Series Of Complexes Research Articles

Abstract A008: Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer

Abstract Metastatic disease represents a complex series of interaction between tumors and their surrounding microenvironment. Here we utilize model systems to define organ specific transcriptional signatures present in metastatic seeding. We have identified unique epigenetic programing necessary for the colonization of the liver or the lung by colorectal cancer. We have shown that manipulation of master regulators of these signatures in vitro and in vivo changes the metastatic potential of the tumor. In specific, we have found that native cytokines within the liver and lung are engaged by the metastatic tumor cells to promote this reprograming. In the case of the liver, we have identified hepatocyte released CCL2 acts on metastasizing tumors to promote colonization. Through in vitro and in vivo models, we showed that CCL2 engagement drives upregulation of the transcription factor TCF7 and subsequent enhancer reprograming to promote survival of the metastatic cells in the liver. In the lung, we have identified additional, unique secreted cytokines which lead to the upregulation of other TCF family members. Together this data identifies an important signaling nodes in colorectal cancer. Here we propose a model in which secreted factors by the host organ, such as CCL2, reprogram genes within the tumor cell to promote growth and survival of the metastatic cell in foreign microenvironments such as the lung or liver. Targeting these proteins may kill existing metastatic lesions as well as block new metastases from forming which will be essential in improving the outcomes of patients with oligometastatic and premetastatic disease. Citation Format: Charlie Niesen, Nathan Wu, Jonathan Rennhack. Microenvironmentally released cytokines mediate organ specific transcriptional profiles for metastatic colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A008.

Comparative Analysis of Tetravalent Actinide Schiff Base Complexes: Influence of Donor and Ligand Backbone on Molecular Geometry and Metal Binding.

A series of isostructural early actinide AnIV complexes was synthesized in order to investigate the influence of a conjugated framework in the ligand backbone on An bonding. Therefore, the AnIV complexes [An(pyrophen)2] (An = Th, U, Np, and Pu) with the pure N-donor ligand bis(2-pyrrolecarbonylaldehyde)-o-phenylenediamine referred to as pyrophen, were synthesized and characterized. Solid state analysis via single-crystal X-ray diffraction (SC-XRD) reveals two sets of ligands binding in an almost orthogonal arrangement to the actinide center. For the larger actinides Th and U, the coordination sphere allows for additional coordination by a solvent molecule. Nuclear magnetic resonance spectroscopy (NMR) studies show the presence of highly symmetrical complexes in solution in good agreement with the solvent-free solid structures. While SC-XRD suggests mainly ionic binding, an analysis of paramagnetic NMR contributions and quantum chemical bond analysis hint towards significant covalency in the U, Np, and Pu compounds. This series of An complexes allowed for a thorough structural and theoretical comparison of a conjugated system to a closely related N-donor ligand (pyren)[1] as well as to the mixed N,O Schiff base ligands salophen (conjugated) and salen (non-conjugated).

Heavy Pentaisopropylcyclopentadienyltriylenes and their Heterobimetallic Complexes.

A series of triylenes of the heavy group 13 elements gallium, indium and thallium, carrying the pentaisopropylcyclopentadienyl ligand is reported. The compounds were characterized in solution and in the solid-state and their donor ligand properties in heterobimetallic complexes were investigated, whereby a series of tungsten carbonyl complexes was isolated. Furthermore, a new synthetic route towards a previously described lithium-aluminum heterobimetallic dimetallocene is reported, which also enabled the isolation of a heterobimetallic polydecker of lithium and gallium.

Photon-Induced Ultrafast Multitemporal Programming of Terahertz Metadevices.

Dynamic terahertz (THz) metasurface can feature modulated and multiplexed electromagnetic functionalities, important for wave-based computation, six-generation communications, and other applications. The versatile dynamic switching typically relies on a series of complex or incompatible multifield activations, with excessive system complexity, additional loss, slow modulation speed, and inertial time-varying properties, limiting more widespread applications. Here, a photon-induced ultrafast programmable THz metadevice is reoprted in time-frequency dimensions with polarization-decoupled temporal responses. By the pixelated design with multi-materials and triggering switches, the multimodal modulation transcends the constraints inherent in materials, enabling the ultrafast programmable temporal evolution. All the resonances can be independently programmed at the working band from 0.6 to 2 THz. The tri-temporal (with switching time of 1.25, 1, and 4.75ps) and bi-temporal (with switching time of 2.25 and 4.75ps) dynamic manipulations are performed by all-optical driven molecularization process of hybrid metasurfaces loaded with silicon (Si)and germanium (Ge) under different polarizations. Combining these features, the temporally programmed THz logic gates are last experimentally demonstrated, possessing basic operation of XNOR, NOR, and OR,as a proof-of-concept application. This reported light-driven programmable THz flat-optics allows ultrafast hybrid molecularization processes and new possibilities for miniaturized, flexible, multifunctional, and temporally programmable integrated devices.

Linear Inverse Sandwich Complexes of Tetraanionic Benzene Stabilized by Covalent δ-Bonding with Late Lanthanides.

A series of dilanthanide benzene inverse sandwich complexes of the type (CpiPr5Ln)2(μ-η6:η6-C6H6) (1-Ln) (Ln = Y, Gd, Tb, Dy, Tm) are reported. These compounds are synthesized by reduction of the respective trivalent dimers CpiPr52Ln2I4 (Ln = Y, Gd, Tb, Dy, Tm) in diethyl ether with potassium graphite in the presence of benzene, and they feature an unusual linear coordination geometry with a highly planar benzene bridge as verified by single-crystal X-ray diffraction. The Ln-Bzcentroid distances of 1-Ln are the shortest distances observed to date, ranging from 1.943(1) Å for 1-Tm to 2.039(6) Å for 1-Gd. Structural, spectroscopic, and magnetic analyses together with density functional theory calculations support the presence of a rare, unsubstituted tetraanionic benzene in each compound, which is stabilized by strong covalent δ bonding interactions involving the filled π* orbitals of (C6H6)4- and vacant dxy and dx2-y2 orbitals of the Ln3+ ions. Notably, 1-Ln are the first examples of compounds of the later lanthanides to feature an unsubstituted tetraanionic benzene.

Mitigating Methylglyoxal-Induced Glycation Stress: The Protective Role of Iron, Copper, and Manganese Coordination Compounds in Saccharomyces cerevisiae.

Glycation-induced stress (G-iS) is a physiological phenomenon that leads to the formation of advanced glycation end-products (AGEs), triggering detrimental effects such as oxidative stress, inflammation, and damage to intracellular structures, tissues, and organs. This process is particularly relevant because it has been associated with various human pathologies, including cancer, neurodegenerative diseases, and diabetes. As therapeutic alternatives, coordination compounds with antioxidant activity show promising potential due to their versatility in attenuating oxidative stress and inflammation. Herein, we investigated the antioxidant-related protective potential of a series of complexes: [Cu(II)(BMPA)Cl2] (1), [Fe(III)(BMPA)Cl3] (2), and [Cl(BMPA)MnII-(μ-Cl)2-MnII(BMPA)-(μ-Cl)- MnII(BMPA)(Cl)2]•5H2O (3), all synthesized with the ligand bis-(2-pyridylmethyl)amine (BMPA) in Saccharomyces cerevisiae exposed to G-iS caused by methylglyoxal (MG). Pre- treatment with complexes 1 - 3 proved highly effective, increasing yeast tolerance to G-iS and attenuating mitochondrial dysfunction. This observed phenotype appears to result from a reduction in intracellular oxidation, lipid peroxidation levels, and glycation. Additionally, an increase in the activity of the antioxidant enzymes superoxide dismutase and catalase was observed following treatment with complexes 1 - 3. Notably, although complexes 1 - 3 provided significant protection against oxidative stress induced by H2O2 and menadione, their protective role was more effective against MG-induced glycation stress. Our results indicate that these complexes possess both antiglycation and antioxidant properties, warranting further investigation as potential interventions for mitigating glycation and oxidative stress-related pathologies.

Regulating Spin‐Crossover Behavior in Iron(II) Complexes: Control over SCO Temperatures by Varying NCE‒ Co‐ligands

In this research, we introduce new members to the [Fe(bzL)(NCE)2] complex series by incorporating NCS− and NCBH3− as co‐ligands, expanding on our established tetradentate bzL ligand. The synthesis of three isostructural structures has allowed for a systematic tuning of SCO temperatures, with T1/2 values ranging from 85 K for the S‐α complex, featuring approximately 15 K thermal hysteresis, to 194 K for the Se‐α complex, and a stable low‐spin state up to 300 K for the B‐α complex. This work demonstrates the efficacy of modulating SCO properties through variation of the NCE− ancillary ligands. Furthermore, we conducted a comparative analysis of 21 analogs within this family. This analysis aims to elucidate the similarities and differences among the complexes and their correlation with SCO properties, furthering our understanding of the structural determinants that influence SCO behavior.

Modulating the Supramolecular Assembly of α-Cyclodextrin and Anderson-type Polyoxometalate through Covalent Modifications.

A series of unprecedented supramolecular complexes of covalently modified Anderson-type polyoxometalates (POMs) and α-cyclodextrins (α-CDs) have been obtained and characterized in solid state by single-crystal X-ray diffraction, and in aqueous solution using various techniques including 1H DOSY, 2D NOESY 1H NMR, isothermal titration calorimetry (ITC), and electrospray ionization time-of-flight mass spectroscopy (ESI-TOF-MS). It has been demonstrated that the supramolecular assembly process can be modulated by different covalent modification modes of the Anderson POMs, giving rise to a new type of POM/α-CD complexes featuring organic-inorganic pseudo-rotaxane structures, which are in good contrast to those of POM/γ-CD with poly-rotaxane type structures. Moreover, it is delighted to find that these pseudo-rotaxanes of POM/α-CD exhibit stable chirality in aqueous solution, which has not been accomplished in previously reported POM/γ-CD assemblies.

Nucleophilic Fluoride Anion Delivery from Triazacyclononane-Supported Molecular Ca-F Complexes.

The major source of fluoride, namely calcium difluoride (CaF2), is derived from the mineral fluorspar. Recent advances in the activation of CaF2 via mechanochemical methods have inspired investigation of the fundamental properties of Ca-F bonds in molecular complexes. However, the paucity of well-defined molecular Ca-F-containing complexes undermines systematic understanding of the factors governing nucleophilic fluoride delivery. Here we report the use of a multidentate bis(phenoxide) ligand based on a 1,4,7-triazacyclononane (TACN) scaffold for the formation of well-defined Ca-F complexes and demonstrate their capabilities in fluoride delivery. Key to this synthesis is a desymmetrization step carried out on the TACN ligand within the Ca coordination sphere. A series of stable anionic dinuclear calcium fluoride complexes has then been accessed and characterized by NMR spectroscopy (critically by 19F NMR) and X-ray crystallography. Nucleophilic fluoride delivery can be used to generate C-F, Si-F and S-F bonds, with a notable advance over amide-derived ligand scaffolds being the reduced extent of side reactions derived from competing attack on the electrophile by the less nucleophilic O-donor anionic ligand set.

Hierarchical Multi‐Component Self‐Assembly Involving Alkali and Lanthanide(III) Metal Ions and Water Soluble Sulfonated Calix[4]arene

AbstractSolid state structural studies of three supramolecular coordination complexes establish the formation of hetero‐bimetallic two‐ and three‐dimensional ensembles involving sulfonated calix[4]arene, and sodium ions and low nuclearity lanthanide(III) ions. The interplay of components is altered in response to the addition of different auxiliary molecules during crystallisation which is associated with significant changes in the metal coordination environments and overall molecular packing, as established in comparing the structures of complexes of similar cell dimensions with those available in the literature. The sulfonated calixarene form a common self‐assembly array despite different lanthanides being incorporated, as an isostructural series of complexes. Crystallographic analysis shows a continually decreasing trend in the lanthanide–oxygen bond length as the lanthanide atomic number increases. As smaller molecules are incorporated to the hetero‐bimetallic calixarene system, the self‐assembly and the metal coordination environment are perturbed.

Molecular Copper-Anthraquinone Photocatalysts for Robust Hydrogen Production.

The development of robust and inexpensive photocatalysts for H2 production under visible light irradiation remains a significant challenge. This study presents a series of square planar copper anthraquinone complexes (R4N)CuL2 (R = ethyl, L = alizarin dianion (CuAA); R = n-butyl, L = purpurin dianion (CuPP), (2-hydroxyanthraquinone)formamide dianion (CuAHA)) as molecular photocatalysts to achieve high long-term stability in visible-light-driven H2 production. These complexes are self-sensitized by the anthraquinone ligands and serve as proton reduction photocatalysts without additional photosensitizers or catalysts. Under irradiation of blue light, complex CuAA produces H2 in a mixture of H2O/DMF with undiminished activity over 42 days, giving a turnover number exceeding 6800. Electrochemical and UV-vis studies are consistent with an EECC mechanism (E: electron transfer and C: protonation) in the catalytic cycle. The initial photochemical steps involve conversion of both anthraquinone ligands to hydroquinones. Further light-driven reductions of the hydroquinones followed by two protonation steps results in formation of H2. Dependence of the catalytic rate on the concentration of H2O suggests that either the generation of a CuII-H intermediate by protonation or heterocoupling between CuII-H and H+ to produce H2 is the turnover-limiting step in catalysis.

Boosting Financial Market Prediction Accuracy With Deep Learning and Big Data

The accuracy of financial market trend prediction directly impacts investors' decisions and financial institutions' risk management, making it a focal point of research in the financial domain. While traditional statistical methods lay the foundation for market forecasting, they still face limitations in handling complex, nonlinear, and non-stationary financial time series data with accuracy and adaptability. Time series analysis plays a pivotal role in financial market prediction, revealing historical patterns and future trends within the data. Addressing the limitations of existing methods, this study proposes a deep learning-based CEEMDAN-CNN-LSTM model. Leveraging the CEEMDAN decomposition method to capture the multi-frequency components of time series, CNN extracts spatial features, and LSTM learns temporal dependencies. Experimental results demonstrate that the performance of the CEEMDAN-CNN-LSTM model surpasses traditional models on standardized evaluation metrics such as RMSE, MAE, and MAPE across four major financial datasets.

Metametaphysical Monism, Dualism, Pluralism, and Holism in the German Idealist Tradition

ABSTRACT During his Jena period, Fichte endorses a curious dictum: ‘the kind of philosophy one chooses depends on the kind of person one is’. How can Fichte’s dictum support a vindication of German idealism over Spinozism, which he also calls ‘dogmatism’? I will show that the answer to this seemingly straightforward question reveals a rather complex series of metametaphysical objections that shape the development of the entire German idealist tradition. Ultimately, as I will suggest, the series of metametaphysical questions that shape the German idealist tradition must culminate in the question of how to understand the relation between philosophy and its presuppositions. I will conclude by briefly considering a hermeneutical response to this question.

Engineering the Coordination Environment in the Silver(I)- and Ruthenium(II)-N-Heterocyclic Carbene Complexes in Instigating the Electrocatalytic Hydrogen Evolution Reaction.

The quest for cost-efficient and high-performance electrocatalysts towards electrocatalytic water splitting is a key and an interdisciplinary area of study. Considerable progress is being driven by developments in the field of energy research. In a fundamental study, we have synthesized NHC precursors (6 and 7) and corresponding metal-NHC complexes of silver(I)- (8 and 9) and ruthenium(II)- (10 and 11) of a N-heterocyclic carbene-based ligand type incorporating coumarins. These NHC precursors and metal-NHC complexes were characterized through various analytical and spectral techniques. The silver(I)-NHC complexes 8 and 9 displayed a linear coordination geometry with a center of inversion, which is evidenced by the single-crystal X-ray diffraction technique. Both the series of complexes were assessed for their efficacies in the hydrogen evolution reaction (HER). The results demonstrated that attributed to its peculiar coordination geometry, high electrical conductivity the silver(I)- and ruthenium(II)-NHC complexes exhibited exemplary electrocatalytic activity. Activities of the hydrogen evolution reaction on two differently modified electrode substrates with metal-NHC complexes have been studied. To attain the benchmark HER current density of 10 mA cm-2, in 1.0 M KOH, an overpotential of -375 to -527 mV vs RHE was required for the metal-NHC complexes. Based on the analysis of the Tafel slope values, the rate-determining step was the adsorption of hydrogen as investigated in the potential window. The molecular electrocatalyst 10 presented a superior stability and maintained the electrocatalytic activity for a duration of 18 h with complex 8 and 24 h with respect to complex 10 in 1.0 M KOH. Apace with these studies, hydrogen oxidation studies were examined in 0.5 M H2SO4 by a substantial current density at the platinum ring electrode. This research offers feasible guidance for developing organometallic-based molecular electrocatalysts with good electrocatalytic performance.

Comparative Study of Docking Tools for Evaluation of Potential Copper Metallodrugs and Their Interaction with TMPRSS2

COVID-19 has caused over seven million deaths globally due to its high transmission rate. The virus responsible for the disease requires a transmembrane protease serine type II (TMPRSS2-7MEQ) to infiltrate host cells and has been linked to several cancers, particularly prostate cancer. To investigate COVID-19 potential therapies, a series of Casiopeina-like copper complexes containing 1,10-Phenanthroline and amino acids were investigated as TMPRSS2 inhibitors. The molecular structures of twelve Phenanthroline copper complexes were calculated, and their global reactivity indices were analyzed using DFT and conceptual DFT methods. Three molecular docking algorithms were employed to identify the most effective inhibitors by examining their interactions with amino acid residues in the target protein’s catalytic activity triad (Asp345, His296, and Ser441). All complexes are docked above the catalytic site, blocking the interaction with substrates. The Phenanthroline complexes showed better interactions than the Bipyridine complexes, likely due to increased hydrophobic contacts. Analogs’ cationic nature and amino acids’ basic side chains bring them near the active site by interacting with Asp435. The top complexes in this study contain Ornithine, Lysine, and Arginine, making them promising alternatives for researching new drugs for COVID-19 and cancers like prostate cancer.

Hyaluronic Acid Hampers the Inflammatory Response Elicited by Extracellular Vesicles from Activated Monocytes in Human Chondrocytes

Background/Objectives: Osteoarthritis (OA) is the most common joint disease in the adult population. OA is the result of multiple mechanisms leading to inflammation and the degradation of the cartilage. A complex series of etiological actors have been identified so far, including extracellular vesicles (EVs). The EV content of the synovial fluid (SF) can release inflammatory mediators that enhance OA progression. An intra-articular viscosupplementation of high-MW hyaluronic acid (HyA) constitutes the first-line conservative treatment for OA. Although attractive for the potential pharmacological implications, the possibility that HyA may interact with EVs in the context of OA has not yet been specifically investigated; therefore, the present study aimed to fill this gap. Methods: We studied the effect of a HyA preparation (a blend of crosslinked and linear polymers, CLHyA) on the relevant inflammatory markers in chondrocytes (HC cells or primary chondrocytes isolated from patients with advanced OA) exposed to the EVs collected from IL-1β-stimulated THP-1 human monocytes (EVs+). Results: EVs+ caused specific inflammatory responses in chondrocytes that could be prevented by coincubation with CLHyA. This anti-inflammatory activity is likely dependent on the direct binding of CLHyA to CD44 receptors highly expressed in EVs+ and on the subsequent hindrance to EVs+ diffusion and docking to target cells. Conclusions: On the whole, the tight interactions identified herein between HMW HyA and EVs+ represent a novel, pharmacologically exploitable mechanism potentially relevant in the context of OA treatment.

Synthesis, characterization, biological activity, DFT and Hirshfeld surface studies of Pd(II) and Pt(II)-1-cyclohexyl-3-phenylthiourea and amine ligands

A series of mixed ligand complexes of Pd(II) and Pt(II) of 1-cyclohexyl-3-phenylthiourea and diamine ligands {2,2'-bipyridyl (Bipy) and 1,10-phenanthroline (Phen)} were prepared and characterized by FT-IR, NMR spectroscopy, molar conductivity. Density functional theory (DFT) calculations and biological activity were carried out on the prepared complexes. In vitro antimicrobial activity was investigated against three pathogenic bacteria (Staphylococcus aureus, Bacillus cereus and Escherichia coli). The most active compound 6 was found more active than free ligand and other complexes. The crystal structure of the free ligand was determined by X-ray diffraction (XRD) analysis. Hirshfeld surface analysis was executed for the free ligand by finding and exploring the interatomic contacts that are important considering the supramolecular assembly of the crystal. The mechanical stability or response is prophesied by voids analysis. The supramolecular assembly is significantly uncovered by intermolecular interaction energies calculations performed at of the B3LYP/6-31G(d,p) electron density level. KEY WORDS: Thiourea, Diamine, Crystal structure, DFT, Hirshfeld surface Bull. Chem. Soc. Ethiop. 2025, 39(1), 15-27. DOI: https://dx.doi.org/10.4314/bcse.v39i1.2

Excitation Dependent Multiemissive Behaviour of Triimidazole Carboxylic Acid anti‐Kasha Luminophore and its Mononuclear Metal Complexes

Materials based on small molecules characterized by multi‐component short and long‐lived emissive behaviour are extremely desirable for various applications. The derivative of cyclic triimidazole (TT) functionalized with a carboxylic group, namely TT‐COOH, is isolated, investigated and used as coordinative ligand to obtain a series of isomorphous mononuclear complexes of general formula [M(TT‐COO)2(H2O)2] (M = Mn(II), Co(II), Ni(II), Cu(II), Zn(II) and Cd(II)). Crystals of TT‐COOH display aggregation induced enhanced emission (AIEE) comprising dual fluorescence and dual phosphorescence of molecular origin together with an aggregation induced long lived, low energy phosphorescence. Emissive features are retained in crystals of the Zn(II) and Cd(II) complexes, where the metal plays the role of an external heavy atom perturber, but strongly quenched in the others. The mechanisms involved in the photophysics of TT‐COOH and its metal complexes have been disclosed thanks to combined structural, spectroscopic and computational investigations which reveal the presence of anti‐Kasha emissions.

Photovoltaic Performance of Naphthol Blue Black Complexes and their Band Gap Energy

Along with the depletion of petroleum-based fuels, the development of renewable energy resources is a must. One of them is through DSSC (Dye Sensitized Solar Cells) technology, which has a dye sensitizer and semiconductor as the main components. The aim of this research is to investigating the photovoltaic performance of complexes series from metals (Mn(II); Fe(II); Co(II) and Ni(II)) and naphthol blue-black (NB) as a ligand. This investigation also successfully revealed factors that are highly influencing photovoltaic efficiency, namely the band-gap energy and the conductance of metal-NB complexes. The Fe(II)-NB complex has performed the highest photovoltaic activity as a result of the d-d electron transition and MLCT (Metal to Ligand Change Transfer) character which are covered by vivid color from the ligand. The bonding between metal and ligand was shown at a wavenumber of 316.33 cm-1 for M-N bonding and 486.06 cm-1 for M-O bonding. Fe(II)-NB complex had the narrowest band gap energy which is 5.86 eV and had the highest value of conductance and the highest efficiency, namely 0.0925%. This experiment successfully demonstrates that the narrower the energy gap of a molecule, the ability to transfer electrons is faster. Thus, the efficiency of the solar cell becomes higher. This investigation has proven that the narrow band gap makes the electron transfer becomes easier.

Inhibition of phosphodiesterase 10A mitigates neuronal injury by modulating apoptotic pathways in cold-induced traumatic brain injury

Brain injury develops from a complex series of pathophysiological phases, resulting in acute necrotic or delayed apoptotic cell death after traumatic brain injury (TBI). Inhibition of apoptotic cell death is critical for the treatment of acute neurodegenerative disorders, such as TBI. Here, we investigated the role of phosphodiesterase 10A (PDE10A) in the development of neuronal injury, particularly in apoptotic cell death. Using the PDE10A inhibitor TAK-063, we found that PDE10A inhibition is associated with decreased brain injury, brain swelling, and blood brain barrier disruption 48 h after cold-induced TBI. Furthermore, a particularly notable result was observed with 3 mg/kg TAK-063, which reduced disseminated neuronal injury. Protein abundance analysis revealed that PDE10A inhibition activates survival kinases AKT and ERK-1/-2, which were associated with the decreased activation of MMP-9 and PTEN. Additionally, iNOS and nNOS levels significantly reduced in the TAK-063 group, playing roles in inflammation and apoptosis. A planar surface immunoassay was performed for in-depth analyses of the apoptotic signaling pathways. We observed that inhibition of PDE10A resulted in the decreased expression of TNFRSF1A, TNFRSF10B, and TNFRSF6 receptors, particularly inducing apoptotic cell death. Moreover, these findings correlated with reduced levels of pro-apoptotic proteins, including PTEN, p27, Cytochrome-c, cleaved Caspase-3, Bad, and p53. Interestingly, TAK-063 treatment reduced levels of anti-apoptotic proteins or enzymes, including XIAP, Claspin, and HIF1α, without affecting Bcl-x, MCL-1, SMAC, HO-1, HO-2, HSP27, HSP60, and HSP70. The findings suggest that PDE10A regulates cellular signaling predominantly pro-apoptotic pathways, and inhibition of this protein is a promising approach for the treatment of acute brain injury.