Tailored Magnetic Spatial Confinement with Enhanced Polarization and Magnetic Response for Electromagnetic Wave Absorption.

For materials with coexisting phases, the transition from a random to an ordered distribution of materials often generates new mechanisms. Although the magnetic confinement effect has improved the electromagnetic (EM) performance, the transition from random to ordered magnetic confinement positions remains a synthetic challenge, and the underlying mechanisms are still unclear. Herein, precise control of magnetic nanoparticles is achieved through a spatial confinement growth strategy, preparing five different modalities of magnetic confined carbon fiber materials, effectively inhibiting magnetic agglomeration. Systematic studies have shown that the magnetic confinement network can refine CoNi NPs size and enhance strong magnetic coupling interactions. Compared to CoNi@HCNFs on the hollow carbon fibers (HCNFs) outer surface, HCNFs@CoNi constructed on the inner surface induce stronger spatial charge polarization relaxation at the interface and exhibit stronger magnetic coupling interactions at the inner surface due to the high-density magnetic coupling units at the micro/nanoscale, thereby respectively enhancing dielectric and magnetic losses. Remarkably, they achieve a minimum reflection loss (RLmin) of -64.54 dB and an absorption bandwidth of 5.60 GHz at a thickness of 1.77 mm. This work reveals the microscale mechanism of magnetic confinement-induced different polarization relaxation and magnetic response, providing a new strategy for designing magnetic materials.

Trifolium pratense as a novel phytogenic supplement, is an anticoccidial agent in chickens.

Coccidiosis, caused by a protozoan parasite of the genus Eimeria, is one of the most severe contagious parasite diseases affecting the poultry industry worldwide. Using phytogenics to prevent chicken coccidiosis is a strategy aimed at combating the increasing issue of drug-resistant strains of Eimeria spp. This study demonstrates the anticoccidial activities of a medicinal herb, Trifolium pratense (TP) powder, and its ethanolic extract (designated TPE) against Eimeria spp. TPE exhibited significant suppressive activity against E. maxima oocyst sporulation and E. tenella sporozoite invasion and reproduction in Madin-Darby bovine kidney cells. Furthermore, administration of basal chicken diets containing TP powder or TPE to Eimeria-infected chickens significantly reduced the output of oocysts and severity of intestinal lesions. Dietary supplementation with TP significantly improved relative weight gain in E. tenella- and E. acervulina-infected chickens, while there was no significant improvement in E. maxima-infected chickens. The anticoccidial activities of TP and TPE on E. acervulina, E. tenella and E. maxima were further supported by anticoccidial index scores, which showed greater efficacy than those of amprolium, a commercial coccidiostat used in poultry. TP supplementation positively impacted the primary metabolism of chickens challenged with E. tenella or E. acervulina. The chemical fingerprints of TPE were established using liquid column chromatography; TPE contained 4 major compounds: ononin, sissotrin, formononetin, and biochanin A. In addition, various spectrometric methods were used to ensure the batch-to-batch consistency of TP/TPE. In conclusion, T. pratense is demonstrated to be a novel phytogenic supplement that can be used to control Eimeria-induced coccidiosis in chickens.

Cryo-EM structure of DNA polymerase of African swine fever virus.

African swine fever virus (ASFV) is one of the most important causative agents of animal diseases and can cause highly fatal diseases in swine. ASFV DNA polymerase (DNAPol) is responsible for genome replication and highly conserved in all viral genotypes showing an ideal target for drug development. Here, we systematically determined the structures of ASFV DNAPol in apo, replicating and editing states. Structural analysis revealed that ASFV DNAPol had a classical right-handed structure and showed the highest similarity to the structure of human polymerase delta. Intriguingly, ASFV DNAPol has a much longer fingers subdomain, and the thumb and palm subdomain form a unique interaction that has never been seen. Mutagenesis work revealed that the loss of this unique interaction decreased the enzymatic activity. We also found that the ß-hairpin of ASFV DNAPol is located below the template strand in the editing state, which is different from the editing structures of other known B family DNAPols with the ß-hairpin above the template strand. It suggests that B family DNAPols have evolved two ways to facilitate the dsDNA unwinding during the transition from replicating into editing state. These findings figured out the working mechanism of ASFV DNAPol and will provide a critical structural basis for the development of antiviral drugs.

Strigolactones Negatively Regulate Tobacco Mosaic Virus Resistance in Nicotiana benthamiana.

Strigolactones (SLs) are plant hormones that regulate diverse developmental processes and environmental responses in plants. It has been discovered that SLs play an important role in regulating plant immune resistance to pathogens but there are currently no reports on their role in the interaction between Nicotiana benthamiana and the tobacco mosaic virus (TMV). In this study, the exogenous application of SLs weakened the resistance of N. benthamiana to TMV, promoting TMV infection, whereas the exogenous application of Tis108, a SL inhibitor, resulted in the opposite effect. Virus-induced gene silencing (VIGS) inhibition of two key SL synthesis enzyme genes, NtCCD7 and NtCCD8, enhanced the resistance of N. benthamiana to TMV. Additionally, we conducted a screening of N. benthamiana related to TMV infection. TMV-infected plants treated with SLs were compared to the control by using RNA-seq. The KEGG enrichment analysis and weighted gene co-expression network analysis (WGCNA) of differentially expressed genes (DEGs) suggested that plant hormone signaling transduction may play a significant role in the SL-TMV-N. benthamiana interactions. This study reveals new functions of SLs in regulating plant immunity and provides a reference for controlling TMV diseases in production.

Frontier and hotspot evolution in cerebrotendinous xanthomatosis: a bibliometric analysis from 1993 to 2023.

Background: Cerebrotendinous xanthomatosis (CTX) is an autosomal recessive disease associated with lipid metabolic disorders. Because of its clinical diversity and rarity, the diagnosis is often unclear. However, there is still a lack of reports on bibliometric analysis of CTX. The aim of this study was to assess the progress and research developments of CTX over the past three decades, identify emerging trends, and establish novel directions for future research. Methods: The eligible literature were screened from the Web of Science Core Collection (WoSCC) database. The annual publication, countries, institutions, authors, journals, keywords and references were visually analyzed by Microsoft Excel 2019, CiteSpace 6.2.R4, VOSviewer 1.6.18 and online bibliometrics website (https://bibliometric.com/). Results: A total of 561 publications from WoSCC were included in this study. The United States is the country with the largest number of publications, and Karolinska Institutet is the institution with the largest number of publications. Björkhem I. ranks as the most published and cited author in the last three decades. Journal of Lipid Research is the most widely published and cited journal. The strongest burst of keywords is "diagnosis." Conclusion: Unraveling the pathogenesis of CTX and improving its diagnosis and treatment continue to be critical challenges that require urgent attention. Future research endeavors will be centered on enhancing the efficiency and accuracy of early diagnosis and intervention.

Intercomparison of measured and modelled photochemical ozone production rates: Suggestion of chemistry hypothesis regarding unmeasured VOCs.

Ozone (O3) pollution is a severe environmental problem in China. The incomplete understanding of atmospheric photochemical reaction mechanisms prevents us from accurately understanding the chemistry of O3 production. Here, we used an improved dual-channel reaction chamber technique to measure net photochemical O3 production rate (P(O3)net) directly in Dongguan, a typical industrial city in China. The maximum P(O3)net was 46.3 ppbv h-1 during the observation period, which is at a relatively high level compared to previous observations under different environment worldwide. We employed an observation-based box model coupled with the state-of-the-art atmospheric chemical mechanism (MCM v3.3.1) to investigate the chemistry of O3 production. Under the base scenario, the modelling underestimates P(O3)net by ~30 %. Additionally considering HO2 uptake by ambient aerosols, inorganic deposition, and Cl chemistry only caused a small change (< 13 %) in the simulation of P(O3)net. Further analysis indicates that unmeasured reactive volatile organic compounds (VOCs), such as oxygenated VOCs and branched alkenes are potential contributors to the underestimation of P(O3)net. This study underscores the underestimation of P(O3)net in conventional atmospheric modelling setups, providing a crucial scientific foundation for further investigation aimed at promoting our understanding of photochemical O3 formation.

[Action mechanism of Huotu Jiji Pellets in the treatment of erectile dysfunction: An exploration based on network pharmacology and molecular docking].

OBJECTIVE: To explore the potential action mechanism of Huotu Jiji Pellets (HJP) in the treatment of erectile dysfunction (ED) based on network pharmacology and molecular docking. METHODS: We identified the main effective compounds and active molecular targets of HJP from the database of Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Integrative Pharmacology-Based Research Platform of Traditional Chinese Medicine (TCMIP) and the therapeutic target genes of ED from the databases of Genecards. Then we obtained the common targets of HJP and ED using the Venny software, constructed a protein-protein interaction (PPI) network of HJP acting on ED, and screened out the core targets with the Cytoscape software. Lastly we performed GO functional enrichment and KEGG pathway enrichment analyses of the core targets followed by molecular docking of HJP and the core targets using Chem3D and AutoDock Tools and QuickVina-W software. RESULTS: A total of 64 effective compounds, 822 drug-related targets, 1 783 disease-related targets and 320 common targets were obtained in this study. PPI network analysis showed that the core targets of HJP for ED included ESR1, HSP90AA1, SRC, and STAT3. GO functional enrichment analysis indicated the involvement of the core targets in such biological processes as response to xenobiotic stimulus, positive regulation of kinase activity, and positive regulation of MAPK cascade. KEGG pathway enrichment analysis suggested that PI3K-Akt, apoptosis, MAPK, HIF-1, VEGF, autophagy and other signaling pathways may be related to the mechanism of HJP acting on ED. Molecular docking prediction exhibited a good docking activity of the key active molecules of HJP with the core targets. CONCLUSION: This study showed that HJP acted on ED through multi-components, multi-targets and multi-pathways, which has provided some evidence and reference for the clinical treatment and subsequent studies of the disease.

Robust and Environmentally Friendly MXene-Based Electronic Skin Enabling the Three Essential Functions of Natural Skin: Perception, Protection, and Thermoregulation.

The development of electronic skin (e-skin) emulating the human skin's three essential functions (perception, protection, and thermoregulation) has great potential for human-machine interfaces and intelligent robotics. However, existing studies mainly focus on perception. This study presents a novel, eco-friendly, mechanically robust e-skin replicating human skin's three essential functions. The e-skin is composed of Ti3C2Tx MXene, polypyrrole, and bacterial cellulose nanofibers, where the MXene nanoflakes form the matrix, the bacterial cellulose nanofibers act as the filler, and the polypyrrole serves as a conductive "cross-linker". This design allows customization of the electrical conductivity, microarchitecture, and mechanical properties, integrating sensing (perception), EMI shielding (protection), and thermal management (thermoregulation). The optimal e-skin can effectively sense various motions (including minuscule artery pulses), achieve an EMI shielding efficiency of 63.32 dB at 78 µm thickness, and regulate temperature up to 129 °C in 30 s at 2.4 V, demonstrating its potential for smart robotics in complex scenarios.

A BODIPY-Ferrocene Conjugate for the Combined Photodynamic Therapy and Chemodynamic Therapy with Improved Antitumor Efficiency.

Photodynamic therapy (PDT) can destroy tumor cells by generating singlet oxygen (1O2) under light irradiation, which is limited by the hypoxia of the neoplastic tissue. Chemodynamic therapy (CDT) can produce toxic hydroxyl radical (•OH) to eradicate tumor cells by catalytic decomposition of endogenous hydrogen peroxide (H2O2), the therapeutic effect of which is highly dependent on the concentration of H2O2. Herein, we propose a BODIPY-ferrocene conjugate with a balanced 1O2 and •OH generation capacity, which can serve as a high-efficiency antitumor agent by combining PDT and CDT. The ferrocene moieties endow the as-prepared conjugates with the ability of chemodynamic killing of tumor cells. Moreover, combined PDT/CDT therapy with improved antitumor efficiency can be realized after exposure to light irradiation. Compared with the monotherapy by PDT or CDT, the BODIPY-ferrocene conjugates can significantly increase the intracellular ROS levels of the tumor cells after light irradiation, thereby inducing the tumor cell apoptosis at low drug doses. In this way, a synergistic antitumor treatment is achieved by the combination of PDT and CDT.

Hexagonal MoO3 Anode with Extremely High Capacity and Cyclability for Lithium-Ion Battery: A Combined Theoretical and Experimental Study.

It is essential and still remains a big challenge to obtain fast-charge anodes with large capacities and long lifespans for Li-ion batteries (LIBs). Among all of the alternative materials, molybdenum trioxide shows the advantages of large theoretical specific capacity, distinct tunnel framework, and low cost. However, there are also some key shortcomings, such as fast capacity decaying due to structural instability during Li insertion and poor rate performance due to low intrinsic electron conductivity and ion diffusion capability, dying to be overcome. A unique strategy is proposed to prepare Ti-h-MoO3-x@TiO2 nanosheets by a one-step hydrothermal approach with NiTi alloy as a control reagent. The density functional theory (DFT) calculations indicate that the doping of Ti element can make the hexagonal h-MoO3-x material show the best electronic structure and it is favor to be synthesized. Furthermore, the hexagonal Ti-h-MoO3-x material has better lithium storage capacity and lithium diffusion capacity than the orthogonal α-MoO3 material, and its theoretical capacity is more than 50% higher than that of the orthogonal α-MoO3 material. Additionally, it is found that Ti-h-MoO3-x@TiO2 as an anode displays extremely high reversible discharge/charge capacities of 1326.8/1321.3 mAh g-1 at 1 A g-1 for 800 cycles and 611.2/606.6 mAh g-1 at 5 A g-1 for 2000 cycles. Thus, Ti-h-MoO3-x@TiO2 can be considered a high-power-density and high-energy-density anode material with excellent stability for LIBs.

Transfer learning across different chemical domains: virtual screening of organic materials with deep learning models pretrained on small molecule and chemical reaction data.

Machine learning is becoming a preferred method for the virtual screening of organic materials due to its cost-effectiveness over traditional computationally demanding techniques. However, the scarcity of labeled data for organic materials poses a significant challenge for training advanced machine learning models. This study showcases the potential of utilizing databases of drug-like small molecules and chemical reactions to pretrain the BERT model, enhancing its performance in the virtual screening of organic materials. By fine-tuning the BERT models with data from five virtual screening tasks, the version pretrained with the USPTO-SMILES dataset achieved R2 scores exceeding 0.94 for three tasks and over 0.81 for two others. This performance surpasses that of models pretrained on the small molecule or organic materials databases and outperforms three traditional machine learning models trained directly on virtual screening data. The success of the USPTO-SMILES pretrained BERT model can be attributed to the diverse array of organic building blocks in the USPTO database, offering a broader exploration of the chemical space. The study further suggests that accessing a reaction database with a wider range of reactions than the USPTO could further enhance model performance. Overall, this research validates the feasibility of applying transfer learning across different chemical domains for the efficient virtual screening of organic materials.Scientific contributionThis study verifies the feasibility of applying transfer learning to large language models in different chemical fields to help organic materials perform virtual screening. Through the comparison of transfer learning from different chemical fields to a variety of organic material molecules, the high precision virtual screening of organic materials is realized.

Malleable, printable, bondable, and highly conductive MXene/liquid metal plasticine with improved wettability.

Integration of functional fillers into liquid metals (LM) induces rheology modification, enabling the free-form shaping of LM at the micrometer scale. However, integrating non-chemically modified low-dimensional materials with LM to form stable and uniform dispersions remain a great challenge. Herein, we propose a solvent-assisted dispersion (SAD) method that utilizes the fragmentation and reintegration of LM in volatile solvents to engulf and disperse fillers. This method successfully integrates MXene uniformly into LM, achieving better internal connectivity than the conventional dry powder mixing (DPM) method. Consequently, the MXene/LM (MLM) coating exhibits high electromagnetic interference (EMI) shielding performance (105 dB at 20 µm, which is 1.6 times that of coatings prepared by DPM). Moreover, the rheological characteristic of MLM render it malleable and facilitates direct printing and adaptation to diverse structures. This study offers a convenient method for assembling LM with low-dimensional materials, paving the way for the development of multifunctional soft devices.

Connectivity preservation control for multiple unmanned aerial vehicles in the presence of bounded actuation.

This paper proposes a novel multi-unmanned aerial vehicle (UAV) connectivity preservation controller, suitable for scenarios with bounded actuation and limited communication range. According to the hierarchical control strategy, controllers are designed separately for the position and attitude subsystems. A distributed position controller is developed, integrating an indirect coupling control mechanism. The innovative mechanism associates each UAV with a virtual proxy, facilitating connections among adjacent UAVs through these proxies. This structuring assists in managing the actuator saturation constraints effectively. The artificial potential function is utilized to preserve network connectivity and fulfill coordination among all virtual proxies. Additionally, an attitude controller designed for finite-time convergence guarantees that the attitude subsystem adheres precisely to the attitude specified by the distributed position controller. Simulation results validate the efficacy of this distributed formation controller with connectivity preservation under bounded actuation conditions. The simulation results confirm the effectiveness of the distributed connectivity preservation controller with bounded actuation.

[Mongolian medicine Naru-3 reduces neuroinflammation in maintenance stage of neuropathic pain by inhibiting astrocyte activation].

Neuropathic pain(NP) is difficult to be treated since it has similar phenotypes but different pathogenesis in different pathological stages. Targeted intervention of the core regulatory elements at different pathological stages of NP has become a new direction of drug research and development in recent years and provides the possibility for the treatment of NP. The Mongolian medicine Naru-3(NR-3) is effective in the treatment of sciatica and trigeminal neuralgia, the mechanisms of which remain unknown. On the basis of the previous study of the priming stage, this study established the mouse model of spinal nerve ligation(SNL) and measured the changes of pain thresholds by behavioral tests. The network analysis, Western blot, immunofluorescence assay, ELISA, and agonist/antagonist were employed to decipher the mechanism of NR-3 in the treatment of NP in the maintenance stage. The results showed that NR-3 increased the mechanical and thermal pain thresholds of SNL mice, while it had no significant effect on the basal pain threshold of normal mice. NR-3 may relieve the pain in the maintenance stage of NP by blocking the matrix metalloproteinase 2(MMP2)/interleukin-1ß(IL-1ß) pathway in the astrocytes of the dorsal root ganglion(DRG) and spinal cord. The findings have enriched the biological connotation of NR-3 in the treatment of the maintenance stage of NP and provide reference for the rational use of this medicine in clinical practice.

Colloidal TiO2 nanocrystals with engineered defectivity and optical properties.

Partially reduced forms of titanium dioxide (sometimes called "black" titania) have attracted widespread interest as promising photocatalysts of oxidation due to their absorption in the visible region. The main approaches to produce it rely on postprocessing at high temperatures (up to 800 °C) and high pressures (up to 40 bar) or on highly reactive precursors (e.g., TiH2), and yield powders with poorly controlled sizes, shapes, defect concentrations and distributions. We describe an approach for the one-step synthesis of TiO2 colloidal nanocrystals at atmospheric pressure and temperatures as low as 280 °C. The temperature of the reaction allows the density of oxygen vacancies to be controlled by nearly two orders of magnitude independently of their size, shape, or colloidal stability. This synthetic pathway appears to produce vacancies that are homogeneously distributed in the nanocrystals, rather than being concentrated in an amorphous shell. As a result, the defects are protected from oxidation and result in stable optical properties in oxidizing environments.

Role of ERß in the ovary and ovary related diseases.

Estrogen and estrogen receptors (ERα and ERß) regulate a multitude of complicated physiological and pathological processes. Jan-Ake Gustafsson's group discovered ERß in 1996, this crucial finding gives us new insights into the understanding of estrogen signaling. ERß is highly expressed in the ovary and particularly exists in granulosa cells (GCs). ERß is a key transcription factor in the maintenance of ovarian granulosa cell growth, differentiation, and homeostasis, and the ovulation function of ovarian follicles and oocytes. Additionally, ERß can modulate the steroidogenic transcriptional program through phosphorylation and regulate both gonadotropin response and FOXL2 expression within the ovary. In this review, we focus on the role of ERß in regulating ovarian granulosa cell development and homeostasis, particularly its significance in ovarian cancer (OC), premature ovarian failure (POF), and polycystic ovary syndrome (PCOS). It also highlights the prospects of small molecule compounds targeting ERß, providing a new strategy for the treatment of ovarian-related diseases.

Seizure control and adverse outcomes of lamotrigine use during pregnancy: A systematic review and meta-analysis.

OBJECTIVE: This review aims to summarize existing evidence on the adverse pregnancy outcomes and seizure control effects of using lamotrigine (LTG) monotherapy in pregnancy women with epilepsy (WWE) during pregnancy. METHODS: A comprehensive search was conducted in various databases including Cochrane, Web of Science, CBM, PubMed, Embase, CNKI, and Pregnancy Registration Center databases to identify relevant studies. The search was concluded up to January 2024. Studies comparing LTG with other antiseizure medications (ASMs) for treating epilepsy in pregnant women were included, with no language or regional restrictions. RESULTS: A total of 19 studies were included for analysis, with 16 studies reporting adverse pregnancy outcomes and 6 studies reporting seizure control outcomes. Meta-analysis showed that compared to monotherapy with carbamazepine (CBZ), sodium valproate (VPA), and levetiracetam (LEV), LTG monotherapy had a slightly weaker ability to control seizures during pregnancy, with ORs and 95 %CIs of 0.65 (0.57-0.75; CBZ), 0.50 (0.32-0.79; VPA), and 0.55 (0.36-0.84; LEV). Regarding adverse pregnancy outcomes, the occurrence rate of LTG monotherapy was significantly lower than that of CBZ, VPA, phenytoin (PHT), and phenobarbital (PHB), with ORs and 95 %CIs ranging from 0.30 (0.25-0.35; VPA) to 0.68 (0.56-0.81; CBZ). CONCLUSION: Based on meta-analysis, LTG and LEV appear to be preferred medications for controlling seizures during pregnancy. This review provides further support for the use of LTG monotherapy in pregnant WWE, building upon existing evidence for clinical practitioners.

Effect of Silica Crystalline State on Hydration Products of Tricalcium Silicate at High Temperatures.

The mechanical performance of grade G oil well cement stones declines significantly when subjected to temperatures exceeding 110 °C; the strategy to mitigate the impact of high temperatures is by incorporating siliceous materials. However, it is important to note that the crystalline properties of siliceous materials vary, leading to different effects on the temperature reduction. This study focuses on tricalcium silicate (C3S), the primary component of oil well cement. The impact of different types of silica, including amorphous silica (nanosilica, silica fume) and crystalline silica (quartz sand), on the hydration of C3S was investigated using 1H NMR, XRD, TGA, and SEM-EDS analyses. The results show that siliceous materials can significantly prevent the strength decrease of C3S hardening products at high temperatures and inhibit the rise of porosity and permeability. Adding excessive amorphous siliceous materials, such as nanosilica, can cause agglomeration, resulting in a porous structure of C3S hardening products and hindering their strength. Amorphous silica fume is more reactive than crystalline silica sand and can rapidly initiate a pozzolanic reaction with calcium hydroxide. Siliceous materials also convert high-Ca/Si of C-S-H (hillebrandite, jaffeite, and reinhardbraunsite) into low-Ca/Si of C-S-H (gyrolite, okenite, tobermorite, nekoite). Siliceous materials reduce the porosity and permeability of C3S hardening products and enhance their mechanical properties through the filling and transformation of hydration products.

Responsive Multi-Arm PEG-Modified COF Nanocomposites: Dynamic Photothermal, pH/ROS Dual-Responsive, Targeted Carriers for Rheumatoid Arthritis Treatment.

Rheumatoid arthritis (RA) is a chronic immune disease characterized by the infiltration of immune cells and the proliferation of fibroblast-like synoviocytes (FLS) at the joint site, leading to inflammation and joint destruction. However, the available treatment options targeting both inflammatory and proliferative FLS are limited. Herein, this work presents three covalent organic frameworks (COFs) photothermal composite systems modified with multi-armed polyethylene glycols (PEG) for the treatment of RA. These systems exhibit a dual response under low pH and high reactive oxygen species (ROS) conditions at the site of inflammation, with a specific focus on delivering the protein drug ribonuclease A (RNase A). Notably, molecular docking studies reveal the interaction between RNase A and NF-κB p65 protein, and Western blotting confirm its inhibitory effect on NF-κB activity. In vitro and in vivo experiments verify the significant reduction in joint swelling and deformities in adjuvant-induced arthritis (AIA) rats after treatment with RNase A delivered by multi-armed PEG-modified COF ligands, restoring joint morphology to normal. These findings underscore the promising therapeutic potential of COFs for the treatment of RA, highlighting their unique capabilities in addressing both inflammatory and proliferative aspects of the disease and expanding the scope of biomedical applications for COFs.

Synergistic cytotoxicity of histone deacetylase and poly-ADP ribose polymerase inhibitors and decitabine in pancreatic cancer cells: Implications for novel therapy.

Histone deacetylase inhibitors (HDACi) can modulate the acetylation status of proteins, influencing the genomic instability exhibited by cancer cells. Poly (ADP ribose) polymerase (PARP) inhibitors (PARPi) have a direct effect on protein poly (ADP-ribosyl)ation, which is important for DNA repair. Decitabine is a nucleoside cytidine analogue, which when phosphorylated gets incorporated into the growing DNA strand, inhibiting methylation and inducing DNA damage by inactivating and trapping DNA methyltransferase on the DNA, thereby activating transcriptionally silenced DNA loci. We explored various combinations of HDACi and PARPi +/- decitabine (hypomethylating agent) in pancreatic cancer cell lines BxPC-3 and PL45 (wild-type BRCA1 and BRCA2) and Capan-1 (mutated BRCA2). The combination of HDACi (panobinostat or vorinostat) with PARPi (talazoparib or olaparib) resulted in synergistic cytotoxicity in all cell lines tested. The addition of decitabine further increased the synergistic cytotoxicity noted with HDACi and PARPi, triggering apoptosis (evidenced by increased cleavage of caspase 3 and PARP1). The 3-drug combination treatments (vorinostat, talazoparib, and decitabine; vorinostat, olaparib, and decitabine; panobinostat, talazoparib, and decitabine; panobinostat, olaparib, and decitabine) induced more DNA damage (increased phosphorylation of histone 2AX) than the individual drugs and impaired the DNA repair pathways (decreased levels of ATM, BRCA1, and ATRX proteins). The 3-drug combinations also altered the epigenetic regulation of gene expression (NuRD complex subunits, reduced levels). This is the first study to demonstrate synergistic interactions between the aforementioned agents in pancreatic cancer cell lines and provides preclinical data to design individualized therapeutic approaches with the potential to improve pancreatic cancer treatment outcomes.