Selective Uptake Research Articles

Development and Validation of Novel Z-360-Based Macromolecules for the Active Targeting of CCK2-R.

The cholecystokinin type 2 receptor (CCK2-R) represents an ideal target for cancer therapy since it is overexpressed in several tumors and is associated with poor prognosis. Nastorazepide (Z-360), a selective CCK2-R antagonist, has been widely investigated as a CCK2-R ligand for targeted therapy; however, its high hydrophobicity may represent a limit to cell selectivity and optimal in vivo biodistribution. Here, we present three new fluorescent Z-360 derivatives (IP-002G-Rho, IP-002L-Rho, and IP-002M-Rho) in which nastorazepide was linked, through spacers bearing different saccharides (glucose (G), lactose (L), and maltotriose (M)), to sulforhodamine B. A fourth compound (IP-002H-Rho) with no pendant sugar was also synthesized as a control. Through two-dimensional (2D) and three-dimensional (3D) in vitro studies, we evaluated the compound association with and selectivity for CCK2-R-overexpressing cells (A431-CCK2-R+) vs CCK2-R-underexpressing cells (A431 WT). 2D in vitro studies highlighted a progressive increase of IP-002x-Rho association with A431-CCK2-R+ cells according to the linker hydrophilicity, that is, maltotriose > lactose > glucose > hydrogen, with IP-002M-Rho showing a 2.4- and a 1.36-fold higher uptake than IP-002G-Rho and IP-002L-Rho, respectively. Unexpectedly, IP-002H-Rho showed a similar cell association to that of IP-002L-Rho but with no difference between the two tested cell lines. On the contrary, association with A431-CCK2-R+ cells as compared to the A431 WT was found to be 1.08-, 1.14-, and 1.37-fold higher for IP-002G-Rho, IP-002L-Rho, and IP-002M-Rho, respectively, proving IP-002M-Rho to be the best-performing compound, as also confirmed by competition studies. Trafficking studies on A431-CCK2-R+ cells incubated with IP-002M-Rho suggested the coexistence of receptor-mediated endocytosis and simple diffusion. On the contrary, a high and selective uptake of IP-002M-Rho by A431-CCK2-R+ cells only was observed on 3D scaffolds embedded with cells, underlining the importance of 3D models in in vitro preliminary evaluation.

Exhaled Anesthetic Xenon Regeneration by Gas Separation Using a Metal-Organic Framework with Sorbent-Sorbate Induced-Fit.

Noble gas xenon (Xe) is an excellent anesthetic gas, but its rarity, high cost and constrained production prohibits wide use in medicine. Here, we have developed a closed-circuit anesthetic Xe recovery and reusage process with highly effective CO2-specific adsorbent CUPMOF-5 that is promising to solve the anesthetic Xe supply problem. CUPMOF-5 possesses spacious cage cavities interconnected in four directions by confinement throat apertures of ~3.4 Å, which makes it an ideal molecular sieving of CO2 from Xe, O2, N2 with the benchmark selectivity and high uptake capacity of CO2. In situ single-crystal X-ray diffraction (SCXRD) and computational simulation solidly revealed the vital sieving role of the confined throat and the sorbent-sorbate induced-fit strengthening binding interaction to CO2. CUPMOF-5 can remove 5 % CO2 even from actual moist exhaled anesthetic gases, and achieves the highest Xe recovery rate (99.8 %) so far, as verified by breakthrough experiments. This endows CUPMOF-5 great potential for the on-line CO2 removal and Xe recovery from anesthetic closed-circuits.

A Synergistic Strategy Combining Chemotherapy and Photodynamic Therapy to Eradicate Prostate Cancer.

Prostate cancer is the most prevalent cancer among men in the United States and is a leading cause of cancer-related death. Prostate specific membrane antigen (PSMA) has been established as a biomarker for prostate cancer diagnosis and treatment. This study aimed to develop a novel theranostic agent, PSMA-1-MMAE-Pc413, which integrates a PSMA-targeting ligand, the photosensitizer Pc413, and the microtubular inhibitor monomethyl auristatin E (MMAE) for synergistic therapeutic efficacy. In vitro uptake studies revealed that PSMA-1-MMAE-Pc413 demonstrated selective and specific uptake in PSMA-positive PC3pip cells but not in PSMA-negative PC3flu cells, with the uptake in PC3pip cells being approximately three times higher. In vitro cytotoxicity assays showed that, when exposed to light, PSMA-1-MMAE-Pc413 had a synergistic effect, leading to significantly greater cytotoxicity in PSMA-positive cells (IC50 = 2.2 nM) compared to PSMA-1-Pc413 with light irradiation (IC50 = 164.9 nM) or PSMA-1-MMAE-Pc413 without light irradiation (IC50 = 12.6 nM). In vivo imaging studies further demonstrated the selective uptake of PSMA-1-MMAE-Pc413 in PC3pip tumors. In in vivo studies, PSMA-1-MMAE-Pc413 dramatically improves the therapeutic outcome for prostate cancer by providing a synergistic effect that surpasses the efficacy of each treatment modality alone in PC3pip tumors. These findings suggest that PSMA-1-MMAE-Pc413 has strong potential for clinical application in improving prostate cancer treatment.

Selective delivery of neuropeptide Y peptides linked to magnetic particles for hyperthermia application

Although standard treatments against cancer have achieved significant effects in growth inhibition and tumor elimination, they still cause severe side effects. Therefore, the specific targeting of cancer cells without affecting healthy tissue is currently an important desire in cancer therapy. Cell surface receptors that bind peptides are often overexpressed on tumor cells and can therefore be considered promising targets for selective tumor therapy. Here, we report on the use of neuropeptide Y receptor 1 (Y1R) specific delivery of magnetic nanoparticles. The Y1R is overexpressed in breast cancer cells including triple negative type tumors. Magnetic particles allow for hyperthermia applications for the treatment of malignant cells and have been proposed for biomedical use for several years. One of the limitations so far was selectivity and intracellular uptake into tumor cells. By using specifically modified nanoparticles and site-specific conjugation to selective peptides specific uptake into Y1R positive cells is demonstrated here.

Prohexadione Calcium and Gibberellin Improve Osmoregulation, Antioxidant Response and Ion Homeostasis to Alleviate NaCl Stress in Rice Seedlings

Prohexadione calcium (EA) and gibberellin (GA) are two different types of plant growth regulators that have different effects on the regulation of plant development. The objective of this study was to evaluate the impacts of EA and GA on rice plant growth, development and morph-physiological traits in two rice varieties: ‘Huang Huazhan’ and ‘Guang Hong 3’. At the three-leaf seedling stage, the plants were treated with 50 mM NaCl 24 h after foliar application of EA (100 mg·L−1) and GA (1 mg·L−1). Data on morphological indexes, osmotic regulators and antioxidant activities were compared with the treatment of EA and GA on the 4th, 7th, 10th and 13th days after NaCl stress. Our data analysis showed that NaCl stress inhibited the leaf area growth of rice seedlings, altered the microstructure and disrupted the antioxidant system, ion uptake and transport balance. The significant increase in malondialdehyde (MDA) content and superoxide anion production rate (O2·¯) indicated that NaCl stress caused a severe oxidative stress response to rice seedlings. Treatment with EA and GA activated the antioxidant system under NaCl stress, significantly elevated superoxide dismutase (SOD), peroxidase (POD) and catalase (CAT) activities and suppressed the increase in MDA content and the O2·¯ production rate. Under NaCl stress, EA and GA treatments improved the osmoregulatory balance, significantly increased soluble protein and proline contents and maintained lower Na+/K+ levels. EA and GA treatments significantly increased the K+ and Ca2+ contents, thereby maintaining ionic balance, which was favorable for maintaining the growth of rice seedlings. In this study, moth plant growth regulators maintained the growth and development of rice seedlings under NaCl stress by inducing an increase in osmoregulation and antioxidant levels, reducing the degree of membrane damage and regulating the selective uptake of ions by rice seedlings. Current findings also clarified that foliar application of EA was more effective than GA in three-leaf seedlings by enhancing the morph-physiological and antioxidant parameters under NaCl stress.

Functionalized metal organic framework (MIL-101(Cr)) as selective adsorbent for the mitigation of uranium (VI) from contaminated lake water

Metal-organic frameworks (MOFs) received much attention due to their distinct porous structure. Diaminomaleonitrile (DAMN) functionalized chromium (III) terephthalate MOF (MIL-101(Cr)) was developed using a facile method as a promising adsorbent for U removal. The functionalized adsorbent contained abundant amine and cyanide groups onto the coordinatively unsaturated metal binding sites. The DAMN-functionalized MIL-101(Cr) was thoroughly characterized. The adsorbent exhibited maximum Langmuir adsorption capacity of 743 mg/g for U at pH 6 and room temperature. Different coexisting ions, having concentration within 10–50 mg/L, show negligible influence on the U adsorption (86.0–99.3 % removal). The effects of other ions on the U removal were studied in terms of U ionic speciation in the aqueous solution. The surface-grafted −C≡N and –NH2 groups were responsible for the coordinative interactions with the U(VI) ionic moieties. The MIL-101(Cr)_DAMN adsorbent was also subjected to five consecutive adsorption–desorption cycles, with >90.5 % U removal after the 5th cycle. An adsorption-pore diffusion based transport model was used to analyze the adsorption kinetics and estimation of the pore diffusivity. The effectiveness of the developed adsorbent was also demonstrated by a batch kinetic run using U contaminated lake water. In general, this research demonstrates the straightforward design and development of DAMN-functionalized MIL-101(Cr) as an effective adsorbent for the selective uptake of U(VI) from aqueous medium.

An Efficient Method for Vault Nanoparticle Conjugation with Finely Adjustable Amounts of Antibodies and Small Molecules.

Vaults are eukaryotic ribonucleoproteins consisting of 78 copies of the major vault protein (MVP), which assemble into a nanoparticle with an about 60 nm volume-based size, enclosing other proteins and RNAs. Regardless of their physiological role(s), vaults represent ideal, natural hollow nanoparticles, which are produced by the assembly of the sole MVP. Here, we have expressed in Komagataella phaffi and purified an MVP variant carrying a C-terminal Z peptide (vault-Z), which can tightly bind an antibody's Fc portion, in view of targeted delivery. Via surface plasmon resonance analysis, we could determine a 2.5 nM affinity to the monoclonal antibody Trastuzumab (Tz)/vault-Z 1:1 interaction. Then, we characterized the in-solution interaction via co-incubation, ultracentrifugation, and analysis of the pelleted proteins. This showed virtually irreversible binding up to an at least 10:1 Tz/vault-Z ratio. As a proof of concept, we labeled the Fc portion of Tz with a fluorophore and conjugated it with the nanoparticle, along with either Tz or Cetuximab, another monoclonal antibody. Thus, we could demonstrate antibody-dependent, selective uptake by the SKBR3 and MDA-MB 231 breast cancer cell lines. These investigations provide a novel, flexible technological platform that significantly extends vault-Z's applications, in that it can be stably conjugated with finely adjusted amounts of antibodies as well as of other molecules, such as fluorophores, cell-targeting peptides, or drugs, using the Fc portion as a scaffold.

Surface functionalization of virus-like particles via bioorthogonal click reactions for enhanced cell-specific targeting

Surface functionalization of nano drug carriers allows for precise delivery of therapeutic molecules to the target site. This technique involves attaching targeting molecules to the nanoparticle surface, facilitating selective interaction. In this study, we engineered virus-like particles (VLPs) to enhance their targeting capabilities. Azide groups incorporated on the lipid membranes of VLPs enabled bioorthogonal click reactions for conjugation with cycloalkyne-bearing molecules, providing efficient conjugation with high specificity. HIV-1 Gag VLPs were chosen due to their envelope, which allows host membrane component incorporation, and the Gag protein, which serves as a recognition motif for human T cells. This combination, along with antibody-mediated targeting, addresses the limitations of intracellular delivery to T cells, which typically exhibit low uptake of exogenous materials. The selective uptake of azide VLPs by CD3-positive T cells was evaluated in a co-culture system. Even without antibody conjugation, VLP uptake was enhanced in T cells, indicating their intrinsic targeting potential. Antibody conjugation further amplified this effect, demonstrating the synergistic benefits of the combined targeting approach. Our study shows that recombinant production of azide functionalized VLPs results in engineered nanoparticles that can be easily modified using bioorthogonal click reactions, providing high specificity and versatility for conjugation with various molecules, making it applicable to a wide range of biological products.

Thermoplastic Polyurethane-poly(N-isopropylacrylamide) Copolymer for Selective Uptake of Alcohol from Aqueous Solution.

Ethanol possesses high economic value, but as an industrial waste, it poses harm to human health and the environment. The paper describes the preparation of a thermoplastic polyurethane-poly(n-isopropylacrylamide) (TPU-PNIPAM) copolymer designed to selectively uptake alcohol in aqueous solution. The material was created by bonding TPU and PNIPAM together through intermolecular hydrogen bonds, enhancing its hydrophobic properties and making it easier to interact with alcohol molecules. As the amount of PNIPAM in TPU increases, the number of hydrophobic isopropyl groups in TPU-PNIPAM also increases, leading to an enhanced selective uptake ability of TPU-PNIPAM for alcohols in aqueous solution. When the temperature reaches 55 °C, the hydrophobic groups in TPU-PNIPAM are more exposed, further enhancing the selective uptake ability of TPU-PNIPAM for alcohols in aqueous solution. TPU-PNIPAM demonstrates selective preferential uptake for various concentrations and types of alcohol in aqueous solutions. The material's selective uptake performance for alcohols increases with their hydrophobicity, so TPU-PNIPAM exhibited the best adsorption performance for a 10 wt% n-propanol solution under the combined effect of steric hindrance. In addition, TPU-PNIPAM exhibited selective adsorption for other organic solvents, which demonstrated the universality of TPU-PNIPAM in removing contaminants from aqueous solutions.

Synthetic genomic nanomedicine with triple-responsiveness for systemic anti-tumor therapy

To overcome the biological barriers in the journey of systemic gene delivery, a multifaceted genomic synthetic nanomedicine was elaborated and strategically equipped with a multiple of intriguing responsiveness. Particularly, core–shell plasmid DNA condensates were created based on polyionic complexation with block copolymer of polyethylene glycol (PEG)-polylysine (PLys), namely, the nanoscaled PLys&pDNA nanoparticle tethered with the biocompatible PEG surroundings. Furthermore, redox-reversible disulfide crosslinking was introduced into PLys&pDNA nanoparticle to accomplish adequate structural stabilities, and thermal-responsive polypropylacrylamide (PNIPAM) was introduced as the secondary intermediate surroundings onto the pre-formulated PLys&pDNA nanoparticle with the aim of preventing the potential enzymatic degradation from the environmental nucleases. Hence, hundreds of times prolonged survival and retention was determined in pertinent to the blood circulation properties. Additionally, the installation of a guide ligand at the distal end of PEG segments was proposed to encourage selective tumor uptake. A linear peptide of GPLGVRG, which is selectively susceptible to digestion by the tumor-enriched matrix metalloproteinase 2 (MMP-2), was used as the linkage between the shell and core. This peptide has been shown to detach the bio-inert PEGylation, resulting in further facilitated cell endocytosis and intracellular trafficking activities. Hence, the precisely defined synthetic nanomedicine, which exhibits desirable characteristics, efficient expression of the therapeutic gene in the affected cells, and contributed to potent therapeutic efficacy in systemic treatment of intractable tumors by encapsulating the anti-angiogenic gene.

Hydroxyl-functionalized linker endows an ultra-microporous aluminum based metal–organic framework with electronegative site for enhancing ethane/ethylene separation

Efficient purification of ethylene (C2H4) from the cracking gas containing a small amount of ethane (C2H6) by selective adsorption of C2H6 is meaningful but remains challenging. Aluminum-based metal–organic frameworks (Al-MOFs) with ultra-microporous structure show preferential adsorption of C2H6 over C2H4, relying on the existence of multiple hydrogen bonding acceptors (e.g., AlO6 polyhedra) for C2H6 molecule in the confined pores. However, most Al-MOFs exhibit limited C2H6/C2H4 selectivity (<2), which lack other strong preferential binding sites for C2H6. Here we report that a hydroxyl functionalized Al-MOF (i.e., CAU-1-OH) exhibits notably improved C2H6/C2H4 selectivity (2.13) and C2H6 uptake (3.95 mmol g−1) at 298 K and 1 bar compared to its amino-functionalized counterpart, CAU-1-NH2. Prior to experiment, theoretical calculations were performed, revealing that O atom from hydroxyl group in CAU-1-OH acts as a fairly strong hydrogen bond acceptor due to its more negative charge than N atom in CAU-1-NH2. The in-situ infrared experiment further confirmed the formation of multiple hydrogen bonds (C–H⋅⋅⋅O) between CAU-1-OH and C2H6 molecules, which plays vital role for C2H6-selective capture. The actual potential for C2H4 purification was fully demonstrated by dynamic breakthrough experiments, in which CAU-1-OH displayed excellent separative performance from C2H6/C2H4 (1/15, v/v) mixture. Moreover, the structural stability and excellent recyclability suggested and the promise for cost-effective industrial application in C2H6/C2H4 separation.

Synthetic Biomimetic Liposomes Harness Efferocytosis Machinery for Highly Efficient Macrophages-Targeted Drug Delivery to Alleviate Inflammation.

Macrophages play pivotal roles in the regulation of inflammatory responses and tissue repair, making them a prime target for inflammation alleviation. However, the accurate and efficient macrophages targeting is still a challenging task. Motivated by the efficient and specific removal of apoptotic cells by macrophages efferocytosis, a novel biomimetic liposomal system called Effero-RLP (Efferocytosis-mediated Red blood cell hybrid Liposomes) is developed which incorporates the membrane of apoptotic red blood cells (RBCs) with liposomes for the purpose of highly efficient macrophages targeting. Rosiglitazone (ROSI), a PPARγ agonist known to attenuate macrophage inflammatory responses, is encapsulated into Effero-RLP as model drug to regulate macrophage functions in DSS-induced colitis mouse model. Intriguingly, the Effero-RLP exhibits selective and efficient uptake by macrophages, which is significantly inhibited by the efferocytosis blocker Annexin V. In animal models, the Effero-RLP demonstrates rapid recognition by macrophages, leading to enhanced accumulation at inflammatory sites. Furthermore, ROSI-loaded Effero-RLP effectively alleviates inflammation and protects colon tissue from injury in the colitis mouse model, which is abolished by deletion of macrophages from mice model. In conclusion, the study highlights the potential of macrophage targeting using efferocytosis biomimetic liposomes. The development of Effero-RLP presents novel and promising strategies for alleviating inflammation.

Therapeutic α-1-microglobulin ameliorates kidney ischemia-reperfusion injury.

α-1-Microglobulin (A1M) is a circulating glycoprotein with antioxidant, heme-binding, and mitochondrial protection properties. The investigational drug RMC-035, a modified therapeutic A1M protein, was assessed for biodistribution and pharmacological activity in a broad set of in vitro and in vivo experiments, supporting its clinical development. Efficacy and treatment posology were assessed in various models of kidney ischemia and reperfusion injury (IRI). Real-time glomerular filtration rate (GFR), functional renal biomarkers, tubular injury biomarkers (NGAL and KIM-1), and histopathology were evaluated. Fluorescently labeled RMC-035 was used to assess biodistribution. RMC-035 demonstrated consistent and reproducible kidney protection in rat IRI models as well as in a model of IRI imposed on renal impairment and in a mouse IRI model, where it reduced mortality. Its pharmacological activity was most pronounced with combined dosing pre- and post-ischemia and weaker with either pre- or post-ischemia dosing alone. RMC-035 rapidly distributed to the kidneys via glomerular filtration and selective luminal uptake by proximal tubular cells. IRI-induced expression of kidney heme oxygenase-1 was inhibited by RMC-035, consistent with its antioxidative properties. RMC-035 also dampened IRI-associated inflammation and improved mitochondrial function, as shown by tubular autofluorescence. Taken together, the efficacy of RMC-035 is congruent with its targeted mechanism(s) and biodistribution profile, supporting its further clinical evaluation as a novel kidney-protective therapy.NEW & NOTEWORTHY A therapeutic A1M protein variant (RMC-035) is currently in phase 2 clinical development for renal protection in patients undergoing open-chest cardiac surgery. It targets several key pathways underlying kidney injury in this patient group, including oxidative stress, heme toxicity, and mitochondrial dysfunction. RMC-035 is rapidly eliminated from plasma, distributing to kidney proximal tubules, and demonstrates dose-dependent efficacy in numerous models of ischemia-reperfusion injury, particularly when administered before ischemia. These results support its continued clinical evaluation.

Prostate Specific Membrane Antigen Expression in a Syngeneic Breast Cancer Mouse Model

PurposeProstate specific membrane antigen (PSMA) has been studied in human breast cancer (BCa) biopsies, however, lack of data on PSMA expression in mouse models impedes development of PSMA-targeted therapies, particularly in improving breast conserving surgery (BCS) margins. This study aimed to validate and characterize the expression of PSMA in murine BCa models, demonstrating that PSMA can be utilized to improve therapies and imaging techniques.MethodsMurine triple negative breast cancer 4T1 cells, and human cell lines, MDA-MB-231, MDA-MB-468, implanted into the mammary fat pads of BALB/c mice, were imaged by our PSMA targeted theranostic agent, PSMA-1-Pc413, and tumor to background ratios (TBR) were calculated to validate selective uptake. Immunohistochemistry was used to correlate PSMA expression in relation to CD31, an endothelial cell biomarker highlighting neovasculature. PSMA expression was also quantified by Reverse Transcriptase Polymerase Chain Reaction (RT-PCR).ResultsAccumulation of PSMA-1-Pc413 was observed in 4T1 primary tumors and associated metastases. Average TBR of 4T1 tumors were calculated to be greater than 1.5—ratio at which tumor tissues can be distinguished from normal structures—at peak accumulation with the signal intensity in 4T1 tumors comparable to that in high PSMA expressing PC3-pip tumors. Extraction of 4T1 tumors and lung metastases followed by RT-PCR analysis and PSMA-CD31 co-staining shows that PSMA is consistently localized on tumor neovasculature with no expression in tumor cells and surrounding normal tissues.ConclusionThe selective uptake of PSMA-1-Pc413 in these cancer tissues as well as the characterization and validation of PSMA expression on neovasculature in this syngeneic 4T1 model emphasizes their potential for advancements in targeted therapies and imaging techniques for BCa. PSMA holds great promise as an oncogenic target for BCa and its associated metastases.

Bioengineered carbohydrate polymers for colon-specific drug release: Current trends and future prospects.

The worldwide health burden of colorectal cancer is still substantial, and traditional chemotherapeutic drugs sometimes have poor selectivity, which can result in systemic toxicity and unfavorable side effects. For colon-specific medication delivery, bioengineered carbohydrate polymers have shown promise as carriers. They may enhance treatment effectiveness while minimizing systemic exposure and associated side effects. The unique properties of these manufactured or naturally occurring biopolymers, such as hyaluronic acid, chitosan, alginate, and pectin, enable targeted medicine release. These qualities can be changed to meet the physiological needs of the colon. In the context of colorectal cancer therapy, this article provides a comprehensive overview of current developments and prospective future directions in the field of bioengineered carbohydrate polymer synthesis for colon-specific drug delivery. We discuss numerous techniques for achieving colon-targeted drug release, including enzyme-sensitive polymers, pH-responsive devices, and microbiota-activated processes. To increase tumor selectivity and cellular uptake, we also examine the inclusion of active targeting approaches, such as conjugating specific ligands. Furthermore, we discuss the potential of combination treatment strategies, which use the coadministration of numerous therapeutic medications to target multiple pathways implicated in cancer growth and address drug resistance mechanisms. We address recent biomimetic advances that potentially improve the biocompatibility, cellular uptake, and tumor penetration of carbohydrate polymer-based nanocarriers. These methods involve protein corona engineering and cell membrane coating. Furthermore, we look at the possibility of intelligent and sensitive systems that may adjust their behaviors in response to certain inputs or feedback loops, allowing for precise and regulated drug distribution.

The Arabidopsis SGN3/GSO1 receptor kinase integrates soil nitrogen status into shoot development

The Casparian strip is a barrier in the endodermal cell walls of plants that allows the selective uptake of nutrients and water. In the model plant Arabidopsis thaliana, its development and establishment are under the control of a receptor-ligand mechanism termed the Schengen pathway. This pathway facilitates barrier formation and activates downstream compensatory responses in case of dysfunction. However, due to a very tight functional association with the Casparian strip, other potential signaling functions of the Schengen pathway remain obscure. In this work, we created a MYB36-dependent synthetic positive feedback loop that drives Casparian strip formation independently of Schengen-induced signaling. We evaluated this by subjecting plants in which the Schengen pathway has been uncoupled from barrier formation, as well as a number of established barrier-mutant plants, to agar-based and soil conditions that mimic agricultural settings. Under the latter conditions, the Schengen pathway is necessary for the establishment of nitrogen-deficiency responses in shoots. These data highlight Schengen signaling as an essential hub for the adaptive integration of signaling from the rhizosphere to aboveground tissues.

Selective Uptake Into Inflamed Human Intestinal Tissue and Immune Cell Targeting by Wormlike Polymer Micelles (Small 21/2024)

Selective Uptake Into Inflamed Human Intestinal Tissue and Immune Cell Targeting by Wormlike Polymer Micelles (Small 21/2024)

YeeD is an essential partner for YeeE-mediated thiosulfate uptake in bacteria and regulates thiosulfate ion decomposition.

Uptake of thiosulfate ions as an inorganic sulfur source from the environment is important for bacterial sulfur assimilation. Recently, a selective thiosulfate uptake pathway involving a membrane protein YeeE (TsuA) in Escherichia coli was characterized. YeeE-like proteins are conserved in some bacteria, archaea, and eukaryotes. However, the precise function of YeeE, along with its potential partner protein in the thiosulfate ion uptake pathway, remained unclear. Here, we assessed selective thiosulfate transport via Spirochaeta thermophila YeeE in vitro and characterized E. coli YeeD (TsuB) as an adjacent and essential protein for YeeE-mediated thiosulfate uptake in vivo. We further showed that S. thermophila YeeD possesses thiosulfate decomposition activity and that a conserved cysteine in YeeD was modified to several forms in the presence of thiosulfate. Finally, the crystal structures of S. thermophila YeeE-YeeD fusion proteins at 3.34-Å and 2.60-Å resolutions revealed their interactions. The association was evaluated by a binding assay using purified S. thermophila YeeE and YeeD. Based on these results, a model of the sophisticated uptake of thiosulfate ions by YeeE and YeeD is proposed.

Targeted interleukin-2 enhances the in vivo anti-cancer activity of Pluvicto™.

Pluvicto™ ([177Lu]Lu-PSMA-617), a radioligand therapeutic targeting prostate-specific membrane antigen (PSMA), has been recently approved for the treatment of metastatic castration-resistant prostate cancer (mCRPR). The drug suffers from salivary gland and kidney uptake that prevents its dose escalation to potentially curative doses. In this work, we sought to potentiate the in vivo anti-cancer activity of Pluvicto™ by combining it with L19-IL2, a clinical-stage investigational medicinal product based on tumor-targeted interleukin-2. We established a new PSMA-expressing model (HT-1080.hPSMA) and validated it using a fluoresceine analogue of PSMA-617 (compound 1). The HT-1080.hPSMA model was used to study the saturation and tumor retention of Pluvicto™ (compound 2) and to run combination therapy studies with L19-IL2. To complement our understanding of the mechanism of action of this novel combination, we conducted proteomics experiments on tumor samples after therapy with Pluvicto™ alone or in combination with the immunocytokine. High, selective, and long-lived tumor uptake was observed for Pluvicto™ (2) in the novel HT-1080.hPSMA model. Therapy studies in HT-1080.hPSMA tumor-bearing mice revealed that the combination of Pluvicto™ (2) plus L19-IL2 mediated curative and durable responses in all animals. Potent in vivo anti-cancer activity was observed solely for the combination modality, at doses that were well tolerated by treated animals. Proteomics studies indicated that L19-IL2 boosts the activation of the immune system in animals pre-treated with Pluvicto™. The therapeutic efficacy of Pluvicto™ at low radioactive doses can be effectively enhanced by the combination with L19-IL2. Our findings warrant further clinical exploration of this novel combination modality.

Biological Removal of Zinc (II) by Fusarium solani under Different Modes of Operational Strategies: A Comparative Study

The goal of the current batch biosorption experiment was to determine how well Fusarium solani (isolated from soil) resting cells could remove zinc (II) from aqueous solution. With an increase in pH (up to pH 5.0) and an increase in initial zinc (II) concentration of up to 500 mg/L, the specific zinc (II) removal increases. By increasing biomass content from 2.5 to 5.5 g/L, the specific zinc (II) removal remained nearly constant. The investigations also utilised resting cells from various growth stages and at an initial zinc (II) concentration of 500 mg/L, the maximum specific zinc (II) uptake (51.7 mg/g) was accomplished (36 h old). The comparison of the results revealed that cells in a growing state (63.9 mg/g) can achieve the highest selective uptake. Hence, the uptake of zinc(II) under various operational strategies was only done with growing cells. The biological uptake of zinc (II) was then done in a fed batch mode of operation using Fusarium solani growing cells. Increased volume pulse feeding (IVPF) and constant volume pulse feeding (CVPF) were used to study the fed batch process and the impacts of these operational methods on biological performance were contrasted with those of a traditional batch process. According to batch experiments, at pH 5.0 and an initial zinc (II) ion concentration of 500 mg/l, the maximum specific zinc (II) removal was 63.9 mg/g. The maximal specific zinc (II) removal in the IVPF process was determined to be 45.47 mg/g and 33.58 mg/g, but the values in the CVPF process were 33.12 mg/g and 22.59 mg/g respectively for the first and second pulse feedings in both cases. The zinc (II) uptake found in prior investigations carried out by the current authors employing the continuous mode of operation was then compared with these results. The process could be run for a longer period of time with a maximum specific zinc (II) removal of 52.8 mg/g when operating in a continuous mode which was shown to be the optimal operational strategy.