- by Huang, M., Celniker, A. F., Chitsazi, R., Dyer, D. P., Jansma, A. L., Kufareva, I., Salanga, C. L., Handel, T.The distinct functional roles of chemokines CCL27 and CCL28 in epithelial immunity of skin and mucosal tissues, respectively, are coordinated by their shared receptor, CCR10 and the CCL28-specific receptor, CCR3. In this study, we conducted structure-function studies focused on the N-termini of these two chemokines to identify determinants of receptor activation, internalization and binding specificity. Deletion of two N-terminal residues of CCL27 resulted in a CCR10 antagonist, highlighting the critical roles of these residues in driving receptor pharmacology. Extension with […]
- by Kekic, M., Stepanov, O., Wang, W., Richardson, S., Olabode, D., Traynor, C., Dearden, R., Zhou, D., Tang, W., Gibbs, M., Nowojewski, A.Covariate selection in population pharmacokinetics modelling is essential for understanding interindividual variability in drug response and optimizing dosing. Traditional stepwise covariate modelling is often time-consuming, compared to the new machine learning alternatives. This study investigates the use of Neural Networks with Stochastic Gates for automated covariate selection, aiming to efficiently identify relevant covariates while penalizing excessive covariate inclusion. On various synthetic datasets the approach demonstrated robustness in detecting important covariates, overcoming challenges such as high correlations, low covariate frequencies, high […]
- by Rubilar, J. C., Szenfeld, B., Cubillos, F. A., Klein, A. D.The biological effects of paraquat (PQ), an herbicide linked to Parkinson's disease (PD) risk in humans can be studied in Saccharomyces cerevisiae due to its evolutionary conservation with mammals. To understand how genetic background influences PQ toxicity, we treated four yeast strains (NA, SA, WA, and WE) with PQ and assessed physiological (growth curves), molecular (superoxide and peroxide levels) and cellular consequences (vacuolar disaggregation) on each genetic background. PQ significantly reduced specific growth rates (uMax) in WE and WA, while […]
- by Robertson, M. J., Papasergi-Scott, M. M., Peroto, M. C., Varga, B. R., Majumdar, S., Skiniotis, G.Distinct ligands for the same G-protein coupled receptor (GPCR) activate intracellular signaling partners to varying extents, but the molecular mechanisms driving these differences remains elusive. Hypothesizing that such differences in signaling efficacy may be captured structurally in intermediate states under non-equilibrium conditions, we implemented a time-resolved (TR) cryo-EM approach to visualize the GTP-induced activation of the GI{beta}{gamma} heterotrimer by the -opioid receptor (MOR) bound to three ligands displaying partial, full, or super-agonism on the receptor. We resolved ensembles of conformational […]
- by Socuellamos, P. G., Viedma-Barba, C., de Benito-Bueno, A., Bonache, M. A., Ropero, M., Diez, S., Elizalde, P., Marin-Olivero, I., Redondo-Moya, M., Naranjo, J. R., Gonzalez-Vera, J. A., Orte, A., Perez-Lara, A., Martin-Martinez, M., Valenzuela, C., Gutierrez-Rodriguez, M.The goal of the present study was to discover novel KChIP ligands as research tools for modulating the KV4.3/KChIP channels. By employing a multidisciplinary approach, combining medicinal chemistry and electrophysiology studies, a novel KV4.3/KChIP modulator (IQM-22110) was successfully identified. IQM-22110 has emerged from the combination of our prior knowledge regarding the (phenylacetamido)benzoic acid moiety as an effective scaffold for KChIP3 ligands and a virtual screening of a focused chemical library. Guided by docking studies, which indicated that incorporating an additional […]
- by Tamada, K., Tomisawa, E., Kuwata, S., Miyake, T., Nagayasu, K., Kaneko, S., Shibasaki, K., Shirakawa, H.Microglia are resident immune cells in the brain. Under pathological conditions, activated microglia trigger neurodegeneration by secreting pro-inflammatory molecules such as NO, TNF, IL6 and IL1{beta}. In contrast, microglia also possess a negative feedback mechanism to prevent the excessive inflammation by secreting anti-inflammatory cytokines such as IL10. It is reported that activation of transient receptor potential vanilloid 4 (TRPV4), one of the non-selective cation channels, suppresses the lipopolysaccharide (LPS)-induced microglial activation. However, the effects of TRPV4 activation on the microglial […]
- by Ramirez, M. F., Gour, A., Sniffen, S. E., Watson, E., Sharma, A., Wesson, D. W.Many substances/drugs are administered intranasally (IN). These include opioid overdose reversal drugs, anti-epileptic medications, migraine medications, hormone treatments, and medicines to treat/prevent allergies, colds, and flues including nasally-administered vaccines, corticosteroids, antihistamines, and decongestants. Additionally, IN administration is the preferred route of entry by users of illicit drugs. Despite the widespread use of the IN route of administration, there is no established paradigm to access this route of administration preclinically to yield precise and reliable control over delivery. This poses major […]
- by Chong, D. J. W., Albulescu, L.-O., Westhorpe, A. R., Clare, R. H., Marriott, A. E., Woodley, C. M., Gunasekar, R., Mosallam, N., Crittenden, E., Stars, E., Dawson, C. A., Kool, J., Wilkinson, M. C., Leung, S. C., Berry, N. G., Casewell, N. R., O.Neill, P. M.Snakebite envenoming is a neglected tropical disease that causes high mortality and morbidity. The current treatment, intravenous antivenom, comes with numerous disadvantages making new therapeutics important. Optimised small molecules offer the possibility for oral use at the onset of envenoming, and the highly pathogenic, zinc-dependent, snake venom metalloproteinase toxin family represents an attractive target for drug discovery. Through systematic chemical modification guided by molecular modelling, we describe the development of hydroxamic acid DC-174, a molecule that displays potent broad spectrum […]
- by Jaskiewicz, J. J., Callahan-Muller, A., Gaby-Biegel, N., Glover, Z., Sandlin, R.Cryoprotective agent (CPA) toxicity is a major limitation in cryobiology. The discovery of new CPAs and formulation of low toxicity CPA cocktails can be streamlined by use of high-throughput screening (HTS) assays. HTS allows for rapid examination of a large chemical space, but assays should be rigorously validated to ensure the production of high-quality datasets. Here, we report the development of a CPA toxicity assay, validation of the assay for HTS using prevailing statistical metrics, and completion of a pilot […]
- by Ricos, M. G., Cole, B. A., Hussain, R., Rychkov, G. G., Shaukat, Z., Pilati, N., Muench, S. P., Simmons, K. J., Dibbens, L. M., Lippiat, J. D.ObjectiveHyperactive KCNT1 potassium channels, caused by gain-of-function mutations, are associated with a range of epilepsy disorders. Patients typically experience drug-resistant seizures and in cases with infantile onset, developmental regression can follow. KCNT1-related disorders include epilepsy of infancy with migrating focal seizures and sleep related hypermotor epilepsy. There are currently no effective treatments for KCNT1-epilepsies, but suppressing over-active channels poses a potential strategy. MethodsUsing KCNT1 channel structural data, we in silico screened a library of known drugs for those predicted to […]
- by Roth, J., Guo, H., Chen, L., Shen, M., Gbadegesin, O., Robey, R. W., Gottesman, M. M., Hall, M. D.AimAntibody-drug conjugates (ADCs) are a form of targeted chemotherapy featuring an antibody recognizing a specific protein on cancer cells joined to a potent toxic payload. Numerous antibody-drug conjugates have received FDA approval; however, clinical resistance arises commonly in tumors. Resistance mechanisms include decreased expression or mutation of the antibody target, failure to release the payload from the ADC, or increased expression of ATP-binding cassette (ABC) efflux transporters associated with multidrug resistance. We therefore sought to characterize the interactions of ABC […]
- by Villarreal, E. S., Marinho, Y., Loya, O., Aboagye, S. Y., Williams, D. L., Sun, J., Erzurum, S., de Jesus Perez, V., Oliveira, S. D.Schistosomiasis-associated Pulmonary Hypertension (Sch-PH) is the most common form of group I PH worldwide. Recently, data revealed that the preclinical animal model of Sch-PH exhibited gut and lung microbiome dysbiosis linked to significant endothelial dysfunction and microvascular apoptosis, but the role of pro/anti-apoptosis sensors, such as the inhibitor of apoptosis protein 2 (c-IAP2) and purinergic receptor P2X7 (P2X7R), remained unclear. Using a novel Cdh5cre-ERT2;cIAP1-/-;cIAP2fl/fl animal model, this study investigated the contribution of endothelial c-IAP2 in this process, revealing P2X7R overexpression […]
- by Lopez Rodriguez, D., Pamies, D., Boccard, J., Meister, I., Galmiche, M., Sajic, T., Maret, E., Heritier, N., Frangiamone, M., Thomas, A., Hopf, N., Rudaz, S., Zurich, M.-G.Exposure to solvents may contribute to the development of neurodevelopmental and neurodegenerative diseases. Glycol ethers consist in a widely used class of organic solvents leading to workers and consumers exposure via many different applications. Ethylene glycol ethers are gradually being replaced by propylene glycol ethers thought to be less toxic. However, their neurotoxicity is not systematically assessed prior to placing them on the market. Therefore, this study investigated the potential neurotoxicity of propylene glycol butyl ether (PGBE) for which no […]
- by Cassell, S. J., Li, W., Krautwald, S., Khoshouei, M., Lee, Y. T., Hou, J., Guan, W., Peukert, S., Weihofen, W., Whicher, J.Small-conductance calcium-activated potassium channel 2 (SK2) serves a variety of biological functions by coupling intracellular calcium dynamics with membrane potential. SK2 modulators are in development for the treatment of neurological and cardiovascular diseases, though the mechanisms of pharmacological modulation remain incompletely understood. We determined structures of an SK2-4 chimeric channel in Ca2+-bound and Ca2+-free conformations and in complex with the bee toxin apamin, a small molecule inhibitor, and a small molecule activator. The structures revealed that the S3-S4 linker forms […]
- by Shafi, S., Maurya, P., Bansal, R., Sharma, J., Mishra, S. K., Najmi, A. K., Singh, S.The emergence of resistance to first-line antimalarial therapies highlights the critical need for next-generation drugs that target distinct molecular pathways and employ novel mechanisms of action. Notably, the intra-erythrocytic parasite development is highly dependent on a sustained glucose supply as their fundamental energy source. Therefore, exploiting a "selective starvation" strategy, by targeting the parasites reliance on glucose metabolism, particularly through the Plasmodium falciparum hexose transporter (PfHT1), which is critical for parasite survival can serve as a promising therapeutic approach to […]
- by Bhuiyan, P., Yi, Y., Wei, B., Yan, A., Dong, L., Wei, H.Calcium dysregulation, caused by pathological activation of ryanodine receptors, contributes to motor neuron degeneration, motor dysfunction, and muscle weakness in SOD1-G93A transgenic amyotrophic lateral sclerosis (ALS) mice. This study investigates the therapeutic efficacy of intranasally administered dantrolene nanoparticles, a ryanodine receptor antagonist, on motor neuron function, muscle strength, spinal cord degeneration, and survival outcomes. Male and female C57BL/6SJLF1 non-transgenic control and SOD1-G93A ALS transgenic mice were assigned to one of three experimental groups: 1) NO TX: No treatment control; 2) […]
- by Ayad, N. G., Jangde, N., Lee, M. H., Ruiz, L., Egan, I., Jermakowicz, A., Wynn, D., Goka, E., Lippman, M., Robbins, D. J.Medulloblastoma (MB) is the most common malignant primary pediatric brain tumor. Current therapies are ineffective for targeting proliferation, leptomeningeal migration, and metastasis of MB cancer cells to visceral organs and therefore, novel treatments are needed. The small GTPase, RAC1, has emerged as an important regulator of actin cytoskeletal dynamics, proliferation, and migration in several cancers. However, it has not been characterized in MB and no clinical drug candidates have been described for RAC1 in MB. Here we demonstrate that RAC1 […]
- by Kumar, A. H., Sagar, V., BM, R.BackgroundLumpy Skin Disease (LSD) lacks targeted treatment options and is managed using antibiotics and anti-inflammatory drugs. This study evaluated the efficacy of a polyherbal combination therapy in the management of LSD in affected bovines. Materials and Methods52 dairy cattle clinically diagnosed with LSD were enrolled in a field trial conducted under veterinary supervision. All animals received LUMPY-NIL Herbal Powder orally at 30 g twice daily, along with topical application of LUMPY-NIL Dermal Spray on closed nodules and LUMPY-NIL Ointment on […]
- by Khajuria, P., Kour, D., Sharma, K., Singh, L., Banoo, R., Manhas, D., P, R., Nandi, U., Bharate, S., Ahmed, Z., Kumar, A.AD pathology is accompanied by increased senescence and reduced levels of autophagy in the brain. We investigated whether pharmacologically inducing autophagy could alter the senescent phenotype and help ameliorate AD pathology. We discovered that Bisdemethoxycurcumin (BDMC), a natural compound found in Curcuma longa, stimulates autophagy in primary astrocytes. We found that autophagy and senescence exhibit an inverse relationship in aging astrocytes, with increased expression of senescent proteins and downregulation of autophagic proteins. However, treatment of aged astrocytes with BDMC reversed […]
- by Zhang, Z., Wen, W., Lin, H., Hu, D., Li, H., Luo, J.Prenatal alcohol exposure (PAE) can lead to fetal alcohol spectrum disorder (FASD), a condition marked by developmental brain defects that result in neurobehavioral and cognitive impairments. However, the underlying molecular mechanisms remain poorly understood. Brain development is a highly regulated process, with neurogenesis playing a crucial role. A key stage in this process is neural differentiation, which is essential for proper brain function. This study aims to investigate how alcohol disrupts neural differentiation. NE-4C cells, a neural stem cell line […]
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