation of energy metabolism and adipose tissue thermogenesis.MATERIAL OR SUBJECTSKinin B1 knockout mice (B1KO) were subjected to acute induction with CL 316,243 and chronic cold exposure.METHODSMetabolic and histological analyses, gene and protein expression and RNA-seq were performed on interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT) of mice.RESULTSB1KO mice, under acute effect of CL 316,243, exhibited increased energy expenditure and upregulated thermogenic genes in iWAT. They were also protected from chronic cold, showing enhanced non-shivering thermogenesis with increased iBAT mass (~ 90%) and recruitment of beige adipocytes in iWAT (~ 50%). Positive modulation of thermogenic and electron transport chain genes, reaching a 14.5-fold increase for Ucp1 in iWAT. RNA-seq revealed activation of the insulin signaling pathways for iBAT and oxidative phosphorylation, tricarboxylic acid cycle, and browning pathways for iWAT.CONCLUSIONB1R deficiency induced metabolic and gene expression alterations in adipose tissue, activating thermogenic pathways and increasing energy metabolism. B1R antagonists emerge as promising therapeutic targets for regulating obesity and associated metabolic disorders, such as inflammation and diabetes.

31 Dec 2023·Bioengineered

A data-driven machine learning approach for discovering potent LasR inhibitors

Article

Author: Wezen, Xavier Chee ; Theng, Lau Bee ; Palombo, Enzo A ; Koh, Christabel Ming Ming ; Xuan, Christopher Ha Heng ; San, Hwang Siaw ; Ping, Lilian Siaw Yung

The rampant spread of multidrug-resistant Pseudomonas aeruginosa strains severely threatens global health. This severity is compounded against the backdrop of a stagnating antibiotics development pipeline. Moreover, with many promising therapeutics falling short of expectations in clinical trials, targeting the las quorum sensing (QS) system remains an attractive therapeutic strategy to combat P. aeruginosa infection. Thus, our primary goal was to develop a drug prediction algorithm using machine learning to identify potent LasR inhibitors. In this work, we demonstrated using a Multilayer Perceptron (MLP) algorithm boosted with AdaBoostM1 to discriminate between active and inactive LasR inhibitors. The optimal model performance was evaluated using 5-fold cross-validation and test sets. Our best model achieved a 90.7% accuracy in distinguishing active from inactive LasR inhibitors, an area under the Receiver Operating Characteristic Curve value of 0.95, and a Matthews correlation coefficient value of 0.81 when evaluated using test sets. Subsequently, we deployed the model against the Enamine database. The top-ranked compounds were further evaluated for their target engagement activity using molecular docking studies, Molecular Dynamics simulations, MM-GBSA analysis, and Free Energy Landscape analysis. Our data indicate that several of our chosen top hits showed better ligand-binding affinities than naringenin, a competitive LasR inhibitor. Among the six top hits, five of these compounds were predicted to be LasR inhibitors that could be used to treat P. aeruginosa-associated infections. To our knowledge, this study provides the first assessment of using an MLP-based QSAR model for discovering potent LasR inhibitors to attenuate P. aeruginosa infections.

01 Dec 2023·Biochemical Pharmacology

Discovery of novel organoarsenicals as robust thioredoxin reductase inhibitors for oxidative stress mediated cancer therapy

Article

Author: Liu, Tingting ; She, Wenyan ; Liu, Yujiao ; Liu, Yi ; Shi, Xuemin

Targeting overexpressed thioredoxin reductase (TrxR) in cancer cells to induce oxidative stress has been proved to be an effective strategy for cancer therapy. However, the treatment was hindered by the low efficiency and frequent administration of TrxR inhibitors, and hence more potent TrxR inhibitors were urgently needed. Herein, we designed and synthesized a series of TrxR inhibitors based on arsenicals. Among these, compound 1d inhibited the proliferation of a variety of cancer cells at low micromolar concentrations and exhibited low toxicity to normal cells. Importantly, compound 1d induced the accumulation of reactive oxygen species (ROS) by inhibiting the TrxR activity, further causing the collapse of the redox system, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and DNA damage, followed by oxidative stress-induced cell apoptosis. In vivo data showed that, compared with the clinical TrxR inhibitor auranofin (AUR), compound 1d could more effectively eliminate tumors by 90 % at a dose of 1.5 mg/kg without any obvious side effects. These results indicated that compound 1d was a potent TrxR inhibitor against cancer.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	CA	Alpha-9 Oncology, Inc.Startup	-

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