Tanshinone analog inhibits castration-resistant prostate cancer cell growth by inhibiting glycolysis in an AR-dependent manner.

Androgen receptor (AR) is one of the key targets for the treatment of castration-resistant prostate cancer (CRPC). Current endocrine therapy can greatly improve patients with CRPC. However, with the change of pathogenic mechanism, acquired resistance often leads to the failure of treatment. Studies have shown that tanshinone IIA (TS-IIA) and its derivatives have significant antitumor activity, and have certain AR-targeting effects, but the mechanism is unknown. In this study, the TS-IIA analog TB3 was found to significantly inhibit the growth of CRPC in vitro and in vivo. Molecular docking, cellular thermal shift assay, and cycloheximide experiments confirmed that AR was the target of TB3 and promoted the degradation of AR. Furthermore, TB3 can significantly inhibit glycolysis metabolism by targeting the AR/PKM2 axis. The addition of pyruvic acid could significantly alleviate the inhibitory effect of TB3 on CRPC cells. Besides, the knockdown of AR or PKM2 also could reverse the effect of TB3 on CRPC cells. Taken together, our study suggests that TS-IIA derivative TB3 inhibits glycolysis to prevent the CRPC process by targeting the AR/PKM2 axis.

Lung-Targeting Perylenediimide Nanocomposites for Efficient Therapy of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis, an idiopathic interstitial lung disease with high mortality, remains challenging to treat due to the lack of clinically approved lung-targeting drugs. Herein, we present PDIC-DPC, a perylenediimide derivative that exhibits superior lung-selective enrichment. PDIC-DPC forms nanocomposites with plasma proteins, including fibrinogen beta chain and vitronectin, which bind to pulmonary endothelial receptors for lung-specific accumulation. Moreover, PDIC-DPC significantly suppresses transforming growth factor beta1 and activates adenosine monophosphate-activated protein kinase. As a result, compared to existing therapeutic drugs, PDIC-DPC achieves superior therapeutic outcomes, evidenced by the lowest Ashcroft score, significantly improved pulmonary function, and an extended survival rate in a bleomycin-induced pulmonary fibrosis model. This study elucidates the lung-selective enrichment of assembled prodrug from biological perspectives and affords a platform enabling therapeutic efficiency on idiopathic pulmonary fibrosis.

Solution Synthesis and Light-Emitting Applications of One-Dimensional Lead-Free Cerium(III) Metal Halides.

Combining rare earth elements with the halide perovskite structure offers valuable insights into designing nonlead (Pb) luminescent materials. However, most of these compositions tend to form zero-dimensional (0D) networks of metal-halide polyhedra, with higher-dimensional (1D, 2D, and 3D) structures receiving relatively less exploration. Herein, we present synthesis and optical properties of Cs3CeCl6·3H2O, characterized by its unique 1D crystal structure. The conduction band minimum of Cs3CeCl6·3H2O becomes less localized as a result of the increased structural dimension, making it possible for the materials to achieve an efficient electrical injection. For both Cs3CeCl6·3H2O single crystals and nanocrystals, we also observed remarkable luminescence with near-unity photoluminescence quantum yield and exceptional phase stability. Cs3CeCl6·3H2O single crystals demonstrate an X-ray scintillation light yield of 31900 photons/MeV, higher than that of commercial LuAG:Ce (22000 photons/MeV); electrically driven light-emitting diodes fabricated with Cs3CeCl6·3H2O nanocrystals yield the characteristic emission of Ce3+, indicating their potential use in next-generation violet-light-emitting devices.

Charge Carrier Regulation for Efficient Blue Quantum-Dot Light-Emitting Diodes Via a High-Mobility Coplanar Cyclopentane[b]thiopyran Derivative.

The performance of blue quantum dot light-emitting diodes (QLEDs) is limited by unbalanced charge injection, resulting from insufficient holes caused by low mobility or significant energy barriers. Here, we introduce an angular-shaped heteroarene based on cyclopentane[b]thiopyran (C8-SS) to modify the hole transport layer poly-N-vinylcarbazole (PVK), in blue QLEDs. C8-SS exhibits high hole mobility and conductivity due to the π···π and S···π interactions. Introducing C8-SS to PVK significantly enhanced hole mobility, increasing it by 2 orders of magnitude from 2.44 × 10-6 to 1.73 × 10-4 cm2 V-1 s-1. Benefiting from high mobility and conductivity, PVK:C8-SS-based QLEDs exhibit a low turn-on voltage (Von) of 3.2 V. More importantly, the optimized QLEDs achieve a high peak power efficiency (PE) of 7.13 lm/W, which is 2.65 times that of the control QLEDs. The as-proposed interface engineering provides a novel and effective strategy for achieving high-performance blue QLEDs in low-energy consumption lighting applications.

A digoxin derivative that potently reduces intraocular pressure: efficacy and mechanism of action in different animal models.

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.

3,3',4,5'-Tetramethoxy-trans-stilbene and 3,4',5-trimethoxy-trans-stilbene prevent oxygen-glucose deprivation-induced injury in brain endothelial cell.

Blood-brain barrier (BBB) disruption is a major pathophysiological event of ischemic stroke. Brain microvascular endothelial cells are critical to maintain homeostasis between central nervous system and periphery. Resveratrol protects against ischemic stroke. 3,3',4,5'-tetramethoxy-trans-stilbene (3,3',4,5'-TMS) and 3,4',5-trimethoxy-trans-stilbene (3,4',5-TMS) are resveratrol derivatives with addition of methoxy groups, showing better pharmacokinetic performance. We aimed to explore their protective effects and underlying mechanisms. Oxygen-glucose deprivation (OGD) model was applied in bEnd.3 cell line, mouse brain microvascular endothelium to mimic ischemia. The cells were pre-treated with 3,3',4,5'-TMS or 3,4',5-TMS (1 and 5 µM, 24 h) and then subjected to 2-h OGD injury. Cell viability, levels of proinflammatory cytokines and reactive oxygen species (ROS), and protein expressions were measured by molecular assays and fluorescence staining. OGD injury triggered cell death, inflammatory responses, ROS production and nuclear factor-kappa B (NF-κB) signalling pathway. These impairments were remarkably attenuated by the two stilbenes, 3,3',4,5'-TMS and 3,4',5-TMS. They also alleviated endothelial barrier injuries through upregulating the expression of tight junction proteins. Moreover, 3,3',4,5'-TMS and 3,4',5-TMS activated 5' adenosine monophosphate-activated protein kinase (AMPK) and endothelial nitric oxide synthase (eNOS). Overall, 3,3',4,5'-TMS and 3,4',5-TMS exert protective effects against OGD damage through suppressing cell death, inflammatory responses, oxidative stress, as well as BBB disruption on bEnd.3 cells.

Tyrosine phosphorylation of recombinant hirudin increases affinity to thrombin and antithrombotic activity.

Thrombin is one of the key enzymes of the blood coagulation system and a promising target for the development of anticoagulants. One of the most specific natural thrombin inhibitors is hirudin, contained in the salivary glands of medicinal leeches. The medicinal use of recombinant hirudin is limited because of the lack of sulfation on Tyr63, resulting in a 10-fold decrease in activity compared to native (sulfated) hirudin. In the present work, a set of hirudin derivatives was tested for affinity to thrombin: phospho-Tyr63, Tyr63(carboxymethyl)Phe, and Tyr63Glu mutants, which mimic Tyr63 sulfation and Gln65Glu mutant and lysine-succinylated hirudin, which enhance the overall negative charge of hirudin, as well as sulfo-hirudin and desulfo-hirudin as references. Using steered molecular dynamics simulations with subsequent umbrella sampling, phospho-hirudin was shown to exhibit the highest affinity to thrombin among all hirudin analogs, including native sulfo-hirudin; succinylated hirudin was also prospective. Phospho-hirudin exhibited the highest antithrombotic activity in in vitro assay in human plasma. Taking into account the modern methods for obtaining phospho-hirudin and succinylated hirudin, they are prospective as anticoagulants in clinical practice.

Scaffold Matcher: A CMA-ES based algorithm for identifying hotspot aligned peptidomimetic scaffolds.

The design of protein interaction inhibitors is a promising approach to address aberrant protein interactions that cause disease. One strategy in designing inhibitors is to use peptidomimetic scaffolds that mimic the natural interaction interface. A central challenge in using peptidomimetics as protein interaction inhibitors, however, is determining how best the molecular scaffold aligns to the residues of the interface it is attempting to mimic. Here we present the Scaffold Matcher algorithm that aligns a given molecular scaffold onto hotspot residues from a protein interaction interface. To optimize the degrees of freedom of the molecular scaffold we implement the covariance matrix adaptation evolution strategy (CMA-ES), a state-of-the-art derivative-free optimization algorithm in Rosetta. To evaluate the performance of the CMA-ES, we used 26 peptides from the FlexPepDock Benchmark and compared with three other algorithms in Rosetta, specifically, Rosetta's default minimizer, a Monte Carlo protocol of small backbone perturbations, and a Genetic algorithm. We test the algorithms' performance on their ability to align a molecular scaffold to a series of hotspot residues (i.e., constraints) along native peptides. Of the 4 methods, CMA-ES was able to find the lowest energy conformation for all 26 benchmark peptides. Additionally, as a proof of concept, we apply the Scaffold Match algorithm with CMA-ES to align a peptidomimetic oligooxopiperazine scaffold to the hotspot residues of the substrate of the main protease of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our implementation of CMA-ES into Rosetta allows for an alternative optimization method to be used on macromolecular modeling problems with rough energy landscapes. Finally, our Scaffold Matcher algorithm allows for the identification of initial conformations of interaction inhibitors that can be further designed and optimized as high-affinity reagents.

A periodic table of monosaccharides.

It is important to recognize the great diversity of monosaccharides commonly encountered in animals, plants, and microbes, as well as to organize them in a visually interesting style that also emphasizes their similarities and relatedness. This article discusses the nature of building blocks, monosaccharides, and monosaccharide derivatives-terms commonly used in discussing "glycomolecules" found in nature. To aid in awareness of monosaccharide diversity, here is presented a Periodic Table of Monosaccharides. The rationale is given for construction of the Table and the selection of 103 monosaccharides, which is largely based on those presented in the KEGG and SNFG websites of monosaccharides, and includes room to enlarge as new discoveries are made. The Table should have educational value and is intended to capture the attention and foster imagination of those not very familiar with glycosciences, and encourage researchers to delve deeper into this fascinating area.

Synthesis of a dehydrodieugenol B derivative as a lead compound for visceral leishmaniasis-mechanism of action and in vivo pharmacokinetic studies.

Leishmaniasis is a parasitic neglected tropical disease, affecting 12 million people. Available treatments present several limitations, with an increasing number of resistance cases. In the search for new chemotherapies, the natural product dehydrodieugenol B was used as a scaffold for the synthesis of a series of derivatives, resulting in the discovery of the promising analog [4-(4-(5-allyl-3-methoxy-2-((4-methoxybenzyl)oxy)phenoxy)-3-methoxybenzyl)morpholine, 1]. In this work, we investigated the effect of compound 1 on cell signaling in Leishmania (L.) infantum, culminating in cell death, as well as its immunomodulatory effect in the host cell. Additionally, we performed a pharmacokinetic profile study in an animal model. After treatment, compound 1 induced the alkalinization of acidocalcisomes and concomitant Ca2+ release in the parasite. These events may induce depolarization of the mitochondrial potential, with successive collapse of the bioenergetic system, leading to a reduction of ATP and reactive oxygen species (ROS) levels. The analysis of total proteins and protein profile by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF/MS) demonstrated that compound 1 also altered the parasite proteins after treatment. Transmission electron microscopy studies revealed ultrastructural damage to mitochondria; together, these data suggest that compound 1 may promote autophagic cell death. Additionally, compound 1 also induced an immunomodulatory effect in host cells, with a reduction of Th1 and Th2 cytokine response, characterizing an anti-inflammatory compound. The obtained pharmacokinetic profile in rats enhances the potential of the compound, with a mean plasma half-life (T1/2) of 21 h. These data reinforce the potential of compound 1 as a new lead for future efficacy studies.

Amoebicidal effect of synthetic indoles against Acanthamoeba spp.: a study of cell death.

Organic and synthetic chemistry plays a crucial role in drug discovery fields. Moreover, chemical modifications of available molecules to enhance their efficacy, selectivity and safety have been considered as an attractive approach for the development of new bioactive agents. Indoles, a versatile group of natural heterocyclic compounds, have been widely used in pharmaceutical industry due to their broad spectrum of activities including antimicrobial, antitumoral and anti-inflammatory among others. Herein, we report the amoebicidal activity of different indole analogs on Acanthamoeba castellanii Neff. Among the 40 tested derivatives, eight molecules were able to inhibit this protistan parasite. The structure-activity relationship (SAR) analysis of their anti-Acanthamoeba activity would suggest that a carboxylation of C-3 position and the incorporation of halogen as chlorine/fluorine would enhance their biological profile, presumably by increasing their lipophilicity and therefore their ability to cross the cell membrane. Fluorescence image base system was used to investigate the effect of indole 6o c-6 on the cytoskeleton network and various programmed cell death features. We were able to highlight that the methyl 6-chloro-1H-indole-3-carboxylate could induce program cell death by the mitochondrial dysfunction.

Extended N-centered ensemble density functional theory of double electronic excitations.

A recent work (arXiv:2401.04685) has merged N-centered ensembles of neutral and charged electronic ground states with ensembles of neutral ground and excited states, thus providing a general and in-principle exact (so-called extended N-centered) ensemble density functional theory of neutral and charged electronic excitations. This formalism made it possible to revisit the concept of density-functional derivative discontinuity, in the particular case of single excitations from the highest occupied Kohn-Sham (KS) molecular orbital, without invoking the usual "asymptotic behavior of the density" argument. In this work, we address a broader class of excitations, with a particular focus on double excitations. An exact implementation of the theory is presented for the two-electron Hubbard dimer model. A thorough comparison of the true physical ground- and excited-state electronic structures with that of the fictitious ensemble density-functional KS system is also presented. Depending on the choice of the density-functional ensemble as well as the asymmetry of the dimer and the correlation strength, an inversion of states can be observed. In some other cases, the strong mixture of KS states within the true physical system makes the assignment "single excitation" or "double excitation" irrelevant.

Investigating the Anti-inflammatory Effect of Quinoline Derivative: N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine Hydrochloride Loaded Soluble Starch Nanoparticles Against Methotrexate-induced Inflammation in Experimental Model.

BACKGROUND: It is necessary to develop advanced therapies utilizing natural ingredients with anti-inflammatory qualities in order to lessen the negative effects of chemotherapeutics. RESULTS: The bioactive N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine hydrochloride (NIQBD) was synthesized. After that, soluble starch nanoparticles (StNPs) was used as a carrier for the synthesized NIQBD with different concentrations (50 mg, 100 mg, and 200 mg). The obtained StNPs loaded with different concentrations of NIQBD were coded as StNPs-1, StNPs-2, and StNPs-3. It was observed that, StNPs-1, StNPs-2, and StNPs-3 exhibited an average size of 246, 300, and 328 nm, respectively. Additionally, they also formed with homogeneity particles as depicted from polydispersity index values (PDI). The PDI values of StNPs-1, StNPs-2, and StNPs-3 are 0.298, 0.177, and 0.262, respectively. In vivo investigation of the potential properties of the different concentrations of StNPs loaded with NIQBD against MTX-induced inflammation in the lung and liver showed a statistically substantial increase in levels of reduced glutathione (GSH) accompanied by a significant decrease in levels of oxidants such as malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), matrix metalloproteinase 9/Gelatinase B (MMP-9), and levels of inflammatory mediators including interleukin 1-beta (IL-1ß), nuclear factor kappa-B (NF-κB) in both lung and liver tissues, and a significant decrease in levels of plasma homocysteine (Hcy) compared to the MTX-induced inflammation group. The highly significant results were obtained by treatment with a concentration of 200 mg/mL. Histopathological examination supported these results, where treatment showed minimal inflammatory infiltration and congestion in lung tissue, a mildly congested central vein, and mild activation of Kupffer cells in liver tissues. CONCLUSION: Combining the treatment of MTX with natural antioxidant supplements may help reducing the associated oxidation and inflammation.

Multifunctional Effects of Biguanide Derivative in the Application of Highly Efficient Tin-Lead Perovskite Solar Cells.

Tin-lead (Sn-Pb) mixed perovskites is beneficial to a single-junction or all-perovskite tandem device. However, the poor quality of the perovskite surface resulting from Sn2+ oxidation and uncontrollable crystallization degrades device performance and stability. Herein, based on interface engineering, a novel biguanide derivative of PZBGACl is employed that integrates different types of N-related groups to reconstruct the surface/grain boundaries of Sn-Pb perovskite. Combined with the microcorrosion effect of isopropanol solvent, PZBGACl can induce surface recrystallization of perovskite, and passivate various types of defects via hydrogen bond or Lewis acid-base interaction, leading to an excellent perovskite film with reduced stress, larger grain size, and more n-type surface. As a result, the obtained Sn-Pb solar cell achieves a power conversion efficiency of 22.0%, and exhibits excellent N2 storage/operation stability.

MOF Derivatives with Gradient Structure Anchored on Carbon Foam for High-Performance Electromagnetic Wave Absorption.

The impedance matching and high loss capabilities of composites with homogeneous distribution are limited owing to high addition and lack of structural design. Developing composites with heterogeneous distribution can achieve strong and wide electromagnetic (EM) wave absorption. However, challenges such as complex design and unclear absorption mechanisms still exist. Herein, a novel composite with a heterogeneous distribution gradient is successfully constructed via MOF derivatives Co@ nitrogen-doped carbon (Co@NC) anchored on carbon foam (CF) matrix (MDCF). Notably, the concentration of MOF can easily control the gradient structure. In particular, the morphologies of MOF derivatives on the surface of CF undergo a transition from the collapse of the inner layer to the integrity of the outer layer, accompanied by a continuous reduction in the size of Co nanoparticles. Correspondingly, enhanced interface polarization from the core-shell of Co@NC and good impedance matching of MDCF can be obtained. The optimized MDCF exhibits the minimum reflection loss of -68.18 dB at 2.01 mm and effective absorption bandwidth covering the entire X-band. Moreover, MDCF exhibits lightweight characteristics, excellent compressive strength, and low radar cross-section reduction. This work highlights the immense potential of composites with heterogeneous distribution for achieving high-performance EM wave absorption.

Managing Pb-Related Imperfections via Rationally Designed Aniline Derivative with Bilateral Cyano and Acetyl Groups as Lewis Base for High-Efficiency Perovskite Solar Cells Exceeding 24.

Pb-related imperfections (surface or halide vacancy induced uncoordinated Pb2+, Pb-I antisite, and Pb2+ vacancy defects) of the ionic crystal perovskite film seriously restrict the photovoltaic performance of perovskite solar cells (PSCs). Here, an aniline derivative N-(4-cyanophenyl)acetamide (CAL) is rationally designed, incorporating bilateral functional sites of cyano and acetyl groups, acting as Lewis base molecule for managing the Pb-related imperfections in perovskite surface through post-treatment. Theoretical calculation and experimental verification together proved the reduced defect density, improved crystallinity, and inhibited ion migration in the CAL-modified perovskite. Precisely, cyano as a side group and acetyl as another side group can both coordinate with Pb2+ for its low electrostatic potential energy. Further, the aniline core and the π-π conjugate structure in the benzene ring of the ligand tend to form a dimer to improve the mobility for carrier transportation and collection. The strategy demonstrates a champion PCE of 24.35% for the air-processed PSCs with over 1200 hours of maximum power point tracking (MPPT) stability. This study presents a comprehensive approach to overcoming the current Pb-related imperfections induced limitations in PSCs, paving the way for their integration into mainstream solar technologies.

Simultaneous Efficient Photocatalytic Hydrogen Evolution and Degradation of Dye Wastewater without Cocatalysts and Sacrificial Agents Based on g-C3N5 and Hybridized Ni-MOF Derivative-CdS-DETA.

Inspired by energy conversion and waste reuse, hybridized Ni-MOF derivative-CdS-DETA/g-C3N5, a type-II heterojunction photocatalyst, is synthesized by a hydrothermal method for simultaneous and highly efficient photocatalytic degradation and hydrogen evolution in dye wastewater. Without the addition of cocatalysts and sacrificial agents, the optimal MOF-CD(2)/CN5 (i.e. Ni-MOF derivative-CdS-DETA (20 wt.%)/g-C3N5) exhibit good bifunctional catalytic activity, with a H2 evolution rate of 2974.4 µmol g-1 h-1 during the degradation of rhodamine B (RhB), and a removal rate of 99.97% for RhB. In the process of H2-evolution-only, triethanolamine is used as a sacrificial agent, exhibiting a high H2 evolution rate (19663.1 µmol g-1 h-1) in the absence of a cocatalyst, and outperforming most similar related materials (such as MOF/g-C3N5, MOF-CdS, CdS/g-C3N5). With the help of type-II heterojunction, holes are scavenged for the oxidative degradation of RhB, and electrons are used in the decomposition of water for H2 evolution during illumination. This work opens a new path for photocatalysts with dual functions of simultaneous efficient degradation and hydrogen evolution.

ACAGT-007a, an anti-cancer compound that modulates ERK MAPK signaling, induces nuclear enrichment of phosphorylated ERK in T3M4 pancreatic cancer cells.

The extracellular-signal-regulated-kinase (ERK) signaling pathway is essential for cell proliferation and is frequently deregulated in human tumors such as pancreatic cancers. ACAGT-007a (GT-7), an anti-cancer compound, stimulates ERK phosphorylation, thereby inducing growth inhibition and apoptosis in T3M4 pancreatic cancer cells. However, how GT-7 stimulates ERK phosphorylation and induces apoptosis in ERK-active T3M4 cells remains unclear. To look into the mechanism, we performed a spatiotemporal analysis of ERK phosphorylation mediated by GT-7 in T3M4 cells. The immunoblotting showed that GT-7 stimulates ERK phosphorylation within 1 h, which was more remarkable after 2 h. Importantly, apoptosis induction as evaluated by the cleaved Caspase-3 was observed only after 2-h incubation with GT-7. The immunofluorescence staining revealed the enrichment of phosphorylated ERK (phospho-ERK) in the nucleus upon 1-h incubation with GT-7. Fractionation experiments showed that GT-7 increases phospho-ERK levels in the cytoplasm within 1 h, whereas nuclear phospho-ERK accumulation is observed after 2-h incubation with GT-7. MEK inhibition by U0126 significantly diminishes nuclear phospho-ERK distribution and apoptosis induction stimulated by GT-7. Thus, GT-7 may initiate the induction of ERK phosphorylation in the cytoplasm, which leads to phospho-ERK enrichment in the nucleus. This nuclear phospho-ERK accumulation by GT-7 precedes and may underlie apoptosis induction in T3M4.

The anthraquinone derivative KA-4s reduces energy metabolism and enhances the sensitivity of ovarian cancer cells to cisplatin.

Ovarian cancer is the leading cause of death from female gynecological cancers. Cisplatin (DDP) is a first-line drug for ovarian cancer treatment. Due to DDP resistance, there is an urgent need for novel therapeutic drugs with improved antitumor activity. AMPK-mediated metabolic regulatory pathways are related to tumor drug resistance. Our study aimed to determine the relationship between reversing DDP resistance with the anthraquinone derivative KA-4s and regulating AMPK energy metabolism in ovarian cancer. The results showed that KA-4s inhibited the proliferation of ovarian cancer cells. The combination of KA-4s with DDP effectively promoted drug-resistant ovarian cancer cell apoptosis and inhibited cell migration and invasion. Moreover, KA-4s decreased the intracellular ATP level and increased the calcium ion level, leading to AMPK phosphorylation. Further studies suggested that the AMPK signaling pathway may be involved in the mechanism through which KA-4s reduce drug resistance. KA-4s inhibited mitochondrial respiration and glycolysis; downregulated the glucose metabolism-related proteins GLUT1 and GLUT4; the lipid metabolism-related proteins SREBP1 and SCD1; and the drug resistance-related proteins P-gp, MRP1, and LRP. The inhibitory effect of KA-4s on GLUT1 was confirmed by the application of the GLUT1 inhibitor BAY-876. KA-4s combined with DDP significantly increased the expression of p-AMPK and reduced the expression of P-gp. In a xenograft model of ovarian cancer, treatment with KA-4s combined with DDP reduced energy metabolism and drug resistance, inducing tumor apoptosis. Consequently, KA-4s might be evaluated as a new agent for enhancing the chemotherapeutic efficacy of treatment for ovarian cancer.

Investigation through naphtho[2,3-a]pyrene on mutated EGFR mediated autophagy in NSCLC: Cellular model system unleashing therapeutic potential.

Mutant epidermal growth factor receptor (EGFR) signaling has emerged as a key cause of carcinogenesis and therapy resistance in non-small cell lung cancer (NSCLC), which continues to pose a serious threat to world health. In this study, we aimed to elucidate the complex molecular pathways of EGFR-mediated autophagy signaling in NSCLC. We identified naphtho[2,3-a]pyrene, an anthraquinolone derivative, to be a promising investigational drug that targets EGFR-mediated autophagy using a cellular model system. By utilizing systems biology, we developed a computational model that explained the signaling of EGFR-mediated autophagy and identified critical crosstalk sites that could be inhibited therapeutically. As a lead compound, naphtho[2,3-a]pyrene was confirmed by molecular docking experiments. It was found to be cytotoxic to NSCLC cells, impact migration, induce apoptosis, and arrest cell cycle, both on its own and when combined with standard drugs. The anticancer efficacy of naphtho[2,3-a]pyrene was validated in vivo on CDX nude mice. It showed synergistic activity against NSCLC when coupled with gefitinib, chloroquine, and radiation. Altogether, our study highlights naphtho[2,3-a]pyrene's therapeutic promise in NSCLC by focusing on EGFR-mediated autophagy and providing a new strategy to fight drug resistance and tumor survival.