A facile fluorescence-coupling approach to visualizing leonurine uptake and distribution in living cells and Caenorhabditis elegans.

BACKGROUND: Caenorhabditis elegans (C. elegans) has been recognized for being a useful model organism in small-molecule drug screens and drug efficacy investigation. However, there remain bottlenecks in evaluating such processes as drug uptake and distribution due to a lack of appropriate chemical tools. PURPOSE: This study aims to prepare fluorescence-labeled leonurine as an example to monitor drug uptake and distribution of small molecule in C. elegans and living cells. METHODS: FITC-conjugated leonurine (leonurine-P) was synthesized and characterized by LC/MS, NMR, UV absorption and fluorescence intensity. Leonurine-P was used to stain C. elegans and various mammalian cell lines. Different concentrations of leonurine were tested in conjunction with a competing parent molecule to determine whether leonurine-P and leonurine shared the same biological targets. Drug distribution was analyzed by imaging. Fluorometry in microplates and flow cytometry were performed for quantitative measurements of drug uptake. RESULTS: The UV absorption peak of leonurine-P was 490∼495 nm and emission peak was 520 nm. Leonurine-P specifically bound to endogenous protein targets in C. elegans and mammalian cells, which was competitively blocked by leonurine. The highest enrichment levels of leonurine-P were observed around 72 h following exposure in C. elegans. Leonurine-P can be used in a variety of cells to observe drug distribution dynamics. Flow cytometry of stained cells can be facilely carried out to quantitatively detect probe signals. CONCLUSIONS: The strategy of fluorescein-labeled drugs reported herein allows quantification of drug enrichment and visualization of drug distribution, thus illustrates a convenient approach to study phytodrugs in pharmacological contexts.

A transaminase-mediated aldol reaction and applications in cascades to styryl pyridines.

Transaminase enzymes are well established biocatalysts that are used in chemical synthesis due to their beneficial sustainability profile, regio- and stereoselectivity and substrate specificity. Here, the use of a wild-type Chromobacterium violaceum transaminase (CvTAm) in enzyme cascades revealed the formation of a novel hydroxystyryl pyridine product. Subsequent studies established it was a transaminase mediated reaction where it was exhibiting apparent aldolase reactivity. This promiscuous enzyme reaction mechanism was then explored using other wild-type transaminases and via the formation of CvTAm mutants. Application of one pot multi-step enzyme cascades was subsequently developed to produce a range of hydroxystyryl pyridines.

A Composite Hydrogel Functionalized by Borosilicate Bioactive Glasses and VEGF for Critical-Size Bone Regeneration.

Critical-size bone defects pose a formidable challenge in clinical treatment, prompting extensive research efforts to address this problem. In this study, an inorganic-organic multifunctional composite hydrogel denoted as PLG-g-TA/VEGF/Sr-BGNPs is developed, engineered for the synergistic management of bone defects. The composite hydrogel demonstrated the capacity for mineralization, hydroxyapatite formation, and gradual release of essential functional ions and vascular endothelial growth factor (VEGF) and also maintained an alkaline microenvironment. The composite hydrogel promoted the proliferation and osteogenic differentiation of rat bone marrow mesenchymal stem cells (rBMSCs), as indicated by increased expression of osteogenesis-related genes and proteins in vitro. Moreover, the composite hydrogel significantly enhanced the tube-forming capability of human umbilical vein endothelial cells (HUVECs) and effectively inhibited the process of osteoblastic differentiation of nuclear factor kappa-B ligand (RANKL)-induced Raw264.7 cells and osteoclast bone resorption. After the implantation of the composite hydrogel into rat cranial bone defects, the expression of osteogenic and angiogenic biomarkers increased, substantiating its efficacy in promoting bone defect repair in vivo. The commendable attributes of the multifunctional composite hydrogel underscore its pivotal role in expediting hydrogel-associated bone growth and repairing critical bone defects, positioning it as a promising adjuvant therapy candidate for large-segment bone defects.

First-line immunotherapy efficacy in advanced squamous non-small cell lung cancer with PD-L1 expression ≥50%: a network meta-analysis of randomized controlled trials.

Objective: The optimal first-line immunotherapy regimen for patients with PD-L1 expression ≥50% in squamous non-small cell lung cancer (Sq-NSCLC) remains uncertain. This study utilized net-work meta-analysis (NMA) to indirectly compare the efficacy of various first-line immuno-therapy regimens in this patient subset. Methods: Systematic searches were conducted across PubMed, the Cochrane Library, Web of Science, and Embase databases for randomized controlled trials reporting overall survival (OS) and progression-free survival (PFS) outcomes. The search spanned from database inception to November 3, 2023. Bayesian network meta-analysis was employed for a comprehen-sive analysis. To ensure scientific rigor and transparency, this study is registered in the Interna-tional Prospective Register of Systematic Reviews (PROSPERO) under the registration number CRD42022349712. Results: The NMA encompassed 9 randomized controlled trials (RCTs), involving 2170 patients and investigating 9 distinct immunotherapy regimens. For OS, the combination of camrelizumab and chemotherapy demonstrated the highest probability (36.68%) of efficacy, fol-lowed by cemiplimab (33.86%) and atezolizumab plus chemotherapy (23.87%). Regarding PFS, the camrelizumab and chemotherapy combination had the highest probability (39.70%) of efficacy, followed by pembrolizumab (22.88%) and pembrolizumab plus chemotherapy (17.69%). Compared to chemotherapy, first-line treatment with immune checkpoint inhibitors (ICIs) in Sq-NSCLC pa-tients exhibited significant improvements in OS (HR 0.59, 95% CI 0.47-0.75) and PFS (HR 0.44, 95% CI 0.37-0.52). Conclusion: This study suggests that, for Sq-NSCLC patients with PD-L1 expression ≥50%, the first-line immunotherapy regimen of camrelizumab plus chemotherapy provides superior OS and PFS outcomes. Furthermore, ICIs demonstrate enhanced efficacy compared to chemotherapy in this patient population. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier: CRD 42022349712.

A sensitive, portable, and smartphone-based whole-cell biosensor device for salicylic acid monitoring.

Considerable effort has been invested in developing salicylic acid (SA) biosensors for various application purposes. Here, by engineering the sensing modules and host cell chassis, we have gradually optimized the NahR-Psal/Pr-based SA biosensor, increasing the sensitivity and maximum output by 17.2-fold and 9.4-fold, respectively, and improving the detection limit by 800-fold, from 80 µM to 0.1 µM. A portable SA sensing device was constructed by embedding a gelatin-based hydrogel containing an optimized biosensor into the perforations of tape adhered to glass slide, which allowed good determination of SA in the range of 0.1 µM-10 µM. Then, we developed a customized smartphone App to measure the fluorescence intensity of each perforation and automatically calculate the corresponding SA concentration so that we could detect SA concentrations in real cosmetic samples. We anticipate that this smartphone-based imaging biosensor, with its compact size, higher sensitivity, cost-effectiveness, and easy data transfer, will be useful for long-term monitoring of SA.

Harnessing Synchronous Photothermal and Photocatalytic Effects of Substoichiometric MoO3-x Nanoparticle-Decorated Membranes for Clean Water Generation.

Solar-driven interfacial evaporation provides a promising pathway for sustainable freshwater and energy generation. However, developing highly efficient photothermal and photocatalytic nanomaterials is challenging. Herein, substoichiometric molybdenum oxide (MoO3-x) nanoparticles are synthesized via step-by-step reduction treatment of l-cysteine under mild conditions for simultaneous photothermal conversion and photocatalytic reactions. The MoO3-x nanoparticles of low reduction degree are decorated on hydrophilic cotton cloth to prepare a MCML evaporator toward rapid water production, pollutant degradation, as well as electricity generation. The obtained MCML evaporator has a strong local light-to-heat effect, which can be attributed to excellent photothermal conversion via the local surface plasmon resonance effect in MoO3-x nanoparticles and the low heat loss of the evaporator. Meanwhile, the rich surface area of MoO3-x nanoparticles and the localized photothermal effect together effectively accelerate the photocatalytic degradation reaction of the antibiotic tetracycline. With the benefit of these advantages, the MCML evaporator attains a superior evaporation rate of 4.14 kg m-2 h-1, admirable conversion efficiency of 90.7%, and adequate degradation efficiency of 96.2% under 1 sun irradiation. Furthermore, after being rationally assembled with a thermoelectric module, the hybrid device can be employed to generate 1.0 W m-2 of electric power density. This work presents an effective complementary strategy for freshwater production and sewage treatment as well as electricity generation in remote and off-grid regions.

Quaternary Ammonium Assisted Synthesis of Melanin-like Poly(l-DOPA) Nanoparticles with a Boosted Photothermal Effect.

Poly(levodopa) nanoparticles (P(l-DOPA) NPs) are another kind of melanin mimetic besides well-established polydopamine nanoparticles (PDA NPs). Due to the presence of carboxyl groups, the oxidative polymerization of l-DOPA to obtain particles was not as efficient as that of dopamine. Several established methods toward P(l-DOPA) NP fabrication do not combine convenience, morphological regularity, size controllability, low cost, and adaptability to metal-free application scenarios. In this work, P(l-DOPA) NPs were successfully prepared in hot water with the assistant of organic quaternary ammonium, due to the extra physical cross-linking mediated by cations. The employed physical interactions could also be affected by quaternary ammonium structure (i.e., number of cation heads, length of alkyl chain) to achieve different polymerization acceleration effects. The obtained P(l-DOPA) NPs retained superior photothermal properties and outperformed PDA-based melanin materials. Furthermore, P(l-DOPA) NPs were used in photothermal tumor therapy and showed better efficacy. This study offers new insights into the synthesis of melanin-like materials, as well as new understanding of the interaction between quaternary ammonium and bioinspired polyphenolic materials.

A membrane associated tandem kinase from wild emmer wheat confers broad-spectrum resistance to powdery mildew.

Crop wild relatives offer natural variations of disease resistance for crop improvement. Here, we report the isolation of broad-spectrum powdery mildew resistance gene Pm36, originated from wild emmer wheat, that encodes a tandem kinase with a transmembrane domain (WTK7-TM) through the combination of map-based cloning, PacBio SMRT long-read genome sequencing, mutagenesis, and transformation. Mutagenesis assay reveals that the two kinase domains and the transmembrane domain of WTK7-TM are critical for the powdery mildew resistance function. Consistently, in vitro phosphorylation assay shows that two kinase domains are indispensable for the kinase activity of WTK7-TM. Haplotype analysis uncovers that Pm36 is an orphan gene only present in a few wild emmer wheat, indicating its single ancient origin and potential contribution to the current wheat gene pool. Overall, our findings not only provide a powdery mildew resistance gene with great potential in wheat breeding but also sheds light into the mechanism underlying broad-spectrum resistance.

Oral-gut microbial transmission promotes diabetic coronary heart disease.

BACKGROUND: Diabetes is a predominant driver of coronary artery disease worldwide. This study aims to unravel the distinct characteristics of oral and gut microbiota in diabetic coronary heart disease (DCHD). Simultaneously, we aim to establish a causal link between the diabetes-driven oral-gut microbiota axis and increased susceptibility to diabetic myocardial ischemia-reperfusion injury (MIRI). METHODS: We comprehensively investigated the microbial landscape in the oral and gut microbiota in DCHD using a discovery cohort (n = 183) and a validation chohort (n = 68). Systematically obtained oral (tongue-coating) and fecal specimens were subjected to metagenomic sequencing and qPCR analysis, respectively, to holistically characterize the microbial consortia. Next, we induced diabetic MIRI by administering streptozotocin to C57BL/6 mice and subsequently investigated the potential mechanisms of the oral-gut microbiota axis through antibiotic pre-treatment followed by gavage with specific bacterial strains (Fusobacterium nucleatum or fecal microbiota from DCHD patients) to C57BL/6 mice. RESULTS: Specific microbial signatures such as oral Fusobacterium nucleatum and gut Lactobacillus, Eubacterium, and Roseburia faecis, were identified as potential microbial biomarkers in DCHD. We further validated that oral Fusobacterium nucleatum and gut Lactobacillus are increased in DCHD patients, with a positive correlation between the two. Experimental evidence revealed that in hyperglycemic mice, augmented Fusobacterium nucleatum levels in the oral cavity were accompanied by an imbalance in the oral-gut axis, characterized by an increased coexistence of Fusobacterium nucleatum and Lactobacillus, along with elevated cardiac miRNA-21 and a greater extent of myocardial damage indicated by TTC, HE, TUNEL staining, all of which contributed to exacerbated MIRI. CONCLUSION: Our findings not only uncover dysregulation of the oral-gut microbiota axis in diabetes patients but also highlight the pivotal intermediary role of the increased abundance of oral F. nucleatum and gut Lactobacillus in exacerbating MIRI. Targeting the oral-gut microbiota axis emerges as a potent strategy for preventing and treating DCHD. Oral-gut microbial transmission constitutes an intermediate mechanism by which diabetes influences myocardial injury, offering new insights into preventing acute events in diabetic patients with coronary heart disease.

Sonochemical Synthesis of Natural Polyphenolic Nanoparticles for Modulating Oxidative Stress.

Natural polyphenolic compounds play a vital role in nature and are widely utilized as building blocks in the fabrication of emerging functional nanomaterials. Although diverse fabrication methodologies are developed in recent years, the challenges of purification, uncontrollable reaction processes and additional additives persist. Herein, a modular and facile methodology is reported toward the fabrication of natural polyphenolic nanoparticles. By utilizing low frequency ultrasound (40 kHz), the assembly of various natural polyphenolic building blocks is successfully induced, allowing for precise control over the particle formation process. The resulting natural polyphenolic nanoparticles possessed excellent in vitro antioxidative abilities and in vivo therapeutic effects in typical oxidative stress models including wound healing and acute kidney injury. This study opens new avenues for the fabrication of functional materials from naturally occurring building blocks, offering promising prospects for future advancements in this field.

UV absorption enhanced polydopamine coating.

Mussel-inspired polydopamine (PDA) coatings have gained significant attention in various fields, including biomedicine, energy, detection, and UV protection, owing to their versatile and promising properties. Among these properties, UV shielding stands out as a key feature of PDA coatings. Nevertheless, the current methods for tuning the UV-shielding properties of PDA coatings are quite limited, and only rely on thickness adjustment, which might involve additional issues like color and visible light transmittance to the coating layer. In this study, we propose a facile and modular approach to enhance the UV absorption of PDA coatings by incorporating thiol-heterocycle (TH) derivatives. Both pre- and post-modification strategies can effectively impede the formation of conjugated structures within PDA, leading to enhanced UV absorption within the PDA layers. More importantly, these strategies can improve the UV absorption of PDA coatings while reducing the visible light absorption. Furthermore, this method enabled efficient regulation of the UV absorption of PDA coatings by altering the ring type (benzene ring or pyridine ring) and substituent on the ring (methoxyl group or hydrogen atom). These PDA coatings with enhanced UV absorption demonstrate great promise for applications in UV protection, antibacterial activity, wound healing and dye degradation.

Predictions of Aeroengines' Infrared Radiation Characteristics Based on HKELM Optimized by the Improved Dung Beetle Optimizer.

To solve the problems of high computational cost and the long time required by the simulation and calculation of aeroengines' exhaust systems, a method of predicting the characteristics of infrared radiation based on the hybrid kernel extreme learning machine (HKELM) optimized by the improved dung beetle optimizer (IDBO) was proposed. Firstly, the Levy flight strategy and variable spiral strategy were introduced to improve the optimization performance of the dung beetle optimizer (DBO) algorithm. Secondly, the superiority of IDBO algorithm was verified by using 23 benchmark functions. In addition, the Wilcoxon signed-rank test was applied to evaluate the experimental results, which proved the superiority of the IDBO algorithm over other current prominent metaheuristic algorithms. Finally, the hyperparameters of HKELM were optimized by the IDBO algorithm, and the IDBO-HKELM model was applied to the prediction of characteristics of infrared radiation of a typical axisymmetric nozzle. The results showed that the RMSE and MAE of the IDBO-HKELM model were 20.64 and 8.83, respectively, which verified the high accuracy and feasibility of the proposed method for predictions of aeroengines' infrared radiation characteristics.

Spatial representation of multidimensional information in emotional faces revealed by fMRI.

Face perception is a complex process that involves highly specialized procedures and mechanisms. Investigating into face perception can help us better understand how the brain processes fine-grained, multidimensional information. This research aimed to delve deeply into how different dimensions of facial information are represented in specific brain regions or through inter-regional connections via an implicit face recognition task. To capture the representation of various facial information in the brain, we employed support vector machine decoding, functional connectivity, and model-based representational similarity analysis on fMRI data, resulting in the identification of three crucial findings. Firstly, despite the implicit nature of the task, emotions were still represented in the brain, contrasting with all other facial information. Secondly, the connection between the medial amygdala and the parahippocampal gyrus was found to be essential for the representation of facial emotion in implicit tasks. Thirdly, in implicit tasks, arousal representation occurred in the parahippocampal gyrus, while valence depended on the connection between the primary visual cortex and the parahippocampal gyrus. In conclusion, these findings dissociate the neural mechanisms of emotional valence and arousal, revealing the precise spatial patterns of multidimensional information processing in faces.

Functional Polyphenol-Based Nanoparticles Boosted the Neuroprotective Effect of Riluzole for Acute Spinal Cord Injury.

Riluzole is commonly used as a neuroprotective agent for treating traumatic spinal cord injury (SCI), which works by blocking the influx of sodium and calcium ions and reducing glutamate activity. However, its clinical application is limited because of its poor solubility, short half-life, potential organ toxicity, and insufficient bioabilities toward upregulated inflammation and oxidative stress levels. To address this issue, epigallocatechin gallate (EGCG), a natural polyphenol, was employed to fabricate nanoparticles (NPs) with riluzole to enhance the neuroprotective effects. The resulting NPs demonstrated good biocompatibility, excellent antioxidative properties, and promising regulation effects from the M1 to M2 macrophages. Furthermore, an in vivo SCI model was successfully established, and NPs could be obviously aggregated at the SCI site. More interestingly, excellent neuroprotective properties of NPs through regulating the levels of oxidative stress, inflammation, and ion channels could be fully demonstrated in vivo by RNA sequencing and sophisticated biochemistry evaluations. Together, the work provided new opportunities toward the design and fabrication of robust and multifunctional NPs for oxidative stress and inflammation-related diseases via biological integration of natural polyphenols and small-molecule drugs.

Clinical effect of roxadustat vs. erythropoietin in non-dialysis CKD with diabetes: a single center propensity score matching analysis.

PURPOSE: Renal anemia is a common complication of chronic kidney disease. Currently, recombinant human erythropoietin and roxadustat are the main treatments. In China, diabetic kidney disease is the primary cause of chronic kidney disease. However, high-quality evidence on the efficacy of roxadustat in patients with non-dialysis-dependent chronic kidney disease and diabetes mellitus is scarce. This study aimed to assess the clinical effect of roxadustat in such patients. METHODS: Patients with non-dialysis-dependent anemia and diabetes mellitus who received roxadustat or recombinant human erythropoietin for ≥ 4 weeks were enrolled. We compared baseline characteristics, including age, gender, hypertension, and hemoglobin level, and then employed a 1:3 ratio propensity score matching. The primary efficacy outcomes were changes in hemoglobin levels. After propensity score matching, 212 patients were analyzed, including the roxadustat (n = 53) and recombinant human erythropoietin (n = 159) groups. Baseline characteristics were comparable, including hemoglobin level, estimated glomerular filtration rate, and glycated hemoglobin A1c (p > 0.05). RESULTS: After 4, 12, and 24 weeks of treatment, the median hemoglobin levels in the roxadustat group were 97.5 g/L, 104 g/L, and 106.5 g/L, respectively, significantly surpassing the corresponding levels in the recombinant human erythropoietin group at 91 g/L, 94.5 g/L, and 94.5 g/L (p = 0.002, p = 0.025, p = 0.006, respectively). Additionally, subgroup analysis demonstrated better treatment efficacy of roxadustat patients with elevated high-sensitivity C-reactive protein and low albumin levels. CONCLUSION: In Chinese patients with anemia and diabetes not on dialysis, roxadustat efficiently and rapidly improved and maintained hemoglobin levels unaffected by elevated high-sensitivity C-reactive protein and low albumin levels.

Mechanically Controlled Enzymatic Polymerization and Remodeling.

In nature, proteins possess the remarkable ability to sense and respond to mechanical forces, thereby triggering various biological events, such as bone remodeling and muscle regeneration. However, in synthetic systems, harnessing the mechanical force to induce material growth still remains a challenge. In this study, we aimed to utilize low-frequency ultrasound (US) to activate horseradish peroxidase (HRP) and catalyze free radical polymerization. Our findings demonstrate the efficacy of this mechano-enzymatic chemistry in rapidly remodeling the properties of materials through cross-linking polymerization and surface coating. The resulting samples exhibited a significant enhancement in tensile strength, elongation, and Young's modulus. Moreover, the hydrophobicity of the surface could be completely switched within just 30 min of US treatment. This work presents a novel approach for incorporating mechanical sensing and rapid remodeling capabilities into materials.

Analysis of resistance risk and mechanism of the 14α-demethylation inhibitor ipconazole in Fusarium pseudograminearum.

Ipconazole is a broad-spectrum triazole fungicide that is highly effective against Fusarium pseudograminearum. However, its risk of developing resistance and mechanism are not well understood in F. pseudograminearum. Here, the sensitivities of 101 F. pseudograminearum isolates to ipconazole were investigated, and the average EC50 value was 0.1072 µg/mL. Seven mutants resistant to ipconazole were obtained by fungicide adaption, with all but one showing reduced fitness relative to the parental isolates. Cross-resistance was found between ipconazole and mefentrifluconazole and tebuconazole, but none between ipconazole and pydiflumetofen, carbendazim, fludioxonil, or phenamacril. In summary, these findings suggest that there is a low risk of F. pseudograminearum developing resistance to ipconazole. Additionally, a point mutation, G464S, was seen in FpCYP51B and overexpression of FpCYP51A, FpCYP51B and FpCYP51C was observed in ipconazole-resistant mutants. Assays, including transformation and molecular docking, indicated that G464S conferred ipconazole resistance in F. pseudograminearum.

Resistance risk, resistance mechanism and the effect on DON production of a new SDHI fungicide cyclobutrifluram in Fusarium graminearum.

Fusarium head blight in wheat is caused by Fusarium graminearum, resulting in significant yield losses and grain contamination with deoxynivalenol (DON), which poses a potential threat to animal health. Cyclobutrifluram, a newly developed succinate dehydrogenase inhibitor, has shown excellent inhibition of Fusarium spp. However, the resistance risk of F. graminearum to cyclobutrifluram and the molecular mechanism of resistance have not been determined. In this study, we established the average EC50 of a range of F. graminearum isolates to cyclobutrifluram to be 0.0110 µg/mL. Six cyclobutrifluram-resistant mutants were obtained using fungicide adaptation. All mutants exhibited impaired fitness relative to their parental isolates. This was evident from measurements of mycelial growth, conidiation, conidial germination, virulence, and DON production. Interestingly, cyclobutrifluram did not seem to affect the DON production of either the sensitive isolates or the resistant mutants. Furthermore, a positive cross-resistance was observed between cyclobutrifluram and pydiflumetofen. These findings suggest that F. graminearum carries a moderate to high risk of developing resistance to cyclobutrifluram. Additionally, point mutations H248Y in FgSdhB and A73V in FgSdhC1 of F. graminearum were observed in the cyclobutrifluram-resistant mutants. Finally, an overexpression transformation assay and molecular docking indicated that FgSdhBH248Y or FgSdhC1A73V could confer resistance of F. graminearum to cyclobutrifluram.

Eumelanin-like Poly(levodopa) Nanoscavengers for Inflammation Disease Therapy.

In the current years, polydopamine nanoparticles (PDA NPs) have been extensively investigated as an eumelanin mimic. However, unlike natural eumelanin, PDA NPs contain no 5,6-dihydroxyindole-2-carboxylic acid (DHICA)-derived units and may be limited in certain intrinsic properties; superior eumelanin-like nanomaterials are still actively being sought. Levodopa (l-DOPA) is a natural eumelanin precursor and expected to convert into DHICA and further remain within the final product through covalent or physical interactions. Herein, poly(levodopa) nanoparticles [P(l-DOPA) NPs] were synthesized with the assistance of zinc oxide as a supplement to synthetic eumelanin. This study found that P(l-DOPA) NPs had ∼90% DHICA-derived subunits on their surface and exhibited superior antioxidant activity compared to PDA NPs due to their looser polymeric microstructure. Benefitting from a stronger ROS scavenging ability, P(l-DOPA) NPs outperformed PDA NPs in treating cellular oxidative stress and acute inflammation. This research opens up new possibilities for the development and application of novel melanin-like materials.

Efficacy, tolerability, and safety of the oral phosphate binder VS-505 (AP301).

BACKGROUND: VS-505 (AP301), an acacia and ferric oxyhydroxide polymer, is a novel fiber-iron-based phosphate binder. This two-part phase 2 study evaluated the tolerability, safety, and efficacy of oral VS-505 administered three times daily with meals in treating hyperphosphatemia in chronic kidney disease (CKD) patients receiving maintenance hemodialysis (MHD). METHODS: In Part 1, patients received dose-escalated treatment with VS-505 2.25, 4.50, and 9.00 g/day for 2 weeks each, guided by serum phosphorus levels. In Part 2, patients received randomized, open-label, fixed-dosage treatment with VS-505 (1.50, 2.25, 4.50, or 6.75 g/day) or sevelamer carbonate 4.80 g/day for 6 weeks. The primary efficacy endpoint was the change in serum phosphorus. RESULTS: The study enrolled 158 patients (Part 1: 25; Part 2: 133), with 130 exposed to VS-505 in total. VS-505 was well tolerated. The most common adverse events were gastrointestinal disorders, mainly feces discolored (56%) and diarrhea (15%; generally during weeks 1‒2 of treatment). Most gastrointestinal disorders resolved without intervention, and none were serious. In Part 1, serum phosphorus significantly improved (mean change -2.0 mg/dL; 95% confidence interval -2.7, -1.4) after VS-505 dose escalation. In Part 2, serum phosphorus significantly and dose-dependently improved in all VS-505 arms, with clinically meaningful reductions with VS-505 4.50 and 6.75 g/day, and sevelamer carbonate 4.80 g/day (mean change -1.6 (-2.2, -1.0), -1.8 (-2.4, -1.2), and -1.4 (-2.2, -0.5) mg/dL, respectively). In both Parts, serum phosphorus reductions occurred within 1 week of VS-505 initiation, returning to baseline within 2 weeks of VS-505 discontinuation. CONCLUSION: VS-505, a novel phosphate binder, was well tolerated with a manageable safety profile, and effectively and dose-dependently reduced serum phosphorus in CKD patients with hyperphosphatemia receiving MHD. Clinical Trial registration number: NCT04551300.