- PRLX-93936 and BMS-214662 are cytotoxic molecular glues that leverage TRIM21 to degrade nucleoporinsby Scemama de Gialluly, M. A., Allen, A. R., Hayes, E. H., Zhuang, P., Goldfarb, R. B., Farrar, A. N., Fedorov, Y., Adams, D. J.Although molecular glues have emerged as innovative tools within the field of chemically induced proximity, approaches for their discovery remain limited. Here we report a phenotypic screening approach in which small molecules whose cytotoxic mechanisms require ubiquitination show gain of viability following pharmacological inhibition of the E1 enzyme UAE. This approach revealed two previously clinically-evaluated cytotoxins of unknown mechanism, PRLX-93936 and BMS-214662, as molecular glues that directly target the E3 ubiquitin ligase TRIM21. These molecules induce TRIM21-mediated proteasomal degradation of […]
- by Meira de Amorim, V. C., Lofrano, A., Szepanowski, L.-P., Loerch, C. C., Wruck, W., Graffmann, N., Adjaye, J.Benzo[a]pyrene diol epoxide (BPDE) is a metabolite of the environmental contaminant Benzo[a]pyrene- a byproduct of incomplete combustion of organic matter. BPDE reacts with DNA to form BPDE-DNA bulky adducts which if not removed can lead to mutations due to DNA base-pair substitutions. While the effects of BPDE on somatic cells are fairly well described, its effects on early human development are currently unknown. In this study, we investigated for the first time the effect of BPDE on human induced pluripotent […]
- by Posa, L., Romano, G., Ji, X., Khan, S., Paz, B., Han, G. W., Nazarova, A. L., Zaidi, S. A., Ranjbar, M., Pleil, K. E., Katritch, V., Gati, C., Trauner, D., Levitz, J.The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a […]
- by Senarath Pathirajage, K., Serradimigni, R., Sharma, S., Dasgupta, S.Tetrabromobisphenol A (TBBPA), a widely used flame retardant in commercial products such as synthetic textiles, plastics, and electronics poses potential toxicity risks through indoor exposure. This study aims to leverage zebrafish as a model to study TBBPA impacts on zebrafish dorsoventral patterning, a process that lays the foundation of an embryo's axial determination and localization of specific tissues and organs. Zebrafish embryos were exposed to varying concentrations of TBBPA ( 0 to 10 microM) at either 0.75 or 6 hours […]
- by Hasse, T. A., Zhang, Z., Huang, Y.-m.The interaction between meiosis-expressed gene 1 (MEIG1) and Parkin co-regulated gene (PACRG) is a critical determinant of spermiogenesis, the process by which round spermatids mature into functional spermatozoa. Disruption of the MEIG1-PACRG complex can impair sperm development, highlighting its potential as a therapeutic target for addressing male infertility or for the development of non-hormonal contraceptive methods. This study used virtual screening, molecular docking, and molecular dynamics (MD) simulations to identify small molecule inhibitors targeting the MEIG1-PACRG interface. MD simulations provided […]
- by Eya'ane Meva, F., Nguadie Mponge, P., Koube, J., Fonye Nyuyfoni, G., Hzounda Fokou, J. B., Ntoumba, A. A., Beglau, T. H. Y., Tako Djimefo, A. K., Djuidje, A. G., Chimi Tchatchouang, G., Wounang, A. L., Evouna, M. I. D., Chameni Nkouankam, M. J., Dada Youte, Y. P., Moussa Ndotti, H., Belle Ebanda Kedi, P., Enone Bertin, S., Janiak, C.IntroductionPlants are a source of bioactive ingredient that can play a key role in development of new drugs. In recent years, plant mediated-biological synthesis of nanoparticles has gained importance due to its simplicity, cost effectiveness and eco-friendly nature. To the best of our readings, nanoparticule from Cylicodiscus gabunensis stem bark is still untaped. This work therefore aimed at assessing the anti-inflammatory properties of the silver nanoparticles obtained from the aqueous extract of the stem bark of Cylicodiscus gabunensis(Cg). MethodologyCylicodiscus gabunensis […]
- by Beal, J. R., Bhurke, A., Carlson, K. E., Katzenellenbogen, J., Yu, J., Flaws, J., Bagchi, I. C., Bagchi, M. K.Di(2-ethylhexyl) phthalate (DEHP), a known endocrine-disrupting chemical, is a plasticizer found in many common consumer products. High levels of DEHP exposure have been linked to adverse pregnancy outcomes, yet little is known about how it affects human uterine functions. We previously reported that the estrogen-regulated transcription factor hypoxia-inducible factor 2 alpha (HIF2) promotes the expression of Rab27b, which controls the trafficking and secretion of extracellular vesicles (EVs). EVs facilitate communication between multiple cell types within the pregnant uterus, ensuring reproductive […]
- by Moreno-Rodriguez, M., Bengoetxea de Tena, I., Martinez-Gardeazabal, J., Pereira-Castelo, G., Llorente-Ovejero, A., Manuel, I., Rodriguez-Puertas, R.The endocannabinoid system is involved in diverse processes, like learning and memory, governed by cholinergic neurotransmission. Recent research demonstrates that in a model of dementia derived from basal forebrain cholinergic degeneration, WIN55,212-2 improves cognition through increased cortical choline levels. However, the effect of cannabinoids on cholinergic deficits is still under investigation. In this work, we studied the effect of this treatment in a pharmacological model of transient cholinergic hypofunction by the acute administration of the muscarinic antagonist, scopolamine, in spatial, […]
- by Elsila, L. V., Nagaeva, E., Luukkonen, J.-P., Korpi, E. R.The current research on psychedelic compounds such as lysergic amide diethylamide (LSD) is leaning heavily on the notion that psychedelics are not addictive. While much of the literature supports this argument, some of the common use patterns and the descriptions of the subjective effects of these compounds in humans, together with rather lacking and mixed data from non-human animal studies leave room for questions of potentially rewarding or reinforcing stimulus effects. Initiated by a surprising finding in a control study, […]
- by Eya'ane Meva, F., Nga Essama, D. M., Nguemfo, E. L., Bamal, H.-D., Ntoumba, A. A., Belle Ebanda Kedi, P., Beglau, T. H. Y., Tako Djimefo, A. K., Djuidje, A. G., Chimi Tchatchouang, G., Nanga, C. C., Fonye Nyuyfoni, G., Tchangou Njimou, A. F., Evouna, M. I. D., Mintang Fongang, A. U., Janiak, C.IntroductionZinc oxide nanoparticles (ZnONPs) have been synthesized using a wide range of techniques, including green chemistry, because of their versatility, cost effectiveness, and environmentally friendly nature, offering thereby interesting and inexpensive therapeutic options. This study aimed to develop zinc oxide nanoparticles as an anti-inflammatory agent using Aframomum citratum seed extract. MethodologyZnONPs were prepared by the reaction between zinc nitrate and an alkalineaqueous extract of A. citratum seeds. The isolated nanoparticles were then characterized using UV-Vis, FTIR, SEM/EDX, PXRD and TEM […]
- by White, A. C., Krout, I. N., Mouhi, S., Chang, J., Kelly, S. D., Caudle, W. M., Sampson, T.Enteroendocrine cells (EECs) are a rare cell type of the intestinal epithelium. Various subtypes of EECs produce distinct repertoires of monoamines and neuropeptides which modulate intestinal motility and other physiologies. EECs also possess neuron-like properties, suggesting a potential vulnerability to ingested environmental neurotoxicants. One such group of toxicants are pyrethroids, a class of prevalent insecticides used residentially and agriculturally. Pyrethroids agonize voltage-gated sodium channels (VGSCs), inducing neuronal excitotoxicity, and affect the function of monoamine-producing neurons. Given their anatomical location at […]
- by Sanders, M., Shinde, A., Kim, S. W., Quach, E., Beringer, P.BackgroundMycobacterium abscessus complex (MABSC) is an emerging opportunistic pathogen that causes chronic, difficult-to-treat pulmonary infections, particularly in people with cystic fibrosis (PwCF), leading to rapid lung function decline, morbidity, and mortality. Effective treatment is particularly challenging due to the pathogens resistance mechanisms and the need for prolonged multidrug therapy, which is often hindered by poor clinical outcomes, highlighting the urgent need for novel therapeutic strategies. Imipenem/cilastatin/relebactam (IMI/REL), a novel {beta}-lactam-{beta}-lactamase inhibitor combination, demonstrates in vitro activity against resistant MABSC strains […]
- by Park, W. S., Zhuang, W., Park, M., Jeong, J., Kim, H. R., Jang, Y., Seo, M. S., An, J. R., Park, H., Jung, W.-K., Choi, I.-W.OBJECTIVETofogliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor widely used to treat T2DM, but it also exhibits cardio-protective effects. This study investigated the vasodilatory action of tofogliflozin using rabbit femoral artery rings pre-contracted with phenylephrine. APPROACH AND RESULTSThe femoral artery quickly separated from the rabbit and fix it to the organ bath chamber. Subsequently, administer an inhibitor that modulates vascular tension in the rings or remove the endothelium to assess its impact on vasodilation. The results showed the concentration-dependent induction […]
- by Venka, K., Chaturvedi, S.Free fatty acid receptor 1 (FFA1 or GPR40), activated by medium- and long-chain fatty acids, amplifies glucose-stimulated insulin secretion, making it a promising target for type 2 diabetes. Radioligand studies revealed distinct binding sites for partial and full agonists, with full agonists showing positive cooperativity. Functional assays demonstrated positive cooperativity between agonists and varying interactions with the endogenous fatty acid DHA. These findings suggest three allosterically linked binding sites on FFA1, with activation influenced by key arginine residues. Potent ligands […]
- by Zhang, S., Wang, Z., Jiao, Y., Shi, X., Ai, Y., Wang, J., Liu, S.Upregulation of protein SUMOylation is associated with various diseases, and SUMOylation inhibitors are promising drug candidates. We performed the first virtual screening of SUMO E1 covalent allosteric inhibitors (CAIs) and identified two SUMO E1 CAIs with new scaffolds and covalent warheads. We further demonstrated that these new CAIs perturbed the SUMOylation pathway and protein SUMOylation. Specifically, these CAIs affected the SUMOylation of the methionine adenosyltransferases MAT2A. The inhibition of MAT2A SUMOylation unexpectedly stimulated polyamine synthesis. Lastly, we showed that the […]
- by Sankar, S., Sahoo, A. K., Baskaran, S. P., Babu, R., Srivastava, S., Samal, A.Cyclotides are naturally occurring peptides characterized by a cyclic cystine knot, which provides them with exceptional structural stability. In addition to their stability, cyclotides exhibit diverse therapeutic activities including antimicrobial, antiviral and antitumor activities, making them promising candidates in drug discovery. However, computational studies aimed at identifying cyclotide-based inhibitors for infectious diseases remain limited. To this end, we conducted a virtual screening of cyclotides from an Indian medicinal plant Viola odorata to identify potential inhibitors against a bacterial pathogen causing […]
- by ARNAUD, D., LAMBERT, V., BENOIST, D., MARTIN, A., GAUTHIER, J., PUCEAT, m.Fibrosis is part of a clinical burden in cardiovascular diseases. The pathological process has been the subject of intensive research with still mitigated therapeutic options. Recently chromatin modifiers have turned out to be potential drugs to modulate fibrosis. Here, in order to address the question of pharmacological inhibition of fibrosis, we used both a mouse model of myocardial infarction with left ventricular fibrosis and a more clinically relevant pig model of right ventricular failure featuring interstitial fibrosis. Treatment of these […]
- by Zhao, L., Shi, M., Winuthayanon, S., MacLean, J. A., Hayashi, K.BackgroundExposure to endocrine-disrupting chemicals (EDCs), such as bisphenol A (BPA), disrupts reproduction across generations. Germ cell epigenetic alterations are proposed to bridge transgenerational reproductive defects resulting from EDCs. Previously, we have shown that prenatal exposure to environmentally relevant doses of BPA or its substitute, BPS, caused transgenerationally maintained reproductive impairments associated with neonatal spermatogonial epigenetic changes in male mice. While epigenetic alterations in germ cells can lead to transgenerational phenotypic variations, the mechanisms sustaining these changes across generations remain unclear. […]
- by Wang, C., Huang, H., Song, Z., Li, Z., Huang, J., Cao, L., Wu, Z., Pan, J., Shen, X.Both preclinical and clinical studies have shown that combining anti-VEGF/VEGFR drugs with immune checkpoint inhibitors (ICIs) significantly enhances anticancer efficacy. Currently, PDL-1/ VEGF bispecific antibodies demonstrate superior antitumor activity compared to monotherapy or even the combination of PD-L1 inhibitors with anti-VEGF antibodies. This enhanced efficacy results from the simultaneous blockade of the PD-1/PD-L1 pathway and the inhibition of VEGF-driven angiogenesis. In this study, we developed a novel bispecific antibody, CVL006, by fusing an anti-PDL1 VHH domain with a humanized IgG1 […]
- by Endzhievskaya, S., Chahal, K., Resnick, J. A., Khare, E., Roy, S., Handel, T. M., Kufareva, I.The constitutive (ligand-independent) signaling of G protein-coupled receptors (GPCRs) is being increasingly appreciated as an integral aspect of their function; however, it can be technically hard to detect for poorly characterized, e.g. orphan, receptors of the cAMP-inhibitory Gi-coupled (GiPCR) family. In this study, we delineate the optimal strategies for the detection of such activity across several GiPCRs in two cell lines. As our study examples, we chose two canonical GiPCRs – the constitutively active Smoothened and the ligand-activated CXCR4,-and one […]
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