- by Nakashima, M., Miyano, M., Kuroyanagi, H., Sasahara, A., Ikegaya, Y., Matsumoto, N.The hippocampus is essential for memory consolidation, a process mediated by high-frequency oscillations known as ripples during non-rapid eye movement (NREM) sleep. Ramelteon, a selective MT1/MT2 receptor agonist, has been reported to possess cognitive-enhancing properties; however, its impact on the fine-scale dynamics of hippocampal ripples remains unclear. We performed chronic local field potential recordings from the dorsal hippocampus and prefrontal cortex in mice. Following the intraperitoneal administration of either vehicle or ramelteon, we evaluated sleep architecture and characterized ripple properties, […]
- by PAN, J., ZHANG, Y., YANG, A., JIANG, L., SHEN, Y., SUN, Y., ZHU, J., FAN, M., SHI, J.Background: Per- and polyfluoroalkyl substances (PFAS), particularly perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), are persistent organic pollutants ubiquitous in the environment. Epidemiological evidence has closely linked them to an elevated risk of prostate cancer (PCa). However, the precise molecular mechanisms by which combined PFOS/PFOA exposure promotes prostate cancer and their dynamic effects on the tumor microenvironment remain unclear. Methods: This study constructed a multi-module analytical framework integrating network pharmacology and computational biology: (1) Through ADMET toxicity prediction, multi-database target […]
- by Zhou, S., Ji, X., Li, H., Lanza, D. G., Jung, S. Y., Liu, J., Dogra, A., Nabet, B., MacKenzie, K. R., Wang, J., Matzuk, M. M., Li, F.Drug-metabolizing enzymes determine therapeutic exposure, efficacy and toxicity, but defining their isoform-specific functions in vivo remains challenging. Cytochrome P450 enzymes (P450s) are central to drug metabolism and pharmacokinetics (DMPK) and mediate the phase I metabolism of [~]75% of all marketed drugs. However, conventional knockout models can induce developmental and compensatory adaptations, and selective inhibitors are unavailable for many P450 isoforms. Here, we report the use of an inducible chemical-genetic platform for acute and specific degradation of the endogenous P450 enzyme […]
- by Asby, S., Wen, X., Goedken, M., Ames, B., Shams, S., Thompson, L., Lanis, J., Kostka-Newman, Z., Larsen, K., Tilden, S., Lang, J., Aleksunes, L., Joy, M.Introduction. Immune checkpoint inhibitors (ICIs) enhance antitumor responses by blocking inhibitory receptors, including PD-1 and CTLA-4. Overactivation can trigger systemic toxicity akin to autoimmune diseases, including kidney manifestations. We sought to 1) profile immune signaling and 2) interrogate potential mechanisms of ICI-related kidney injury in a Human Immune System (HIS) tumor-bearing mouse model treated with nivolumab and ipilimumab. Methods. Immunodeficient BRGS (BALB/c-Rag2nullIl2r{gamma}nullSirpNOD) neonates were engrafted with human CD34+ cells to generate HIS-BRGS mice. Human MDA-MB-231 tumor cells were implanted subcutaneously; […]
- by Frick, A., Whyte-Fagundes, P. C., Baraban, S. C.Syntaxin-binding protein 1 (STXBP1) mutations lead to severe epilepsy, intellectual disability, developmental delay, and movement disorder. Effective treatments for these conditions do not exist. Recent studies in Munc18-1 (STXBP1) C.elegans models demonstrate that 4-phenylbutyrate (4-PBA) or related pharmacological chaperones stabilize Munc18-1 protein levels and rescue locomotion deficits. These studies suggest a novel treatment strategy for these patients. Here,we used a stxbp1a zebrafish model with a profound movement disorder to screen 4-PBA and alternative structural analogs identified using artificial intelligence (AI)-based […]
- by Startek, J. B., Milici, A., Held, K., Talavera, A., Talavera, K.TRPA1 is a non-selective cation channel that plays a crucial role in several pain and inflammatory conditions. Agents reducing membrane cholesterol decrease TRPA1 activation, but it remains unclear how cholesterol-lowering medications affect TRPA1 function. Given that TRPA1 is activated by a wide variety of chemicals, we explored whether statins have acute effects on this channel. We found that five commonly used statins activate human and mouse TRPA1 in a reversible and concentration-dependent manner. The effective concentrations were above the micromolar […]
- by Shinohara, R. C., Ishikawa, S., Matsumoto, R., Ito, K., Tonosaki, M., Matsuyama, S., Ohgidani, M., Koga, M., Hashimoto, N., Kusumi, I., Takahiro, K. A.While inflammation has been generally considered to exacerbate symptoms of schizophrenia, some clinical observations suggest that acute inflammation may alleviate positive symptoms. However, animal models often use excessive inflammatory stimuli, and the effects of acute inflammation – comparable to levels observed in patients – remain unknown. To address this, we examined whether acute inflammation induced under relatively mild, clinically relevant conditions suppresses behavioural sensitization in methamphetamine (METH)-sensitized mice, a model of psychostimulant-induced psychosis with relevance to certain aspects of positive […]
- by Kaoullas, M. G., Mobbs, J. I., Vuckovic, Z., Belousoff, M. J., Xiao, F., Joshi, K., Wang, J., Barnes, N., Pham, V., Yeasmin, M., Thompson, G., van der Westhuizen, E. T., Jörg, M., Capuano, B., Tobin, A. B., Wootten, D., Sexton, P. M., Danev, R., Scammells, P. J., Miao, Y., Christopoulos, A., Valant, C., Thal, D. M.Positive allosteric modulators (PAMs) of the M4 muscarinic acetylcholine receptor (mAChR) represent a promising therapeutic strategy for treating cognitive deficits and neuropsychiatric disorders. While first-generation M4 mAChR PAMs, like LY2033298, demonstrated proof-of-concept, second-generation compounds, such as MK-97, exhibit substantially improved potency and reduced species variability. Here we report the cryo-EM structure of the M4 mAChR bound to the endogenous agonist, acetylcholine, and MK-97 at 2.7 [A] resolution, revealing the molecular basis for improved M4 mAChR PAM activity. MK-97 adopts a […]
- by Magesh Raghavan, T. A.Women experience drug-induced Torsades de Pointes (TdP) at approximately twice the rate of men across more than 50 QT-prolonging drug classes, yet the quantitative ionic basis of this sex disparity remains incompletely characterised. The slow delayed rectifier current (IKs) is reduced by ~45% in female compared with male human ventricular cardiomyocytes, reducing the repolarization reserve available to compensate pharmacological IKr block. We implemented the O'Hara-Rudy (ORd) 2011 undiseased human ventricular epicardial action potential model in Python and parameterised sex variants […]
- by Becker, J., Pantzke, J., Offer, S., Das, A., Mudan, A., Neukirchen, C., Streibel, T., Adam, T., Sklorz, M., Di Bucchianico, S., Zimmermann, R.Railway catenary sparking generates airborne ultrafine particles (UFPs) that may pose health risks due to their metallic composition and ability to penetrate deep into the alveolar region of the lungs. Copper, widely used in wires and pantographs, is a major component of these emissions, making copper rich particles common in railway environments such as subways. However, exposure levels and health impacts remain poorly characterized, and localized hotspots may represent an underrecognized risk in densely populated areas. This study investigated the […]
- by Taffe, M. A., Mehl, S. L., Grant, Y., Vandewater, S. A.BackgroundEvidence suggests steeper accelerating opioid-related overdose, and non-medical use rates, in middle aged men in recent years compared with younger cohorts. Little is known about whether this is driven by age-related differences in the effects of opioids compared with socio-cultural factors driving non-medical consumption. Rodent models can be useful for dissociating biological from psychosocial factors, however, only minimal evidence exists on the effects of opioids in middle-age rats. ObjectiveTo determine if the anti-nociceptive and rewarding effects of opioids differ between […]
- by Ishikawa, T., Clark, C. W., Tapaswi, A., Sala-Hamrick, K. E., Herron, T. J., Jimenez-Vazquez, E. N., Jain, A., Jones, D. K., Colacino, J., Monteiro Da Rocha, A., Svoboda, L. K.The early developmental environment plays a critical role in the etiology of cardiovascular diseases (CVDs), but underlying molecular mechanisms are poorly understood. Exposure to per and polyfluoroalkyl substances (PFAS) are linked to various CVDs, but effects of developmental PFAS exposures on the human heart remain unclear. Using human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), the objective of this study was to investigate the effects of PFAS exposure during cardiac differentiation on gene expression and function of cardiomyocytes. We exposed two hiPSC […]
- by besbassi, h.Cytokine release syndrome (CRS) is a major dose-limiting toxicity of T cell-engaging immunotherapies. Existing CRS models are drug-class-specific and have not addressed whether a single mechanistic cytokine network can capture severity differences across mechanistically distinct drug classes. Here, we developed a PK-driven quantitative systems pharmacology (QSP) model linking drug exposure, T cell activation dynamics, and a macrophage-amplified cytokine network to clinical CRS severity. The 17-parameter downstream amplification network with macrophage-gated STAT3 positive feedback was developed iteratively. The network was calibrated […]
- by Ragazzi, E., Zagotto, G., Sartore, G.BackgroundEpidemiological studies consistently report inverse associations between caffeinated coffee consumption and dementia risk. However, the molecular mechanisms linking coffee-derived phytochemicals to neuroprotection remain only partially understood. ObjectiveTo evaluate, through integrated in silico pharmacology, the relative contribution of adenosine receptor modulation versus direct amyloidogenic enzyme and kinase inhibition in mediating the putative neuroprotective effects of major coffee constituents. MethodsMolecular docking analyses were conducted for caffeine, paraxanthine, chlorogenic acid, trigonelline, cafestol, and kahweol against adenosine A2A and A1 receptors (A2AR, A1R), {beta}-secretase […]
- by Gevertz, J. L., Kareva, I.The challenge of stratifying patients for combination therapy is both technically demanding and clinically crucial. In previous work, we introduced a multi-objective optimization framework for identifying optimally synergistic combination protocols that are robust to competing definitions of additivity. This manuscript extends this methodology to quantify how inter-individual variability in drug sensitivity influences the combination doses that optimally balance the competing objectives of synergy of efficacy and synergy of potency (a proxy measure of toxicity). For this methodology, we introduce a […]
- by Mochalova, E. N., Yurchenko, M. A., Timofeeva, M. P., Maedi, D. A., Nikitin, P. I., Nikitin, M. P.While engineered nanomaterials offer unprecedented precision in targeting tumor cells, their efficacy is often limited by rapid clearance from the bloodstream via the mononuclear phagocyte system (MPS). To overcome this limitation, a promising strategy known as MPS-cytoblockade has been developed. This approach involves administering antibodies against host erythrocytes. The resulting saturation of the MPS with erythrocyte clearance creates a critical window, allowing subsequently administered nanoparticles to evade immune surveillance and circulate for a significantly extended period. However, MPS-cytoblockade induces a […]
- by Hung, A., Wang, X., Gao, M., Ng, M., Oliinyk, D., Weaver, R., Zollbrecht, E., Cardoso, S., Ronel, G. S., Paolucci, C., Ye, J., Fan, Q. R., Rhea, E., Mann, M., Baker, D., Accili, D., Choi, E.Computational protein engineering provides a powerful approach to address longstanding clinical challenges. Severe insulin resistance syndromes caused by mutations in the insulin receptor (IR) are life-threatening disorders for which effective long-term therapies remain lacking. Here, we define the in vivo activity and therapeutic potential of RF-409, a de novo-designed IR agonist that activates the receptor through a mechanism distinct from insulin. RF-409 exhibits markedly prolonged circulation compared to insulin and produces sustained improvements in glucose homeostasis without detectable adverse effects […]
- by Huo, S., Ma, M., Qian, S., Zhang, M., Pu, J., Zhu, X., Rasam, S., Barone, T., Plunkett, R., Zhou, C., Qu, J.Whole-tissue spatial proteomics level provides critical insights into region-specific biological regulations but remains challenging. Previously, we introduced the Micro-scaffold Assisted Spatial Proteomics (MASP) concept for whole-tissue mapping. However, this prototype required substantial development in spatial resolution, practicality, and throughput for practical application. Here we present a next-generation MASP technique (hex-MASP) featuring i) a new design of hexagonal-micro-wells fabricated with optimized Projection Micro-Stereolithography (P{micro}SL) 3D-printing, achieving high spatial resolution, sampling robustness and mechanical strength for reproducibly compartmentalizing even tough tissues; ii) […]
- by Zsido, B., Mernyak, E., Földes, F., Kopasz, Z., Leiner, K., Madai, M., Zana, B., Kuczmog, A., Hetenyi, C.The rise of new, rapidly mutating viruses presents increasing challenges for drug developers. Traditional methods, such as high-throughput screening and drug repurposing against mutagenic viral targets, have recently shown their limitations. Our current rational molecular engineering approach offers a sustainable solution by targeting viral ion channels, which generally have low mutation rates. First, extending the amantadine molecule led to the development of new compounds that better match the alternating hydrophobic and hydrophilic patterns of the inner walls of ion channels–a […]
- by Huang, Y., Fu, F., Deng, L., Wang, Y., Li, J., Zhang, J., Yang, J., Long, Y., Wang, M., Han, C., Deng, L., Li, P., Chen, H., Dong, J., Fu, X., Xia, Q., Du, D.Lethal sterile inflammatory diseases are linked to amino acid metabolism, but the role of serine remains unclear. Here, we show that dysregulated serine metabolism and reduced plasma serine levels correlate with disease severity of acute pancreatitis (AP) in patients and mouse models. Elevating serine levels via exogenous serine supplementation or pancreatic phosphoglycerate dehydrogenase (PHGDH) overexpression mitigates pancreatic injury, whereas a serine deprivation diet or pancreatic PHGDH knockdown exacerbates AP. Serine prevents cell death and oxidative stress in pancreatic acinar cells, […]
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