Directly Suppressing MYC Function with Novel Alkynyl-Substituted Phenylpyrazole Derivatives that Induce Protein Degradation and Perturb MYC/MAX Interaction.

Despite being a highly sought-after therapeutic target for human malignancies, myelocytomatosis viral oncogene homologue (MYC) has been considered intractable due to its intrinsically disordered nature, making the discovery of in vivo effective inhibitors that directly block its function challenging. Herein, we report structurally novel alkynyl-substituted phenylpyrazole derivatives directly perturbing MYC function. Among them, compound 37 exhibited superior antiproliferative activities to those of MYCi975 against multiple malignant cell lines. It induced dose-dependent MYC degradation in cells with degradation observed at the concentration as low as 1.0 µM. Meanwhile, its direct suppression of MYC function was confirmed by the capability to inhibit the binding of MYC/MYC-associated protein X (MAX) heterodimer to DNA consensus sequence, induce MYC thermal instability, and disturb MYC/MAX interaction. Moreover, 37 demonstrated enhanced therapeutic efficacy over MYCi975 in a mouse allograft model of prostate cancer. Overall, 37 deserves further development for exploring MYC-targeting cancer therapeutics.

Micropattern Fabricated by Acropetal Migration Controlled through Sequential Photo and Thermal Polymerization.

Bottom-up patterning technology plays a significant role in both nature and synthetic materials, owing to its inherent advantages such as ease of implementation, spontaneity, and noncontact attributes, etc. However, constrained by the uncontrollability of molecular movement, energy interaction, and stress, obtained micropatterns tend to exhibit an inevitable arched outline, resulting in the limitation of applicability. Herein, inspired by auxin's action mode in apical dominance, a versatile strategy is proposed for fabricating precision self-organizing micropatterns with impressive height based on polymerization-induced acropetal migration. The copolymer containing fluorocarbon chains (low surface energy) and tertiary amine (coinitiator) is designed to self-assemble on the surface of the photo-curing system. The selective exposure under a photomask establishes a photocuring boundary and the radicals would be generated on the surface, which is pivotal in generating a vertical concentration difference of monomer. Subsequent heating treatment activates the material continuously transfers from the unexposed area to the exposed area and is accompanied by the obviously vertical upward mass transfer, resulting in the manufacture of a rectilinear profile micropattern. This strategy significantly broadens the applicability of self-organizing patterns, offering the potential to mitigate the complexity and time-consuming limitations associated with top-down methods.

CO2 electrolysis to multi-carbon products in strong acid at ampere-current levels on La-Cu spheres with channels.

Achieving satisfactory multi-carbon (C2+) products selectivity and current density under acidic condition is a key issue for practical application of electrochemical CO2 reduction reaction (CO2RR), but is challenging. Herein, we demonstrate that combining microenvironment modulation by porous channel structure and intrinsic catalytic activity enhancement via doping effect could promote efficient CO2RR toward C2+ products in acidic electrolyte (pH ≤ 1). The La-doped Cu hollow sphere with channels exhibits a C2+ products Faradaic efficiency (FE) of 86.2% with a partial current density of -775.8 mA cm-2. CO2 single-pass conversion efficiency for C2+ products can reach 52.8% at -900 mA cm-2. Moreover, the catalyst still maintains a high C2+ FE of 81.3% at -1 A cm-2. The channel structure plays a crucial role in accumulating K+ and OH- species near the catalyst surface and within the channels, which effectively suppresses the undesired hydrogen evolution and promotes C-C coupling. Additionally, the La doping enhances the generation of *CO intermediate, and also facilitates C2+ products formation.

Cocaine and amphetamine-regulated transcript improves myocardial ischemia-reperfusion injury through PI3K/AKT signalling pathway.

Myocardial ischemia-reperfusion injury (MIRI) is a common clinic scenario that occurs in the context of reperfusion therapy for acute myocardial infarction. It has been shown that cocaine and amphetamine-regulated transcript (CART) can ameliorate cerebral ischemia-reperfusion (I/R) injury, but the effect of CART on MIRI has not been studied yet. Here, we revealed that CART protected the heart during I/R process by inhibiting apoptosis and excessive autophagy, indicating that CART would be a potential drug candidate for the treatment of MIRI. Further analysis showed that CART upregulated the activation of phospho-AKT, leading to downregulation of lactate dehydrogenase (LDH) release, apoptosis, oxidative stress and excessive autophagy after I/R, which was inhibited by PI3K inhibitor, LY294002. Collectively, CART attenuated MIRI through inhibition of cardiomyocytes apoptosis and excessive autophagy, and the protective effect was dependent on PI3K/AKT signalling pathway.

Natural mineral and industrial solid waste-based adsorbent for perfluorooctanoic acid and perfluorooctane sulfonate removal from surface water: Advances and prospects.

PER: and polyfluorinated alkyl substances, especially perfluorooctanoic acid and perfluorooctane sulfonic acid (PFOX), have attracted considerable attention lately because of their widespread occurrence in aquatic environment and potential biological toxicity to animals and human beings. The development of economical, efficient, and engineerable adsorbents for removing PFOX in water has become one of the research focuses. This review summarized the recent progress on natural mineral and industrial solid based adsorbent (NM&ISW-A) and removal mechanisms concerning PFOX onto NM&ISW-A, as well as proposed the current challenges and future perspectives of using NM&ISW-A for PFOX removal in water. Kaolinite and montmorillonite are usually used as model clay minerals for PFOX removal, and have been proved to adsorb PFOX by ligand exchange and electrostatic attraction. Fe-based minerals, such as goethite, magnetite, and hematite, have better PFOX adsorption capacity than clay minerals. The adsorbent prepared from industrial solid waste by high temperature roasting has great potential application prospects. Fabricating nanomaterials, amination modification, surfactant modification, fluorination modification, developing versatile composites, and designing special porous structure are beneficial to improve the adsorption performance of PFOX onto NM&ISW-A by enhancing the specific surface area, positive charge, and hydrophobicity. Electrostatic interaction, hydrophobic interaction, hydrogen bond, ligand and ion exchange, and self-aggregation (formation of micelle or hemimicelle) are the main adsorption mechanisms of PFOX by NM&ISW-A. Among them, electrostatic and hydrophobic interactions play a considerable role in the removal of PFOX by NM&ISW-A. Therefore, NM&ISW-A with electrostatic functionalities and considerable hydrophobic segments enables rapid, efficient, and high-capacity removal of PFOX. The future directions of NM&ISW-A for PFOX removal include the preparation and regeneration of engineerable NM&ISW-A, the development of coupling technology for PFOX removal based on NM&ISW-A, the in-depth research on adsorption mechanism of PFOX by NM&ISW-A, as well as the development of NM&ISW-A for PFOX alternatives removal. This review paper would be helpful the comprehensive understanding of NM&ISW-A potential for PFOX removal and the PFOX removal mechanisms, and identifies the gaps for future research and development.

Intertwined role of mechanism identification by DFT-XAFS and engineering considerations in the evolution of P adsorbents.

Adsorption method exhibits promising potential in effectively removal of phosphate from wastewater, yet it faces tremendous challenges in practical application. Limited comprehension of adsorption mechanisms and the lack of evaluation method for scaling up application are the two main obstacles. To fully realize the practical application of P adsorbents, we reviewed advanced tools, including density functional theory (DFT) and/or X-ray absorption fine structure (XAFS) to elucidate mechanisms, underscored the significance of thermodynamics and kinetics in engineering design, and proposed strategies for regenerating and reusing P adsorbents. Specifically, we delved into the utilization of DFT and XAFS to gain insights into adsorption mechanisms, focusing on active site verification and molecular interaction configurations. Additionally, we explored precise calculation methods for adsorption thermodynamics and adsorption kinetics, encompassing thermodynamic equilibrium constants, reactor selection, and the regeneration, recovery, and disposal of P adsorbents. Our comprehensive review aims to serve as a guiding light in advancing the development of highly efficient P adsorbents for engineering applications.

Peniapyrones A-I, Cytotoxic Tricyclic-Fused α-Pyrone Derivatives from an Endophytic Penicillium brefeldianum F4a.

Five cyclopenta[d]pyrano[4,3-b]pyran-1,7(6H)-dione 6/6/5-fused tricyclic ring system containing metabolites peniapyrones A-E (1-5), and four previously undescribed cyclopenta[4,5]furo[3,2-c]pyran-1-one 6/5/5-fused tricyclic ring system containing compounds peniapyrones F-I (6-9), were isolated from the endophytic Penicillium brefeldianum F4a. Their structures, including absolute configurations, were determined through spectroscopic analysis and quantum chemical calculations. Peniapyrones D (4) and E (5) were a pair of diastereoisomers. Compounds 1, 3, and 5-9 showed cytotoxic activity against AsPC-1, CRL-2234, and MCF-7 cancer cell lines. Compounds 1, 3, 6, 8, and 9 inhibited the Kirsten rat sarcoma viral oncogene homologue (KRAS) mutant AsPC-1 cell line.

Heat-resistant boron-nitrogen doped lignin-derived adsorbent-catalyst for gaseous aromatic pollutants removal.

Lignin-based carbon material can be utilized as carbonaceous adsorbents for the removal of toxic gaseous organic pollutants, while the poor heat-resistance limited its widely application. Here in, B-N co-doped lignin carbon (BN-C) with high thermal stability was synthesized, and the optimized BN-C (1:2) exhibited notably improved heat resistance with the decomposition temperature up to 505 °C, and excellent adsorption capacity for o-dichlorobenzene (o-DCB) (1510.0 mg/g) and toluene (947.3 mg/g), together with good cyclic stability over 10 cycles for o-dichlorobenzene. The existence of abundant hexagonal boron nitride (h-BN) with good thermal conductivity contributed to the superior heat-resistance of BN-C (1:2), and the high specific surface area (1764.5 m2/g), enriched hydroxyl functional groups and improved graphitization degree contributed to its enhanced adsorption performance. More importantly, BN-C (1:2) supported Ru could effectively remove o-DCB and toluene at wide temperature range (50-300 °C). The present work guided the development of heat-resistant lignin-derived adsorbent-catalyst for gaseous aromatic pollutants removal, which benefits both environmental protection and resource utilization.

Development of Aptamer-DNAzyme based metal-nucleic acid frameworks for gastric cancer therapy.

The metal-nucleic acid nanocomposites, first termed metal-nucleic acid frameworks (MNFs) in this work, show extraordinary potential as functional nanomaterials. However, thus far, realized MNFs face limitations including harsh synthesis conditions, instability, and non-targeting. Herein, we discover that longer oligonucleotides can enhance the synthesis efficiency and stability of MNFs by increasing oligonucleotide folding and entanglement probabilities during the reaction. Besides, longer oligonucleotides provide upgraded metal ions binding conditions, facilitating MNFs to load macromolecular protein drugs at room temperature. Furthermore, longer oligonucleotides facilitate functional expansion of nucleotide sequences, enabling disease-targeted MNFs. As a proof-of-concept, we build an interferon regulatory factor-1(IRF-1) loaded Ca2+/(aptamer-deoxyribozyme) MNF to target regulate glucose transporter (GLUT-1) expression in human epidermal growth factor receptor-2 (HER-2) positive gastric cancer cells. This MNF nanodevice disrupts GSH/ROS homeostasis, suppresses DNA repair, and augments ROS-mediated DNA damage therapy, with tumor inhibition rate up to 90%. Our work signifies a significant advancement towards an era of universal MNF application.

Modelling the dynamic gas/particle partitioning process of semi-volatile organic compounds emitted from point sources: Quantitative analysis and impact assessment.

The deleterious impact of pollution point sources on the surrounding environment and human has long been a focal point of environmental research. When considering the local atmospheric dispersion of semi-volatile organic compounds (SVOCs) around the emission sites, it is essential to account the dynamic process for the gas/particle (G/P) partitioning, which involves the transition from an initial state to a steady state. In this study, we have developed a model that enables the prediction of the dynamic process for G/P partitioning of SVOCs, particularly considering the influence from emission. It is important to note that the dynamic processes of the concentrations of SVOCs in particle phase (CP) and in gas phase (CG) differ significantly. These differences arise due to the influence of two critical factors: particulate proportion of SVOCs in the emissions (ϕ0) and octanol-air partitioning coefficient (KOA). The validity of our model was assessed by comparing its predictions of the extremum value of the G/P partitioning quotient (KP) with the results obtained from the steady-state model. Remarkably, the characteristic time (tC), used to evaluate the timescale required for SVOCs to reach steady state, demonstrated different variations with KOA for CP and CG. Additionally, the values of tC were quite different for CP and CG, which were markedly influenced by ϕ0. For some SVOCs with high KOA values, it took approximately 35 h to reach steady state. Furthermore, it was found that the time to achieve 95 % of steady state (t95 ≈ 3tC) could reach approximately 105 h. This duration is sufficient for chemicals to disperse from their emission site to the surrounding areas. Therefore, it is crucial to consider the dynamic process of G/P partitioning in local atmospheric transport studies. Moreover, the influence of ϕ0 should be incorporated into future investigations examining the dynamic process of G/P partitioning.

Photochemical Design for Diverse Controllable Patterns in Self-Wrinkling Films.

Harnessing the spontaneous surface instability of pliable substances to create intricate, well-ordered, and on-demand controlled surface patterns holds great potential for advancing applications in optical, electrical, and biological processes. However, the current limitations stem from challenges in modulating multidirectional stress fields and diverse boundary environments. Herein, this work proposes a universal strategy to achieve arbitrarily controllable wrinkle patterns via the spatiotemporal photochemical boundaries. Utilizing constraints and inductive effects of the photochemical boundaries, the multiple coupling relationship is accomplished among the light fields, stress fields, and morphology of wrinkles in photosensitive polyurethane (PSPU) film. Moreover, employing sequential light-irradiation with photomask enables the attainment of a diverse array of controllable patterns, ranging from highly ordered 2D patterns to periodic or intricate designs. The fundamental mechanics of underlying buckling and the formation of surface features are comprehensively elucidated through theoretical stimulation and finite element analysis. The results reveal the evolution laws of wrinkles under photochemical boundaries and represent a new effective toolkit for fabricating intricate and captivating patterns in single-layer films.

Synthesis of Hydroxylamine via Ketone-Mediated Nitrate Electroreduction.

Hydroxylamine (HA, NH2OH) is a critical feedstock in the production of various chemicals and materials, and its efficient and sustainable synthesis is of great importance. Electroreduction of nitrate on Cu-based catalysts has emerged as a promising approach for green ammonia (NH3) production, but the electrosynthesis of HA remains challenging due to overreduction of HA to NH3. Herein, we report the first work on ketone-mediated HA synthesis using nitrate in water. A metal-organic-framework-derived Cu catalyst was developed to catalyze the reaction. Cyclopentanone (CP) was used to capture HA in situ to form CP oxime (CP-O) with C═N bonds, which is prone to hydrolysis. HA could be released easily after electrolysis, and CP was regenerated. It was demonstrated that CP-O could be formed with an excellent Faradaic efficiency of 47.8%, a corresponding formation rate of 34.9 mg h-1 cm-2, and a remarkable carbon selectivity of >99.9%. The hydrolysis of CP-O to release HA and CP regeneration was also optimized, resulting in 96.1 mmol L-1 of HA stabilized in the solution, which was significantly higher than direct nitrate reduction. Detailed in situ characterizations, control experiments, and theoretical calculations revealed the catalyst surface reconstruction and reaction mechanism, which showed that the coexistence of Cu0 and Cu+ facilitated the protonation and reduction of *NO2 and *NH2OH desorption, leading to the enhancement for HA production.

Design, synthesis, and evaluation of the novel ozagrel-paeonol codrug with antiplatelet aggregation activities as a potent anti-stroke therapeutic agent.

Introduction: Ischemic stroke is the second most common chronic disease worldwide and is associated with high morbidity and mortality. Thromboembolism and platelet aggregation are the most characteristic features of stroke. Other than aspirin, no standard, accepted, or effective treatment for acute ischemic stroke has been established. Consequently, it is essential to identify novel therapeutic compounds for this condition. Methods: In this study, novel ozagrel/paeonol-containing codrugs were synthesized and characterized using 1H-NMR, 13C-NMR, and mass spectroscopy. Their antiplatelet aggregation activity was evaluated, with compound PNC3 found to exhibit the best effect. Subsequently, studies were conducted to assess its neuroprotective effect, pharmacokinetic properties and model its binding mode to P2Y12 and TXA2, two proteins critical for platelet aggregation. Results: The results indicated that PNC3 has good bioavailability and exerts protective effects against oxygen-glucose deprivation injury in PC12 cells. Molecular docking analysis further demonstrated that the compound interacts with residues located in the active binding sites of the target proteins. Conclusion: The codrugs synthesized in this study display promising pharmacological activities and have the potential for development as an oral formulation.

Hypothermia protects the integrity of corticospinal tracts and alleviates mitochondria injury after intracerebral hemorrhage in mice.

Disruption of corticospinal tracts (CST) is a leading factor for motor impairments following intracerebral hemorrhage (ICH) in the striatum. Previous studies have shown that therapeutic hypothermia (HT) improves outcomes of ICH patients. However, whether HT has a direct protection effect on the CST integrity and the underlying mechanisms remain largely unknown. In this study, we employed a chemogenetics approach to selectively activate bilateral warm-sensitive neurons in the preoptic areas to induce a hypothermia-like state. We then assessed effects of HT treatment on the integrity of CST and motor functional recovery after ICH. Our results showed that HT treatment significantly alleviated axonal degeneration around the hematoma and the CST axons at remote midbrain region, ultimately promoted skilled motor function recovery. Anterograde and retrograde tracing revealed that HT treatment protected the integrity of the CST over an extended period. Mechanistically, HT treatment prevented mitochondrial swelling in degenerated axons around the hematoma, alleviated mitochondrial impairment by reducing mitochondrial ROS accumulation and improving mitochondrial membrane potential in primarily cultured cortical neurons with oxyhemoglobin treatment. Serving as a proof of principle, our study provided novel insights into the application of HT to improve functional recovery after ICH.

Quantitative proteomics of the miR-301a/SOCS3/STAT3 axis reveals underlying autism and anxiety-like behavior.

Autism is a widespread neurodevelopmental disorder. Although the research on autism spectrum disorders has been increasing in the past decade, there is still no specific answer to its mechanism of action and treatment. As a pro-inflammatory microRNA, miR-301a is abnormally expressed in various psychiatric diseases including autism. Here, we show that miR-301a deletion and inhibition exhibited two distinct abnormal behavioral phenotypes in mice. We observed that miR-301a deletion in mice impaired learning/memory, and enhanced anxiety. On the contrary, miR-301a inhibition effectively reduced the maternal immune activation (MIA)-induced autism-like behaviors in mice. We further demonstrated that miR-301a bound to the 3'UTR region of the SOCS3, and that inhibition of miR-301a led to the upregulation of SOCS3 in hippocampus. The last result in the reduction of the inflammatory response by inhibiting phosphorylation of AKT and STAT3, and the expression level of IL-17A in poly(I:C)-induced autism-like features in mice. The obtained data revealed the miR-301a as a critical participant in partial behavior phenotypes, which may exhibit a divergent role between gene knockout and knockdown. Our findings ascertain that miR-301a negatively regulates SOCS3 in MIA-induced autism in mice and could present a new therapeutic target for ameliorating the behavioral abnormalities of autism.

m6A/m1A/m5C-Associated Methylation Alterations and Immune Profile in MDD.

Major depressive disorder (MDD) is a prevalent psychiatric condition often accompanied by severe impairments in cognitive and functional capacities. This research was conducted to identify RNA modification-related gene signatures and associated functional pathways in MDD. Differentially expressed RNA modification-related genes in MDD were first identified. And a random forest model was developed and distinct RNA modification patterns were discerned based on signature genes. Then, comprehensive analyses of RNA modification-associated genes in MDD were performed, including functional analyses and immune cell infiltration. The study identified 29 differentially expressed RNA modification-related genes in MDD and two distinct RNA modification patterns. TRMT112, MBD3, NUDT21, and IGF2BP1 of the risk signature were detected. Functional analyses confirmed the involvement of RNA modification in pathways like phosphatidylinositol 3-kinase signaling and nucleotide oligomerization domain (NOD)-like receptor signaling in MDD. NUDT21 displayed a strong positive correlation with type 2 T helper cells, while IGF2BP1 negatively correlated with activated CD8 T cells, central memory CD4 T cells, and natural killer T cells. In summary, further research into the roles of NUDT21 and IGF2BP1 would be valuable for understanding MDD prognosis. The identified RNA modification-related gene signatures and pathways provide insights into MDD molecular etiology and potential diagnostic biomarkers.

Design, Synthesis, and Biological Evaluation of Pierardine Derivatives as Novel Brain-Penetrant and In Vivo Potent NMDAR-GluN2B Antagonists for Ischemic Stroke Treatment.

A series of structurally novel GluN2B NMDAR antagonists were designed, synthesized, and biologically evaluated as anti-stroke therapeutics by optimizing the chemical structure of Pierardine, the active ingredient of traditional Chinese medicine Dendrobium aphyllum (Roxb.) C. E. Fischer identified via in silico screening. The systematic structure-activity relationship study led to the discovery of 58 with promising NMDAR-GluN2B binding affinity and antagonistic activity. Of the two enantiomers, S-58 exhibited significant inhibition (IC50 = 74.01 ± 12.03 nM) against a GluN1/GluN2B receptor-mediated current in a patch clamp assay. In addition, it displayed favorable specificity over other subtypes and off-target receptors. In vivo, S-58 exerted therapeutic efficacy comparable to that of the approved GluN2B NMDAR antagonist ifenprodil and excellent safety profiles. In addition to the attractive in vitro and in vivo potency, S-58 exhibited excellent brain exposure. In light of these merits, S-58 has been advanced to further preclinical investigation as a potential anti-stroke candidate.

Comparative skin histological and transcriptomic analysis of Rana kukunoris with two different skin colors.

This study compares the skin structures of Rana kukunoris with two different skin colors living in the same area of Haibei in the Northeastern Qinghai-Tibet Plateau. The skin thickness of the khaki R. kukunoris was significantly greater than that of the brown R. kukunoris (P < 0.01), and significantly more mucous and granular glands were present on the dorsal skin of the khaki frog (P < 0.05). Meanwhile, the melanocytes on the dorsal skin of the brown frog were significantly larger than those on the khaki one (P < 0.05). Morphological changes in the expansion and aggregation of melanocytes seemed to deepen the skin color of R. kukunoris. Moreover, transcriptome sequencing identified tyrosine metabolism, melanogenesis, and riboflavin metabolism as the main pathways involved in melanin formation and metabolism in brown R. kukunoris. TYR, MC1R was upregulated as the skin color of R. kukunoris was deepened and contributed to melanin production and metabolism. In contrast, the khaki frog had significantly more upregulated genes and metabolic pathways related to autoimmunity. The khaki frog appeared to defend against ultraviolet (UV) radiation-induced damage by secreting mucus and small molecular peptides, whereas the brown frog protected itself by distributing a large amount of melanin. Hence, the different skin colors of R. kukunoris might represent different adaptation strategies for survival in the intense UV radiation environment of the Qinghai-Tibet Plateau.

Asymmetric adhesive SIS-based wound dressings for therapeutically targeting wound repair.

Severe tissue injuries pose a significant risk to human health. Conventional wound dressings fall short in achieving effective tissue regeneration, resulting in suboptimal postoperative healing outcomes. In this study, an asymmetric adhesive wound dressing (marked as SIS/PAA/LAP) was developed, originating from acrylate acid (AA) solution with laponite (LAP) nanoparticles polymerization and photo-crosslinked on the decellularized extracellular matrix small intestinal submucosa (SIS) patch. Extensive studies demonstrated that the SIS/PAA/LAP exhibited higher tissue adhesion strength (~ 33 kPa) and burst strength (~ 22 kPa) compared to conventional wound dressings like Tegaderm and tissue adhesive products. Importantly, it maintained favorable cell viability and demonstrated robust angiogenic capacity. In animal models of full-thickness skin injuries in rats and skin injuries in Bama miniature pigs, the SIS/PAA/LAP could be precisely applied to wound sites. By accelerating the formation of tissue vascularization, it displayed superior tissue repair outcomes. This asymmetrically adhesive SIS-based patch would hold promising applications in the field of wound dressings.