Degradation Efficacy Research Articles

Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins

AbstractTargeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis‐related proteins. Aptamer‐based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off‐target effects due to the non‐covalent interaction with target proteins. We here report the first design of a covalent aptamer‐based autophagosome‐tethering chimera (CApTEC) for the enhanced autophagic degradation of cell‐surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL). This strategy relies on the site‐specific incorporation of sulfonyl fluoride groups onto aptamers to enable the cross‐linking with target proteins, coupled with the conjugation of an LC3 ligand to hijack the autophagy‐lysosomal pathway for targeted protein degradation. The chemically engineered CApTECs exhibit enhanced on‐target retention and improved structural stability. Our results also demonstrate that CApTECs achieve remarkably enhanced and prolonged degradation of membrane proteins compared to the non‐covalent designs. Furthermore, the CApTEC targeting TfR1 is combined with 5‐fluorouracil (5‐FU) for synergistic tumor therapy in a mouse model, leading to substantial suppression of tumor growth. Our strategy may provide deep insights into the LC3‐mdiated autophagic degradation, affording a modular and effective strategy for membrane protein degradation and precise therapeutic applications.

Engineering Covalent Aptamer Chimeras for Enhanced Autophagic Degradation of Membrane Proteins.

Targeted degradation of membrane proteins represents an attractive strategy for eliminating pathogenesis-related proteins. Aptamer-based chimeras hold great promise as membrane protein degraders, however, their degradation efficacy is often hindered by the limited structural stability and the risk of off-target effects due to the non-covalent interaction with target proteins. We here report the first design of a covalent aptamer-based autophagosome-tethering chimera (CApTEC) for the enhanced autophagic degradation of cell-surface proteins, including transferrin receptor 1 (TfR1) and nucleolin (NCL). This strategy relies on the site-specific incorporation of sulfonyl fluoride groups onto aptamers to enable the cross-linking with target proteins, coupled with the conjugation of an LC3 ligand to hijack the autophagy-lysosomal pathway for targeted protein degradation. The chemically engineered CApTECs exhibit enhanced on-target retention and improved structural stability. Our results also demonstrate that CApTECs achieve remarkably enhanced and prolonged degradation of membrane proteins compared to the non-covalent designs. Furthermore, the CApTEC targeting TfR1 is combined with 5-fluorouracil (5-FU) for synergistic tumor therapy in a mouse model, leading to substantial suppression of tumor growth. Our strategy may provide deep insights into the LC3-mdiated autophagic degradation, affording a modular and effective strategy for membrane protein degradation and precise therapeutic applications.

Recent developments in moving bed biofilm reactor (MBBR) for the treatment of phenolic wastewater -A review

BackgroundPhenol, a toxic and carcinogenic compound found in industrial effluent, poses a severe threat to the environment and aquatic life. Conventional methods such as physio-chemical techniques have limitations in efficiency, cost, and sustainability, leading to the development of advanced hybrid approaches like the Moving Bed Biofilm Reactor (MBBR) to treat phenols. Review methodIn this study, we aimed at an in-depth review of MBBR for the remediation of phenolic wastewater at an industrial scale. The review uses a methodology that involves a comparative analysis of various conventional methods, including activated sludge process (ASP), sequencing batch biofilm reactor (SBBR), Fluidized Bed Biofilm Rector (FBBR), and trickling filter (TF) with MBBR, to determine their efficacy in phenol degradation. In this context, a thorough bibliometric assay of MBBR is carried out to understand the recent publication trends. The study also examines the impact of different types and shapes of bio-carriers and their filling ratios on phenol biodegradation. Significant findingThe present work demonstrates the feasibility of using an aerobic MBBR along with a Fenton-like system (advanced oxidation processes) to treat phenolic effluent LCCA is discussed for selected treatment methods for assessing the sustainability aspects. In light of recent advancements, future research endeavors should prioritize the refinement and optimization of MBBR systems to strengthen their efficiency and sustainability, thus paving the way for a greener and cleaner future.

Removal of tetracycline using an ultrastable Pt-decorated-BNCB photocatalyst under efficient solar-driven conditions

The pursuit of optimizing the photocatalytic performance of the novel perovskite-like Bi4NbO8X materials remains a vibrant area of research. In this paper, we report the successful synthesis of the Bi4Nb4O8Cl0.935Br0.065 (BNCB) composite photocatalyst, loaded with Pt nanoparticles, utilizing a combination of solid-state reaction and sodium borohydride reduction methods. Notably, the surface plasmon resonance (SPR) effect exhibited by Pt broadened the spectral response range, while the Schottky junction formed at the Pt/BNCB interface significantly accelerated the separation of photogenerated electron-hole pairs and facilitated the swift migration of photogenerated electrons towards Pt. Experimental outcomes underscore the superior photocatalytic degradation efficacy of the Pt/BNCB composite towards tetracycline (TC), achieving a degradation rate of up to 67%, significantly outperforming pure BNCB. Pt/BNCB exhibits excellent photocatalytic degradation and excellent stability in various pH and ionic environments. Collectively, this work presents a novel approach for designing highly efficient and stable perovskite-type photocatalytic materials, holding immense potential for applications in environmental remediation.

Novel Approaches in Targeting Cell Surface and Secreted Proteins for Lysosomal Degradation.

Protein degradation is pivotal for all biochemical aspects of cellular function. In mammalian cells, protein degradation is mediated mainly by the ubiquitin proteasome system (UPS) and the autophagic-lysosomal system (ALS). Over the last two decades, different types of targeted protein degradation approaches have been developed including proteolysis targeting chimeras (PROTACs) and lysosome targeting chimeras (LYTACs), which employ the UPS to degrade intracellular proteins and the ALS to degrade extracellular and membrane proteins respectively. Nevertheless, Current targeted membrane protein degradation approaches face some inherent challenges including limited target protein degradation efficacy and cell type specific applicability. Herein, we highlight some recent developments of novel targeted membrane protein degradation modalities that exhibit wide-applicability and high protein degradation efficiency. These novel membrane protein degraders hold tremendous promise as new pharmacological and biochemical tools in targeting membrane and secretory proteins for lysosomal degradation.

Efficient Degradation of Recalcitrant Pharmaceuticals in Greywater Using Treatment of MBR and Immobilized TiO2 Porous Layers.

Traditional wastewater treatment often fails to remove pharmaceuticals, necessitating advanced solutions, such as TiO2 photocatalysis, for post-treatment. However, conventionally applied powder TiO2 can be cumbersome to separate from treated water. To solve this issue, this study immobilized three TiO2 photocatalysts (Anatase 16, Anatase 5, and P25) into porous layers and evaluated their efficacy for the degradation of three pharmaceuticals (naproxen, NPX; sulfamethoxazole, SMX; metformin, MTF) in standard solutions and greywater pretreated in a membrane bioreactor (MBR). In standard solutions, photocatalysis tests revealed a high degradation efficacy (NPX 100%, SMX 76-95%, MTF 57-75%) and challenged the belief that OH• is the predominant reactive oxygen species (ROS). The primary ROS were 1O2 for NPX and OH• for SMX and MTF. The raw greywater (NPX, SMX, MTF - 0.5 mg·L-1) treatment in MBR removed only 17-22% of the pharmaceuticals, highlighting the need for post-treatment. Using this pretreated greywater, P25 layers excelled for NPX (78 ± 5%) and SMX (73 ± 4%) but were less effective for MTF (40 ± 16%) compared to Anatase 16 (60 ± 10%). Moreover, the effluent toxicity (Aliivibrio fischeri) was reduced, and the degradation products were identified. Overall, TiO2 layers are a high-potential method for removing pharmaceuticals from MBR-treated greywater.

Sonodynamic Nano-LYTACs Reverse Tumor Immunosuppressive Microenvironment for Cancer Immunotherapy.

Extracellular and transmembrane proteins, which account for the products of approximately 40% of all protein-encoding genes in tumors, play a crucial role in shaping the tumor immunosuppressive microenvironment (TIME). While protein degradation therapy has been applied to membrane proteins of cancer cells, it has rarely been extended to immune cells. We herein report a polymeric nanolysosome targeting chimera (nano-LYTAC) that undergoes membrane protein degradation on M2 macrophages and generates a sonodynamic effect for combinational cancer immunotherapy. Nano-LYTAC is found to have higher degradation efficacy to the interleukin 4 receptor (IL-4R) compared to traditional inhibitors. More importantly, it is revealed that the effect of nano-LYTAC on the function of the M2 macrophage is concentration-dependent: downregulating CD206 expression and interleukin 10 (IL-10) secretion from M2 macrophages at low concentration, while triggering their apoptosis at high concentration. Moreover, nano-LYTAC is found to possess long tumor retention (>48 h), allowing for multiple sonodynamic treatments with a single dose. Such a synergistic sonodynamic immunotherapy mediated by nano-LYTAC effectively reprograms the TIME via inhibiting the functions of M2 macrophages and regulatory T cells (Tregs), as well as promoting the maturation of dendritic cells (DCs) and tumor infiltration of T effector cells (Teffs), completely suppressing tumor growth, inhibiting pulmonary metastasis, and preventing recurrence under preclinical animal models.

Comparative Study on the Biosynthesis of Magnetite Nanoparticles Using Aspergillus Elegans Extract and Their Efficacy in Dye Degradation Versus Commercial Magnetite Nanoparticles

This study compares magnetite (Fe3O4) nanoparticles synthesized using Aspergillus elegans extract versus commercially available magnetite nanoparticles, focusing on their efficacy in dye degradation. The biosynthesis of Fe3O4 nanoparticles using fungal extracts offers a sustainable and eco-friendly alternative to conventional chemical methods. The nanoparticles were characterized using various techniques, including UV-Vis spectroscopy, XRD, FTIR, SEM, TEM, DLS, zeta potential, and VSM analysis, to assess their structural, morphological, and magnetic properties. Results showed that fungus-mediated Fe3O4 nanoparticles were smaller, with an average size of 19.2 nm, and exhibited better crystallinity, surface functionalization, and colloidal stability than their commercial counterparts, which had an average size of 60 nm. Additionally, the fungal nanoparticles displayed superior magnetic properties with a saturation magnetization of 50 emu/g compared to 36 emu/g for commercial Fe3O4. The dye degradation potential of the nanoparticles was tested using methyl violet, methyl orange, and rose bengal dyes. Fungus-mediated Fe3O4 nanoparticles demonstrated higher dye removal efficiency than commercial Fe3O4, indicating enhanced catalytic activity due to their smaller size and larger surface area. This study highlights the potential of myco-synthesized Fe3O4 nanoparticles as effective agents for environmental remediation, particularly in removing of hazardous synthetic dyes from wastewater.

Green Synthesis of Zinc Oxide Nanoparticles Using Dillenia Indica and Mikania Micrantha Leaf Extracts: Applications in Photocatalysis and Antibacterial Activity.

Researchers are keenly interested in developing metal-based nanoparticles using plant sources as they are eco-friendly, less expensive and simpler. Zinc oxide nanoparticles, symbolized as D-ZnONPs and M-ZnONPs were synthesized in this study utilizing the leaves of D. indica and M. micrantha, respectively, and studied their impact on the growth inhibition of various bacterial strains and on the photocatalysis. By displaying the distinctive surface plasmon resonance (SPR) band at 373 nm in UV-Vis and bands at 450-480 cm-1 corresponding to Zn-O stretching FTIR spectroscopy imparted the formation of ZnONPs which was further supported by X-ray diffraction analysis by showing the polycrystalline nature and a hexagonal wurtzite structure. The spherical form and average particle size of 30 nm of the produced ZnONPs, as confirmed by electron microscopy, are also confirmed to be crystalline. Under natural sunlight, both ZnONPs demonstrate excellent degradation efficacy about 96-99 % within 100 min towards methylene blue (MB). Furthermore, it is noteworthy that both the synthesized ZnONPs exhibited 55-60 % efficacy with respect to antibiotics in inhibiting the growth of various pathogenic bacterial strains. Overall, ZnONPs can be produced on a large-scale using plant sources and employed them in environmental remediation and cosmetic industries as prominent components.

Surface-modified ZnO nanoparticles for enhanced environmental and biomedical performance

The present study explores the synthesis of cetyltrimethylammonium bromide-modified zinc oxide nanoparticles (CTAB: ZnO NPs) via a precipitation-cum-hydrothermal route, optimizing their multifunctional capabilities for photocatalytic dye degradation and antibacterial applications. The synthesized ZnO NPs exhibit a wurtzite hexagonal structure, as confirmed by X-ray diffraction (XRD), with an average crystallite size of 47.12 nm, refined through Williamson-Hall (107.8 nm) and modified Debye-Scherrer (41 nm) analyses to account for lattice strain effects. UV–visible spectroscopy reveals a sharp absorption peak at 430 nm, with a corresponding band gap of 3.2 eV, indicative of strong quantum confinement effects. High-resolution transmission electron microscopy (HRTEM) and field emission scanning electron microscopy (FESEM) confirm the quasi-spherical morphology with minimal agglomeration, while energy-dispersive X-ray spectroscopy (EDX) validates the purity of the ZnO composition. Photocatalytic investigations demonstrate a remarkable degradation efficiency of 100 % for reactive blue-81 (RB-81) dye under UV irradiation within 1.3 h, with a kinetic reaction rate of 5.71 × 102 μmol g⁻1 h⁻1. Quantum yield (QY) and space-time yield (STY) values of 2.53 × 10⁻⁴ molecules photon⁻1 and 1.27 × 10⁻⁵ molecules photon⁻1 mg⁻1, respectively, highlight the superior photonic utilization efficiency compared to conventional TiO₂-based photocatalysts. Antibacterial studies using the agar well diffusion method reveal significant inhibition zones of up to 3.42 cm and 2.14 cm for Staphylococcus aureus and Pseudomonas aeruginosa, respectively, demonstrating potent antibacterial activity. The findings indicate that CTAB: ZnO NPs not only enhance photocatalytic degradation and antibacterial efficacy but also offer scalable potential for environmental remediation and biomedical applications.

Novel Synthesis of Polystyrenesulfonate@AC Based on Olive Tree Leaves Biomass for the Photo-Degradation of Methylene Blue from Aqueous Solution.

Water pollution poses significant environmental challenges, particularly from dyes used in various industrial processes. Effective removal methods are essential to mitigate their impact on aquatic environments. Activated carbon (AC) is widely used for its adsorption properties, and further modifications can enhance its efficiency. In this study, we developed polystyrene sulfonate-modified activated carbon (AC@PSS) using a facile and efficient method to improve the photo-degradation of methylene blue (MB) in aquatic environments. The modification enhanced the activated carbon's surface features and adsorption, improving its photocatalytic activity. The photocatalysts were characterized using XRD, SEM, FTIR, and TGA. Based on Tauc's equation, the band gap value of AC@PSS was 4.0 eV. The photocatalytic efficacy of the AC@PSS catalyst was assessed by studying the degradation of MB dye under UV-rich solar irradiation. The influence of various variables on the photo-degradation of MB dye such as pH (2-12), reaction time (0-160 min), catalyst dosage (20-80 mg), and dye concentration (10-300 mg/L) was investigated. The AC@PSS catalyst demonstrated impressive degradation efficacy for MB dye of 98% in 160 min at pH 11, a temperature of 25 °C, a catalyst dose of 60 mg, and initial MB content of 10 mg/L. The superior performance of the AC@PSS catalyst could be due to the effective separation of photogenerated electron holes. Accordingly, the photo-degradation of MB is affected by the photo-produced radical •OH. Finally, we conclude that synthesizing AC@PSS is highly effective for the degradation of MB dye.

Revolutionizing pollution control with innovative CuO@TiO2 nanocomposite for enhanced photocatalytic degradation and antimicrobial efficacy

Facing the crisis of rising global pollution levels and the increasing threat of new pathogens, innovative and efficient strategies for degrading industrial waste and eliminating harmful pathogens are urgently needed. Therefore, we carefully designed and integrated CuO@TiO2 nanocomposite with a p-n heterojunction structure. Tests such as XRD, SEM, EDS and TEM showed that CuO was successfully and uniformly compounded on the surface of TiO2 to form nanoparticles with an average particle size of about 21 nm. Through carefully controlled experiments, we have demonstrated that these nanocomposites can degrade methylene blue by up to 83.90 % under irradiation with a xenon lamp, and maintain a relatively stable high degradation rate in repeatable photocatalytic tests, which highlights their great potential for pollution reduction. In addition, these nanocomposites also have a certain antibacterial effect. After 12 h of incubation in the dark, the bacterial survival rate was reduced to 94.07 %, and under light conditions, it was reduced to 92.35 %. It can be clearly seen under the microscope that the cell contents have leaked out and appear flocculent due to the rupture of the bacterial cells. These results are attributed to the synergistic effect of the release of Cu2+ and photocatalytic activity in the nanocomposite. This integrated approach positions CuO@TiO2 nanocomposite as a sustainable and cost-effective alternative to conventional antimicrobial agents and photocatalysts, paving the way for their wide application in environmental purification and microbial control.

Impact of Metal Ions, Peroxymonosulfate (PMS), and pH on Sulfolane Degradation by Pressurized Ozonation

This study investigated the degradation of sulfolane using pressurized ozonation under varying initial concentrations and the influence of different catalysts and peroxymonosulfate activation methods on the degradation efficiency. Initial sulfolane concentrations of 1 mg L−1, 20 mg L−1, and 100 mg L−1 were tested over 120 min, revealing a degradation efficiency of 73%, 41%, and 18%, respectively. The addition of various metal ions (Zn2+, Mg2+, Cu2+, Ni2+, and Co2+) demonstrated that only zinc and magnesium enhanced degradation, with zinc achieving a 92% removal efficiency and magnesium achieving 86%. Different doses of magnesium and zinc were further tested, showing optimal degradation at specific concentrations. The combination of PMS with ozonation was explored, revealing that zinc activation did not significantly enhance degradation, while NaOH activation achieved near-total degradation, with a 100 mg L−1 NaOH concentration. Varying PMS concentrations indicated that altering pH was more effective than changing PMS dosage. Finally, the impact of pH changes in both reverse osmosis water and tap water matrices confirmed that higher pH levels significantly improved degradation efficacy, achieving up to 98% removal with NaOH concentrations of 50 mg L−1 in reverse osmosis water. These results suggest that optimizing pH and catalyst type are critical for enhancing sulfolane degradation in pressurized ozonation systems.

Associative analysis of sludge microbiota and wastewater degradation efficacy within swine farm sludge systems

Industrial wastewater management is a significant global challenge. Sludge microbiota from swine farms may play a crucial role in enhancing wastewater treatment processes, thereby reducing water pollution from industrial activities. A deeper understanding of this complex community could lead to innovative approaches for improving wastewater treatment methods. Sludge samples were collected from the anaerobic, sedimentation, and thickening tanks of ten swine farms. The microbiota communities were analyzed using 16S rRNA full-length sequencing on the PacBio platform, with subsequent data analysis conducted on the QIIME2 platform utilizing the SILVA database. Compared to anaerobic and thickening tanks, the sedimentation tanks exhibited a unique profile of sludge microbiota, with higher abundances of the phyla Proteobacteria, Bacteroidota, and Caldatribacteriota. Additionally, sludges from farms already utilized in processing industrial water—specifically farms B, G, and J—contained higher concentrations of bacteria (>20 ng/μL), indicating the robustness of the bacterial load for practical industrial use. Furthermore, sludge from farms with higher alpha diversity, such as E, G, I, and J, exhibited enriched degradation profiles, including the degradation of aromatic compounds, polymers, industrial compounds, toluene, and vanillin. The farms were categorized based on wastewater ammonia nitrogen degradation levels, revealing a clustering effect of the microbiota from the sedimentation tanks in the Principal Coordinates Analysis (PCoA) plot. A higher relative abundance of the families Rhodocyclaceae, AKYH767, and Comamonadaceae, and a lower abundance of the families Anaerolineaceae and Christensenellaceae, were found in groups with high ammonia nitrogen reduction, suggesting potential targets for bioaugmentation strategies. In conclusion, this study underscores the critical role of microbial abundance, composition, and biodiversity in optimizing wastewater treatment and advocates for comprehensive microbiota analysis to identify suitable sludge for industrial applications.

Ultrastable cobalt-based chainmail catalyst for degradation of emerging contaminants in water

Developing stable and efficient cobalt-based catalysts for degradation of emerging contaminants (ECs) in water is deemed as a practical strategy to avoid secondary pollution in advanced oxidation processes (AOPs). Herein, we developed a ultrastable cobalt-based chainmail catalysts (Co-NC900) using 2, 2’-bipyridine-assistant pyrolysis method. More than 96.6 % of imidacloprid (IMD) in water could be degraded within 5 min in the presence of Co-NC900 and peroxymonosulfate (PMS). Amazingly, Co-NC900 still give 95 % degradation efficacy for IMD after15 runs. And only 0.083 μg L−1 of Co could be detected in the reaction mixture after continuous using 7 d. Density Functional Theory (DFT) calculations demonstrated that Co-NC900 can efficiently activate PMS through unique ping-pong mechanism (C-N bond breaking and re-forming process), and further degrade ECs. This study presents a novel approach for the development of efficient and stable metal-based catalysts for the removal of ECs from water.

Innovative S-Scheme heterojunctions: Boosting methylene blue degradation and antimicrobial efficacy with Ni–CoS@S-g-C3N4

The release of waste, including organic dyes from various industries, directly into water bodies significantly contributes to environmental pollution. Consequently, there is a need for photocatalytic materials that can effectively remove harmful pollutants from water, ensuring its purity and safety. Carbon-based photocatalysts have garnered significant attention in this context because of their exceptional stability, high conductivity, and very small band gap. In the current project, a series of CoS, Ni–CoS, and Ni–CoS/S-g-C3N4 with different concentrations of S-g-C3N4 were synthesized using a simple, efficient, and cost-effective co-precipitation technique, while S-g-C3N4 was constructed through a thermal degradation process using thiourea as a precursor. The produced photocatalysts underwent characterization utilizing sophisticated analytical methods including FTIR, XRD, SEM, and EDX. The photocatalytic degradation behavior of the prepared photocatalysts was assessed using a UV–visible spectrophotometer, and the doping of Ni-metal was found to significantly enhance the degradation rate of methylene blue (MB), a standard pollutant dye in the order of CoS < %8Ni–CoS <8%Ni–CoS@50 % S-g-C3N4.the maximum photocatalytic degradation was shown by the nanocomposites (8%Ni–CoS@50 % S-g-C3N4) i.e. 94 %. The EIS spectra for CoS, 8 % Ni–CoS, and Ni–CoS/50 % SCN were analyzed, and their antimicrobial effectiveness was evaluated.

Flower-like layered ZnO nanoflakes for cost-effective visible light-assisted photodynamic oxidation of tetracycline and bacterial disinfection

The conventional precipitation method was employed to synthesize the flower-like layered ZnO nano-flakes, characterized, and their photocatalytic potential was investigated for control of tetracycline antibiotics and high-strength pathogenic bacteria in wastewater effluent. Scanning electron microscope measurements confirm the formation of flower-like nano-flakes. Under white light, the catalytic efficiency of the ZnO nano-flakes is higher compared to blue light for the photocatalytic degradation of tetracycline, the inactivation of multidrug-resistant bacteria, and total coliforms. Under white light irradiation with the intensity of 80 mW/cm2, the ZnO nano-flakes showed the highest tetracycline degradation efficacy of 86 % within 120 min and complete inactivation of bacteria within 90 min without any additional oxygen sources. Scavenging experiments have clarified the photocatalytic mechanism of the degradation of tetracycline. The used catalyst was simply recovered by centrifugation (5 min) and could be reused without significant loss of photocatalytic activity. The remarkable efficiency and stability of the ZnO nano-flakes in this study mark a distinct approach to the development of heterogeneous photocatalysts for pollutant degradation. To evaluate the feasibility of a photocatalytic process for achieving consistent disinfection, microbial inactivation experiments were conducted using a batch-scale photocatalytic reactor with blue and white LEDs. The study targeted high-strength multidrug-resistant bacteria, including E. coli (Gram-negative) and S. aureus (Gram-positive), as well as total coliform in secondary effluent. This research clarifies the practical potential of ZnO nano-flakes for cost-effective photocatalytic oxidation treatment of wastewater pollutants.

Development of 2-Aminoadenine-Based Proteolysis-Targeting Chimeras (PROTACs) as Novel Potent Degraders of Monopolar Spindle 1 and Aurora Kinases.

Monopolar spindle 1 (Mps1, also known as TTK) and Aurora kinase (AURK) A and B are critical regulators of mitosis and have been linked to the progression of various cancers. Here, we report the design, synthesis, and biological evaluation of a series of PROTACs (proteolysis-targeting chimeras) targeting TTK and AURKs. We synthesized various degrader molecules based on four different 2-aminoadenine-based ligands, recruiting either cereblon or VHL as the E3-ligase. Our research showed that the nature of the linker and modification of the ligand significantly influence the target specificity and degradation efficacy. Notably, compound 19, among the most potent degraders, demonstrated robust proteasome-mediated degradation of TTK with D max of 66.5% and DC50 value (6 h) of 17.7 nM as compared to its structurally akin inhibitor control, 23. The cytotoxicity of most of the synthesized chimeras against acute myeloid leukemia cell line MV4-11 was lower than that of the corresponding parent inhibitors. However, we could also identify degraders such as 15 and 26 that induce potent AURKA degradation and display comparable antiproliferative activities to their parent compound SF1. Compound 15 degrades AURKA with low DC50 value of 2.05 nM, which is 77-fold and 21-fold more selective toward AURKB and TTK and has an EC50 value of 39 nM against cancer MV4-11 cells. Overall, the observations we made with the degrader molecules we developed can further aid in the design and development of optimized TTK or AURK degraders for cancer therapy.

Enhancing the degradation of microplastics through combined KMnO4 oxidation and UV radiation

The pervasive issue of microplastics in aquatic environments presents a formidable challenge to traditional water treatment methodologies, including those utilizing KMnO4. This study pioneers advanced oxidation processes (AOPs) method aimed at improving the degradation of PE microplastics by employing a dual treatment strategy that combines KMnO4 oxidation with UV irradiation. Detailed analysis of the surface modifications and chemical functional groups of the treated PE microplastics revealed the establishment of Mn-O-Mn linkages on their surfaces. Weight reductions of 3.9%, 4.9%, and 7.5% were observed for the KMnO4/UVA, KMnO4/UVB, and KMnO4/UVC treatments over seven days, respectively. The emergence of carboxyl and hydroxyl groups played a crucial role in accelerating the degradation process. Notably, the combined application of UVC rays and KMnO4 resulted in the most effective degradation of PE microplastics observed in our study. The process significantly enhanced the formation of MnO2 particles from KMnO4 oxidation, with concentrations ranging from 0.036 to 0.070 mM for KMnO4/UVA, 0.066–0.097 mM for KMnO4/UVB, and 0.086–0.180 mM for KMnO4/UVC. Furthermore, the influence of varying pH levels, KMnO4 concentrations, and different water sources on the degradation efficacy was investigated. The pivotal role of free radicals and reactive manganese species in promoting the degradation of PE microplastics was identified. A comparative evaluation with treatments solely utilizing KMnO4 or UV light highlighted the enhanced effectiveness of the combined approach, demonstrating its potential as an efficient solution for reducing microplastic contamination in aquatic systems.

Sequential responsive nano-PROTACs for precise intracellular delivery and enhanced degradation efficacy in colorectal cancer therapy

PROteolysis TArgeting Chimeras (PROTACs) have been considered the next blockbuster therapies. However, due to their inherent limitations, the efficacy of PROTACs is frequently impaired by limited tissue penetration and particularly insufficient cellular internalization into their action sites. Herein, based on the ultra-pH-sensitive and enzyme-sensitive nanotechnology, a type of polymer PROTAC conjugated and pH/cathepsin B sequential responsive nanoparticles (PSRNs) are deliberately designed, following the construction of the PROTAC for Cyclin-dependent kinase 4 and 6 (CDK4/6). Colorectal cancer (CRC) which hardly responds to many treatments even immune checkpoint blockades was selected as the tumor model in this study. As a result, PSRNs were found to maintain nanostructure (40 nm) in circulation and efficiently accumulated in tumors via enhanced permeation and retention effect. Then, they were dissociated into unimers (<10 nm) in response to an acidic tumor microenvironment, facilitating tumor penetration and cellular internalization. Eventually, the CDK4/6 degrading PROTACs were released intracellularly following the cleavage of cathepsin B. Importantly, PSRNs led to the enhanced degradation of target protein in vitro and in vivo. The degradation of CDK4/6 also augmented the efficacy of immune checkpoint blockades, through the upregulation of programmed cell death-ligand 1 (PD-L1) expression in cancer cells and the suppression of regulatory T cells cell proliferation in tumor microenvironment. By combination with α-PD-1, an enhanced anti-tumor outcome is well achieved in CT26 tumor model. Overall, our study verifies the significance of precise intracellular delivery of PROTACs and introduces a promising therapeutic strategy for the targeted combination treatment of CRC.