Natural Target Research Articles

Production and radiochemical separation of Tb-161 as a feasible beta therapeutic radioisotope from reactor irradiated Gd target

Terbium-161 (161Tb) is a promising therapeutic radionuclide that has gained significant attention in the field of nuclear medicine in recent years. 161Tb has several favorable characteristics that make it a valuable candidate for targeted radionuclide therapy. The production of No-carrier-added 161Tb was carried out by the neutron activation of natural gadolinium target in the Egyptian Second Research Reactor (ETRR-2) at a thermal neutron flux position of 1.8 × 1014 n cm-2 s-1. The radioactivities of 161Tb as well as coproduced Gd radioimpurities were computed theoretically by the MCNPX2.7.0 code and verified by actual measurements, where accepted discrepancies were obtained. The purification of 161Tb from irradiated Gd target was developed by Chelex-100 resin. The elution performance was studied using different eluents, and 0.1 M HNO3 was found to be the best medium to obtain a high separation efficiency of more than 92% in a short time. The eluted 161Tb was of high chemical, radiochemical, and radionuclidic purities, indicating its potential for effective application in radiopharmaceutical preparation.

Determination of optimal solar-viewing geometry for in-flight polarization calibration using sun glint over ocean

The sun glint has been proven to be a valuable natural polarization calibration target because it is strongly polarized, and its polarization characteristics can be accurately simulated with models. It is convenient to calibrate the satellite’s in-flight polarimetry by comparing the polarization simulations with actual measurements. Meanwhile, the accuracy of polarization simulation at the top of the atmosphere (TOA) over sun glint is affected by several atmospheric and oceanic surface factors and depends on the specific solar-viewing geometry. In this paper, the sensitivity of the degree of linear polarization (DOLP) at the TOA to the uncertainties of the aerosol optical depth, aerosol model, absorption gas content (CWV, O3), sea surface instantaneous wind speed (WS), and chlorophyll concentration (Chl) under different solar-viewing geometries is analyzed via radiative transfer simulation. The error budgets indicate that aerosols and WS are the main error factors for polarization calibration, while the uncertainties of Chl and absorbing gases can be disregarded. The total DOLP error increases with the solar zenith angle and viewing zenith angle (i.e., the increase of atmospheric optical path) and the sun glint angle (SGA, the angle between the viewing and the specular directions of the sun) (i.e., the decrease of sun glint brightness). The dependence of the total DOLP error on SGA decreases with the WS (i.e., the increase of sun glint spot area and the decrease of the sun glint intensity) and increases with the wavelength (i.e., the decrease of atmospheric scattering contribution). Based on the error budgets, an optimized solar-viewing geometry screening strategy is proposed to ensure that the simulated DOLP error is limited to 0.02. The in-flight DOLP calibration result of POLDER/PARASOL shows that the proposed screening strategy obtained more calibration samples and covered a wider range of DOLP, especially for the samples with DOLP of less than 0.2, compared with the screening strategies of Toubbe et al. [IEEE Trans. Geosci. Remote Sens. 37, 513 (1999)IGRSD20196-289210.1109/36.739104]and Hagolle et al. [IEEE Trans. Geosci. Remote Sens. 42, 1472 (2004)IGRSD20196-289210.1109/TGRS.2004.826805] in previous work. The smaller standard error (SE) of the samples indicates more stable calibration results obtained for the optimized strategy. This research presents an optimized strategy for screening the solar-viewing geometry of the samples to calibrate satellite in-flight polarization measurements using the sun glint.

Sustainable production of radionuclidically pure antimony-119

BackgroundRadiopharmaceutical therapy (RPT) uses radionuclides that decay via one of three therapeutically relevant decay modes (alpha, beta, and internal conversion (IC) / Auger electron (AE) emission) to deliver short range, highly damaging radiation inside of diseased cells, maintaining localized dose distribution and sparing healthy cells. Antimony-119 (119Sb, t1/2 = 38.19 h, EC = 100%) is one such IC/AE emitting radionuclide, previously limited to in silico computational investigation due to barriers in production, chemical separation, and chelation. A theranostic (therapeutic/diagnostic) pair can be formed with 119Sb’s radioisotopic imaging analogue 117Sb (t1/2 = 2.80 h, Eγ = 158.6 keV, Iγ = 85.9%, β+ = 262.4 keV, Iβ+ = 1.81%).ResultsWithin, we report techniques for sustainable and cost-effective production of pre-clinical quality and quantity, radionuclidically pure 119Sb and 117Sb, novel low energy photon measurement techniques for 119Sb activity determination, and physical yields for various tin target isotopic enrichments and thicknesses using (p, n) and (d, n) nuclear reactions. Additionally, we present a two-column separation providing a radioantimony yield of 73.1% ± 6.9% (N = 3) and tin separation factor of (6.8 ± 5.5) x 105 (N = 3). Apparent molar activity measurements for deuteron produced 117Sb using the chelator TREN-CAM were measured at 42.4 ± 25 MBq 117Sb/µmol (1.14 ± 0.68 mCi/µmol), and we recovered enriched 119Sn target material at a recycling efficiency of 80.2% ± 5.5% (N = 6) with losses of 11.6 mg ± 0.8 mg (N = 6) per production.ConclusionWe report significant steps in overcoming barriers in 119Sb production, chemical isolation and purification, enriched target material recycling, and chelation, helping promote accessibility and application of this promising therapeutic radionuclide. We describe a method for 119Sb activity measurement using its low energy gamma (23.87 keV), negating the need for attenuation correction. Finally, we report the largest yet-measured 119Sb production yields using proton and deuteron irradiation of natural and enriched targets and radioisotopic purity > 99.8% at end of purification.

Recent strategies in target identification of natural products: Exploring applications in chronic inflammation and beyond.

Natural products are a treasure trove for drug discovery, especially in the areas of infection, inflammation and cancer, due to their diverse bioactivities and complex, and varied structures. Chronic inflammation is closely related to many diseases, including complex diseases such as cancer and neurodegeneration. Improving target identification for natural products contributes to elucidating their mechanism of action and clinical progress. It also facilitates the discovery of novel druggable targets and the elimination of undesirable ones, thereby significantly enhancing the productivity of drug discovery and development. Moreover, the rise of polypharmacological strategies, considered promising for the treatment of complex diseases, will further increase the demand for target deconvolution. This review underscores strategies for identifying natural product targets (NPs) in the context of chronic inflammation over the past 5 years. These strategies encompass computational methodologies for early target discovery and the anticipation of compound binding sites, proteomics-driven approaches for target delineation and experimental biology techniques for target validation and comprehensive mechanistic exploration.

Copper-61 is an advantageous alternative to gallium-68 for PET imaging of somatostatin receptor-expressing tumors: a head-to-head comparative preclinical study.

Gallium-68 positron emission tomography (68Ga-PET) with the two registered somatostatin analogs, [68Ga]Ga-DOTA-Tyr3-octreotide ([68Ga]Ga-DOTA-TOC) and [68Ga]Ga-DOTA-Tyr3-octreotate ([68Ga]Ga-DOTA-TATE), where DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid, is routinely used for imaging of somatostatin receptor (SST)-expressing tumors. We investigated copper-61 (61Cu) as an alternative radiometal for PET imaging of SST-expressing tumors. Compared to gallium-68, copper-61 (t1/2 = 3.33 h, E β + max = 1.22 MeV) can be produced on a large scale, enables late time point imaging, and has the therapeutic twin copper-67. Herein, DOTA-TOC and 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)-TOC were labeled with copper-61 and compared with the clinically used [68Ga]Ga-DOTA-TOC. [61Cu]CuCl2 was produced from an irradiated natural nickel target. DOTA-TOC and NODAGA-TOC were labeled with [61Cu]CuCl2 in ammonium acetate buffer so to achieve a reaction pH of 5-6 and a temperature of 95°C for DOTA-TOC or room temperature for NODAGA-TOC. The radioligands were evaluated head-to-head in vitro using human embryonic kidney (HEK)-SST2 cells (affinity, binding sites, cellular uptake, and efflux) and in vivo using HEK-SST2 xenografts [PET/computed tomography (CT) imaging, biodistribution, and pharmacokinetics] and compared with [68Ga]Ga-DOTA-TOC, which was prepared using a standard procedure. Dosimetry estimates were made for [61Cu]Cu-NODAGA-TOC. [61Cu]Cu-DOTA-TOC and [61Cu]Cu-NODAGA-TOC were prepared at an apparent molar activity of 25 MBq/nmol with radiochemical purities of ≥96% and ≥98%, respectively. In vitro, both presented a sub-nanomolar affinity for SST2 (IC50 = 0.23 and 0.34 nM, respectively). They were almost entirely internalized upon binding to SST2-expressing cells and had similar efflux rates at 37°C. In vivo, [61Cu]Cu-DOTA-TOC and [61Cu]Cu-NODAGA-TOC showed the same accumulation in SST2-expressing tumors. However, PET/CT images and biodistribution analyses clearly showed an unfavorable biodistribution for [61Cu]Cu-DOTA-TOC, characterized by accumulation in the liver and the abdomen. [61Cu]Cu-NODAGA-TOC displayed favorable biodistribution, comparable with [68Ga]Ga-DOTA-TOC at 1 h post-injection (p.i.). Notwithstanding, [61Cu]Cu-NODAGA-TOC showed advantages at 4 h p.i., due to the tumor retention and improved tumor-to-non-tumor ratios. The effective dose (2.41 × 10-3 mSv/MBq) of [61Cu]Cu-NODAGA-TOC, but also the dose to the other organs and the kidneys (9.65 × 10-2 mGy/MBq), suggested a favorable safety profile. Somatostatin receptor 61Cu-PET imaging not only matches the performance of 68Ga-PET at 1 h p.i. but has advantages in late-time imaging at 4 h p.i., as it provides improved tumor-to-non-tumor ratios. [61Cu]Cu-NODAGA-TOC is superior to [61Cu]Cu-DOTA-TOC in vivo. The use of the chelator NODAGA allows quantitative labeling with copper-61 at room temperature and enables the straightforward use of a kit formulation for simple manufacturing in medical centers.

A Comparative Overview of the Role of Human Ribonucleases in Nonsense-Mediated mRNA Decay.

Eukaryotic cells possess surveillance mechanisms that detect and degrade defective transcripts. Aberrant transcripts include mRNAs with a premature termination codon (PTC), targeted by the nonsense-mediated decay (NMD) pathway, and mRNAs lacking a termination codon, targeted by the nonstop decay (NSD) pathway. The eukaryotic exosome, a ribonucleolytic complex, plays a crucial role in mRNA processing and turnover through its catalytic subunits PM/Scl100 (Rrp6 in yeast), DIS3 (Rrp44 in yeast), and DIS3L1. Additionally, eukaryotic cells have other ribonucleases, such as SMG6 and XRN1, that participate in RNA surveillance. However, the specific pathways through which ribonucleases recognize and degrade mRNAs remain elusive. In this study, we characterized the involvement of human ribonucleases, both nuclear and cytoplasmic, in the mRNA surveillance mechanisms of NMD and NSD. We performed knockdowns of SMG6, PM/Scl100, XRN1, DIS3, and DIS3L1, analyzing the resulting changes in mRNA levels of selected natural NMD targets by RT-qPCR. Additionally, we examined the levels of different human β-globin variants under the same conditions: wild-type, NMD-resistant, NMD-sensitive, and NSD-sensitive. Our results demonstrate that all the studied ribonucleases are involved in the decay of certain endogenous NMD targets. Furthermore, we observed that the ribonucleases SMG6 and DIS3 contribute to the degradation of all β-globin variants, with an exception for βNS in the former case. This is also the case for PM/Scl100, which affects all β-globin variants except the NMD-sensitive variants. In contrast, DIS3L1 and XRN1 show specificity for β-globin WT and NMD-resistant variants. These findings suggest that eukaryotic ribonucleases are target-specific rather than pathway-specific. In addition, our data suggest that ribonucleases play broader roles in mRNA surveillance and degradation mechanisms beyond just NMD and NSD.

Non-termination Proving at Scale

Program termination is a classic non-safety property whose falsification cannot in general be witnessed by a finite trace. This makes testing for non-termination challenging, and also a natural target for symbolic proof. Several works in the literature apply non-termination proving to small, self-contained benchmarks, but it has not been developed for large, real-world projects; as such, despite its allure, non-termination proving has had limited practical impact. We develop a compositional theory for non-termination proving, paving the way for its scalable application to large codebases. Discovering non-termination is an under-approximate problem, and we present UNTer, a sound and complete under-approximate logic for proving non-termination. We then extend UNTer with separation logic and develop UNTer SL for heap-manipulating programs, yielding a compositional proof method amenable to automation via under-approximation and bi-abduction. We extend the Pulse analyser from Meta and develop Pulse ∞ , an automated, compositional prover for non-termination based on UNTer SL . We have run Pulse ∞ on large codebases and libraries, each comprising hundreds of thousands of lines of code, including OpenSSL, libxml2, libxpm and CryptoPP; it discovered several previously-unknown non-termination bugs and have reported them to developers of these libraries.

Accelerometer-assisted computer vision data fusion framework for structural dynamic displacement reconstruction

Accurate displacement measurement provides crucial information for evaluating the structural health condition. It is important to note that both direct and indirect displacement measurement methods have their own limitations, which can be remedied by leveraging each other’s strengths. In this study, a novel accelerometer-assisted computer vision data fusion framework is developed for accurately reconstructing structural dynamic displacement. The framework does not require a specific mathematical model or prior knowledge about the data’s characteristics, allowing it to be applied more broadly across different applications without the constraints of model assumptions. The core of this framework is to integrate successive variational mode decomposition (SVMD) and Bayesian optimization approaches to adaptively determine the weight factors of the fusion components. Importantly, an enhanced optical flow approach is presented for converting pixel movement to structural displacement from natural targets. This approach can effectively reduce the selection of mis-matched points within the ROI (Region of Interest), thereby reducing drift errors. The developed framework is verified via shaking table tests of a reinforced concrete frame structure under seismic excitation. Results indicate that the developed framework excels in accurately estimating structural dynamic displacement. Compared to single-vision displacement identification results, the proposed framework demonstrates lower peak error (< 1.65 mm) and normalized root mean square error (< 0.30). Meanwhile, the reconstructed displacement, by introducing dynamic displacement component from acceleration measurement, presents a wider frequency range than the vision-based displacement.

An analytical approach to optimization of isotope production by bremsstrahlung radiation

Based on analytical description of isotope production by bremsstrahlung (X-ray) radiation, an algorithm is proposed for calculating the optimal dimensions of a cylindrical target of given mass positioned at a given distance from a bremsstrahlung converter to ensure the maximum yield of the isotope product. The expressions are derived for the total activity and its distribution along the target axis. A technique of γ-spectrometric measuring the activity of a thick production target is proposed. The novel approach is validated by the 100Mo(γ,n)99Mo reaction induced in a natural molybdenum target by mass in the range 10-100g with the X-ray photons at an end-point energy of 40 MeV. The analytical predictions are in good agreement with the results of Monte-Carlo simulations and experiment.

An "R-spondin code" for multimodal signaling ON-OFF states.

R-spondins (RSPOs) are a family of secreted proteins and stem cell growth factors that are potent co-activators of Wnt signaling. Recently, RSPO2 and RSPO3 were shown to be multifunctional, not only amplifying Wnt- but also binding BMP- and FGF receptors to downregulate signaling. The common mechanism underlying these diverse functions is that RSPO2 and RSPO3 act as "endocytosers" that link transmembrane proteins to ZNRF3/RNF43 E3 ligases and trigger target internalization. Thus, RSPOs are natural protein targeting chimeras for cell surface proteins. Conducting data mining and cell surface binding assays we report additional candidate RSPO targets, including SMO, PTC1,2, LGI1, ROBO4, and PTPR(F/S). We propose that there is an "R-spondin code" that imparts combinatorial signaling ON-OFF states of multiple growth factors. This code involves the modular RSPO domains, notably distinct motifs in the divergent RSPO-TSP1 domains to mediate target interaction and internalization. The RSPO code offers a novel framework for the understanding how diverse signaling pathways may be coordinately regulated in development and disease.

Hypoxia-Responsive Biomimetic Nanobubbles for Oxygen Delivery Promote Synergistic Ischemic Stroke Protection.

Effective, precise, and controllable oxygen delivery is crucial for regulating the oxygenation balance of brain tissue at the early stages of acute ischemic stroke (AIS) because the absence of oxygen may result in a series of highly interconnected vascular-neural pathological events, including oxidative stress, inflammation, and neuroapoptosis. In this study, platelet membrane-reassembled oxygen nanobubbles (PONBs) were constructed for oxygen delivery to protect AIS. Benefiting from the preserved natural targeting ability of platelet membranes, oxygen can be controlled release into the hypoxia lesion at the preperfusion stage due to vascular injury targeting and oxygen sustained diffusion capability after PONBs administration. Furthermore, synergizing with bioactive components carried by platelet membranes, PONBs can inhibit post-AIS vascular occlusion and maintain blood-brain barrier integrity, thereby facilitating enhanced oxygen delivery of PONBs, establishing a positive feedback loop between oxygen delivery and AIS protection. Additionally, the accumulation of PONBs enhances the ultrasound imaging contrast, enabling precise localization and dynamic monitoring of AIS lesions. Thus, PONBs represent a promising strategy for the diagnosis and treatment of AIS.

Catalyst-Free, Three-Component Synthesis of Amidinomaleimides.

Maleimide and amidine functionalities often appear in medicinal and natural product targets. We describe a catalyst-free, three-component coupling reaction for the synthesis of amidinomaleimides. This one-pot reaction fuses a broad range of secondary amines and aldehydes with azidomaleimides. The conditions are mild, simple, modular, high yielding, and amenable to aqueous solvents. Most reaction products can be sufficiently purified without column chromatography. The synthesis creates complex, multifunctional molecules with four different molecules, including a tripeptide, arrayed around an amidinomaleimide core.

Host Tropism and Structural Biology of ABC Toxin Complexes.

ABC toxin complexes are a class of protein toxin translocases comprised of a multimeric assembly of protein subunits. Each subunit displays a unique composition, contributing to the formation of a syringe-like nano-machine with natural cargo carrying, targeting, and translocation capabilities. Many of these toxins are insecticidal, drawing increasing interest in agriculture for use as biological pesticides. The A subunit (TcA) is the largest subunit of the complex and contains domains associated with membrane permeation and targeting. The B and C subunits, TcB and TcC, respectively, package into a cocoon-like structure that contains a toxic peptide and are coupled to TcA to form a continuous channel upon final assembly. In this review, we outline the current understanding and gaps in the knowledge pertaining to ABC toxins, highlighting seven published structures of TcAs and how these structures have led to a better understanding of the mechanism of host tropism and toxin translocation. We also highlight similarities and differences between homologues that contribute to variations in host specificity and conformational change. Lastly, we review the biotechnological potential of ABC toxins as both pesticides and cargo-carrying shuttles that enable the transport of peptides into cells.

Detection of Sulfonamide Antibiotics Using an Elastic Hydrogel Microparticles-Based Optical Biosensor.

Sulfonamide antibiotics were the first synthetic antibiotics on the market and still have a broad field of application. Their extensive usage, wrong disposal, and limited degradation technologies in wastewater treatment plants lead to high concentrations in the environment, resulting in a negative impact on ecosystems and an acceleration of antibiotic resistance. Although lab-based analytical methods allow for sulfonamide detection, comprehensive monitoring is hampered by the nonavailability of on-site, inexpensive sensing technologies. In this work, we exploit functionalized elastic hydrogel microparticles and their ability to easily deform upon specific binding with enzyme-coated surfaces to establish the groundwork of a biosensing assay for the fast and straightforward detection of sulfonamide antibiotics. The detection assay is based on sulfamethoxazole-functionalized hydrogel microparticles as sensor probes and the biomimetic interaction of sulfonamide analytes with their natural target enzyme, dihydropteroate synthase (DHPS). DHPS from S. pneumoniae was recombinantly produced by E. coli and covalently coupled on a glass biochip using a reactive maleic anhydride copolymer coating. Monodisperse poly(ethylene glycol) hydrogel microparticles of 50 μm in diameter were synthesized within a microfluidic setup, followed by the oriented coupling of a sulfamethoxazole derivative to the microparticle surface. In proof-of-concept experiments, sulfamethoxazole, as the most used sulfonamide antibiotic in medical applications, was demonstrated to be specifically detectable above a concentration of 10 μM. With its straightforward detection principle, this assay has the potential to be used for point-of-use monitoring of sulfonamide antibiotic contaminants in the environment.

Exploring the Efficacy and Sustainability of Natural Pesticides in Plant Protection

With the increasing demand for sustainable agricultural practices, the efficacy and sustain-ability of natural pesticides in plant protection, providing a critical assessment of their potential as alternatives to synthetic chemical pesticides is the basic demand of the future. This study aimes to examine the diverse categories of natural pesticides, including plant-based, microbial, and mineral-based options, and evaluate their effectiveness against a broad range of pests and diseases. We exam-ine the environmental impact of natural pesticides on non-target organisms, their persistence and degradation, and the potential for bioaccumulation, focusing on their reduced chemical residues and ecological compatibility. Typically, natural pesticides target specific areas of the insect, like its nerv-ous system, leading to the insect's downfall, loss of coordination, paralysis, and eventual death. The majority of botanical pesticides affect the target organism by poisoning its stomach, lungs, or other bodily systems. Sincebotanical pesticides are typically fairly biodegradable and may be quickly bro-ken down by the stomach acids of mammals, their toxicity to humans and animals is typically quite low, and they are environmentally beneficial. Natural pesticides offer significant environmental, health, economic, and social benefits, making them an essential component of modern sustainable agriculture. Their use supports ecological balance, human safety, and long-term agricultural produc-tivity. Overall, it highlights the promising efficacy and sustainability of natural pesticides, underscor-ing their potential for enhancing plant protection while minimizing environmental risks.

Towards a unifying model for B-cell receptor triggering.

Antibodies are exceptionally versatile molecules with remarkable flexibility in their binding properties. Their natural targets range from small-molecule toxins, across viruses of different sizes, to bacteria and large multicellular parasites. The molecular determinants bound by antibodies include proteins, peptides, carbohydrates, nucleic acids, lipids and even synthetic molecules that have never existed in nature. Membrane-anchored antibodies also serve as receptors on the surface of the B cells that produce them. Despite recent structural insights, there is still no unifying molecular mechanism to explain how antibody targets (antigens) trigger the activation of these B-cell receptors(BCRs). After cognate antigen encounter, somatic hypermutation and class-switch recombination allow BCR affinity maturation and immunoglobulin class-specific responses, respectively. This raises the fundamental question of how one receptor activation mechanism can accommodate a plethora of variant receptors and ligands, and how it can ensure that individual B cells remain responsive to antigen after somatic hypermutation and class switching. There is still no definite answer. Here we give a brief historical account of the different models proposed to explain BCR triggering and discuss their merit in the context of the current knowledge of the structure of BCRs, theirdynamic membrane distribution, and recent biochemical and cell biological insights.

Radiochemical separation of 161 Tb from neutron irradiated Gd target by liquid-liquid extraction technique

Abstract No-carrier-added (NCA) 161 Tb, which has advisable nuclear properties to be applied for cancer radiotherapy was produced at the Egyptian Second Research Reactor (ETRR-2) by neutron irradiation of natural gadolinium target via indirect nuclear reaction. The radiochemical separation of 161 Tb from irradiated gadolinium target was investigated based on solvent extraction technique using Cyanex 302. Several separation parameters were checked and optimized. According to the obtained results, the separation process of the investigated radioisotopes proceeds in two steps. The first step is an extraction of all of them into the organic phase in which the extraction % (98 %) was optimized at pH 4, 0.15 M of Cyanex 302 and 2.5 h extraction time. Moreover, the slope analysis method confirmed the participation of 2 mol of the organic extractant for the separation of 161 Tb from irradiated gadolinium. The second step is the separation of the 161 Tb isotope that was purified by the stripping of 159Gd with a citrate solution at pH 9, which is considered as a highly efficient and promising method for separation and purification of the two radioisotopes.

Automated preparation of Actinium-225 with accelerator-based production from irradiated natural thorium targets

Towards the goal of accelerator-based 225Ac production from proton and nitrogen irradiated natural thorium targets, this work hereby presents a self-designed preparation system that allows for continuous operation with improved multi-column ion-exchange method. The system with advantageous features validated the feasibility of the automatic separation and purification of actinium from hundreds of impurity nuclides. Through automated experiments with multiple targets, the recovery yield and the radionuclide purity of final 225Ac products was stabilized to be around 63 % and 92 % ∼ 96 %, respectively. The total content of stable impurities is measured to be less than 2.4 μg in the final actinium product. The radioactivity levels of 226Ac and 227Ac in the product are evaluated over time. Based on the results of evaluation, the optimal time to start separation is determined to be around the 10th day after the end of bombardment. Additionally, the 225Ac-PSMA-617 compound was synthesized with the 225Ac product that meets the requirement of nuclear medicine.

Natural Product Auraptene Targets SLC7A11 for Degradation and Induces Hepatocellular Carcinoma Ferroptosis.

The natural product auraptene can influence tumor cell proliferation and invasion, but its effect on hepatocellular carcinoma (HCC) cells is unknown. Here, we report that auraptene can exert anti-tumor effects in HCC cells via inhibition of cell proliferation and ferroptosis induction. Auraptene treatment induces total ROS and lipid ROS production in HCC cells to initiate ferroptosis. The cell death or cell growth inhibition of HCC cells induced by auraptene can be eliminated by the ROS scavenger NAC or GSH and ferroptosis inhibitor ferrostatin-1 or Deferoxamine Mesylate (DFO). Mechanistically, the key ferroptosis defense protein SLC7A11 is targeted for ubiquitin-proteasomal degradation by auraptene, resulting in ferroptosis of HCC cells. Importantly, low doses of auraptene can sensitize HCC cells to ferroptosis induced by RSL3 and cystine deprivation. These findings demonstrate a critical mechanism by which auraptene exhibits anti-HCC effects via ferroptosis induction and provides a possible therapeutic strategy for HCC by using auraptene or in combination with other ferroptosis inducers.

Identification of Novel Target DCTPP1 for Colorectal Cancer Therapy with the Natural Small-molecule Inhibitors Regulating Metabolic Reprogramming.

Colorectal cancer (CRC) is one of the most common malignant tumours. Identification of new effective drug targets for CRC and exploration of bioactive small-molecules are clinically urgent. The human dCTP pyrophosphatase 1 (DCTPP1) is a newly identified pyrophosphatase regulating the cellular nucleotide pool but remains unexplored as potential target for CRC treatment. Here, twelve unprecedented chemical architectures terpene-nonadride heterodimers (1-12) and their monomers (13-20) were isolated from endophyte Bipolaris victoriae S27. Compounds 1-12 represented the first example of terpene-nonadride heterodimers, in which nonadride monomers of 1 and 2 were also first example of 5/6 bicyclic nonadrides. A series of assays showed that 2 could repress proliferation and induce cell cycle arrest, apoptotic and autophagic CRC cell death in vitro and in vivo. Clinical cancer samples data revealed that DCTPP1 was a novel target associated with poor survival in CRC. DCTPP1 was also identified as a new target protein of 2. Mechanistically, compound 2 bound to DCTPP1, inhibited its enzymatic activity, intervened with amino acid metabolic reprogramming, and exerted anti-CRC activity. Our study demonstrates that DCTPP1 was a novel potential biomarker and therapeutic target in CRC, and 2 was the first natural anti-CRC drug candidate targeting DCTPP1.