Research progress of the netrins and their receptors in cancer.

Netrins, a family of secreted and membrane-associated proteins, can regulate axonal guidance, morphogenesis, angiogenesis, cell migration, cell survival, and tumorigenesis. Four secreted netrins (netrin 1, 3, 4 and 5) and two glycosylphosphatidylinositols-anchored membrane proteins, netrin-G1 and G2, have been identified in mammals. Netrins and their receptors can serve as a biomarker and molecular therapeutic target for pathological differentiation, diagnosis and prognosis of malignant cancers. We review here the potential roles of the netrins family and their receptors in cancer.

Fine mapping of TFL, a major gene regulating fruit length in snake gourd (Trichosanthes anguina L).

Fruit length is a crucial agronomic trait of snake gourd (Trichosanthes anguina L); however, genes associated with fruit length have not been characterised. In this study, F2 snake gourd populations were generated by crossing the inbred lines, S1 and S2 (fruit lengths: 110 and 20 cm, respectively). Subsequently, bulk segregant analysis, sequencing, and fine-mapping were performed on the F2 population to identify target genes. Our findings suggest that the fruit length of snake gourd is regulated by a major-effect regulatory gene. Mining of genes regulating fruit length in snake gourd to provide a basis for subsequent selection and breeding of new varieties. Genotype-phenotype association analysis was performed on the segregating F2 population comprising 6,000 plants; the results indicate that the target gene is located on Chr4 (61,846,126-61,865,087 bp, 18.9-kb interval), which only carries the annotated candidate gene, Tan0010544 (designated TFL). TFL belongs to the MADS-box family, one of the largest transcription factor families. Sequence analysis revealed a non-synonymous mutation of base C to G at position 202 in the coding sequence of TFL, resulting in the substitution of amino acid Gln to Glu at position 68 in the protein sequence. Subsequently, an InDel marker was developed to aid the marker-assisted selection of TFL. The TFL in the expression parents within the same period was analysed using quantitative real-time PCR; the TFL expression was significantly higher in short fruits than long fruits. Therefore, TFL can be a candidate gene for determining the fruit length in snake gourd. Collectively, these findings improve our understanding of the genetic components associated with fruit length in snake gourds, which could aid the development of enhanced breeding strategies for plant species.

Chromosome-level reference genome and resequencing of 322 accessions reveal evolution, genomic imprint and key agronomic traits in adzuki bean.

Adzuki bean (Vigna angularis) is an important legume crop cultivated in over 30 countries worldwide. We developed a high-quality chromosome-level reference genome of adzuki bean cultivar Jingnong6 by combining PacBio Sequel long-read sequencing with short-read and Hi-C technologies. The assembled genome covers 97.8% of the adzuki bean genome with a contig N50 of approximately 16 Mb and a total of 32 738 protein-coding genes. We also generated a comprehensive genome variation map of adzuki bean by whole-genome resequencing (WGRS) of 322 diverse adzuki beans accessions including both wild and cultivated. Furthermore, we have conducted comparative genomics and a genome-wide association study (GWAS) on key agricultural traits to investigate the evolution and domestication. GWAS identified several candidate genes, including VaCycA3;1, VaHB15, VaANR1 and VaBm, that exhibited significant associations with domestication traits. Furthermore, we conducted functional analyses on the roles of VaANR1 and VaBm in regulating seed coat colour. We provided evidence for the highest genetic diversity of wild adzuki (Vigna angularis var. nipponensis) in China with the presence of the most original wild adzuki bean, and the occurrence of domestication process facilitating transition from wild to cultigen. The present study elucidates the genetic basis of adzuki bean domestication traits and provides crucial genomic resources to support future breeding efforts in adzuki bean.

Research on optical simulation of dim target based on passive detection link analysis.

In order to meet the ground calibration requirements of optical detection equipment to identify optical characteristics of dim targets, an optical simulation method of dim targets based on passive detection link analysis and bidirectional scattering distribution function model is proposed. The off-axis collimation system for long focal length, the simulated energy transmission model of dim targets and the simplified model of bidirectional scattering distribution function are established. An internal stray light suppression baffle was designed to effectively suppress secondary scattering, and an optical simulation system for dim targets was built. The experimental results show that the system can simulate +7 Mv∼+20 Mv, and the simulation accuracy is better than 0.07 Mv. At the same time, the detection ability of the camera is tested by using the +15 Mv point simulated by the system. The signal-to-noise of the star point target reaches 6.7, which meets the requirements of detection rate and false alarm rate, and realizes the ground test of the camera's detection ability of the dim target.

Fully Flexible Molecular Alignment Enables Accurate Ligand Structure Modeling.

Accurate protein-ligand binding poses are the prerequisites of structure-based binding affinity prediction and provide the structural basis for in-depth lead optimization in small molecule drug design. However, it is challenging to provide reasonable predictions of binding poses for different molecules due to the complexity and diversity of the chemical space of small molecules. Similarity-based molecular alignment techniques can effectively narrow the search range, as structurally similar molecules are likely to have similar binding modes, with higher similarity usually correlated to higher success rates. However, molecular similarity is not consistently high because molecules often require changes to achieve specific purposes, leading to reduced alignment precision. To address this issue, we propose a new alignment method─Z-align. This method uses topological structural information as a criterion for evaluating similarity, reducing the reliance on molecular fingerprint similarity. Our method has achieved success rates significantly higher than those of other methods at moderate levels of similarity. Additionally, our approach can comprehensively and flexibly optimize bond lengths and angles of molecules, maintaining a high accuracy even when dealing with larger molecules. Consequently, our proposed solution helps in achieving more accurate binding poses in protein-ligand docking problems, facilitating the development of small molecule drugs. Z-align is freely available as a web server at https://cloud.zelixir.com/zalign/home.

FOXO1 induced fatty acid oxidation in hepatic cells by targeting ALDH1L2.

BACKGROUND AND AIM: Lipid metabolism disorder is the primary feature of numerous refractory chronic diseases. Fatty acid oxidation, an essential aerobic biological process, is closely related to the progression of NAFLD. The forkhead transcription factor FOXO1 has been reported to play an important role in lipid metabolism. However, the molecular mechanism through which FOXO1 regulates fatty acid oxidation remains unclear. METHODS: Transcriptomic analysis was performed to examine the cellular expression profile to determine the functional role of FOXO1 in HepG2 cells with palmitic acid (PA)-induced lipid accumulation. FOXO1-binding motifs at the promoter region of aldehyde dehydrogenase 1 family member L2 (ALDH1L2) were predicted via bioinformatic analysis and confirmed via luciferase reporter assay. Overexpression of ALDH1L2 was induced to recover the impaired fatty acid oxidation in FOXO1-knockout cells. RESULTS: Knockout of FOXO1 aggravated lipid deposition in hepatic cells. Transcriptomic profiling revealed that knockout of FOXO1 increased the expression of genes associated with fatty acid synthesis but decreased the expression of carnitine palmitoyltransferase1a (CPT1α) and adipose triglyceride lipase (ATGL), which contribute to fatty acid oxidation. Mechanistically, FOXO1 was identified as a transcription factor of ALDH1L2. Knockout of FOXO1 significantly decreased the protein expression of ALDH1L2 and CPT1α in vitro and in vivo. Furthermore, overexpression of ALDH1L2 restored fatty acid oxidation in FOXO1-knockout cells. CONCLUSION: The findings of this study indicate that FOXO1 modulates fatty acid oxidation by targeting ALDH1L2.

Exoskeleton rehabilitation robot training for balance and lower limb function in sub-acute stroke patients: a pilot, randomized controlled trial.

PURPOSE: This pilot study aimed to investigate the effects of REX exoskeleton rehabilitation robot training on the balance and lower limb function in patients with sub-acute stroke. METHODS: This was a pilot, single-blind, randomized controlled trial. Twenty-four patients with sub-acute stroke (with the course of disease ranging from 3 weeks to 3 months) were randomized into two groups, including a robot group and a control group. Patients in control group received upright bed rehabilitation (n = 12) and those in robot group received exoskeleton rehabilitation robot training (n = 12). The frequency of training in both groups was once a day (60 min each) for 5 days a week for a total of 4 weeks. Besides, the two groups were evaluated before, 2 weeks after and 4 weeks after the intervention, respectively. The primary assessment index was the Berg Balance Scale (BBS), whereas the secondary assessment indexes included the Fugl-Meyer Lower Extremity Motor Function Scale (FMA-LE), the Posture Assessment Scale for Stroke Patients (PASS), the Activities of Daily Living Scale (Modified Barthel Index, MBI), the Tecnobody Balance Tester, and lower extremity muscle surface electromyography (sEMG). RESULTS: The robot group showed significant improvements (P < 0.05) in the primary efficacy index BBS, as well as the secondary efficacy indexes PASS, FMA-LE, MBI, Tecnobody Balance Tester, and sEMG of the lower limb muscles. Besides, there were a significant differences in BBS, PASS, static eye-opening area or dynamic stability limit evaluation indexes between the robotic and control groups (P < 0.05). CONCLUSIONS: This is the first study to investigate the effectiveness of the REX exoskeleton rehabilitation robot in the rehabilitation of patients with stroke. According to our results, the REX exoskeleton rehabilitation robot demonstrated superior potential efficacy in promoting the early recovery of balance and motor functions in patients with sub-acute stroke. Future large-scale randomized controlled studies and follow-up assessments are needed to validate the current findings. CLINICAL TRIALS REGISTRATION: URL: https://www.chictr.org.cn/index.html.Unique identifier: ChiCTR2300068398.

Inactivation of pathogenic microorganisms in water by electron beam excitation multi-wavelength ultraviolet irradiation: Efficiency, influence factors and mechanism.

Due to the limitations of traditional ultraviolet (UV) in microbial inactivation in water, it is necessary to explore a more suitable and efficient UV disinfection method. In this study, an electron beam excitation multi-wavelength ultraviolet (EBE-MW-UV) system was established and aims to analyze its differential microbial inactivation capabilities in comparison to single-wavelength UV-LEDs in waterborne applications. Furthermore, the inactivation mechanisms of this system on microorganisms were explored. The results showed that EBE-MW-UV had significantly higher inactivation effects on the Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis and Candida albicans in water compared to UV-LEDs (p＜0.05), and the inactivation effect of EBE-MW-UV on Escherichia coli and Pseudomonas aeruginosa at the same UV dose was 3.8 and 1.9 log higher than that of UV-LEDs, respectively, EBE-MW-UV exhibited better inactivation effects on Gram-negative bacteria. Further research found that, under the majority of irradiation doses, neither EBE-MW-UV nor UV-LEDs were significantly affected by the concentration of suspended solids (5 and 20 mg/L) or humic acids (2 and 5 mg/L) in the water. Mechanism analysis revealed that during the disinfection process of EBE-MW-UV, microbial DNA and proteins were initially damaged, which prevented the occurrence of dark repair and led to bacterial inactivation. In addition, UV irradiation led to the production of additional reactive oxygen species (ROS) inside the cells, increasing cell membrane permeability and exacerbating membrane damage. This was accompanied by a decrease in energy metabolism and depletion of ATP, ultimately resulting in microbial inactivation. Therefore, EBE-MW-UV demonstrated more effective disinfection than single-wavelength UV-LEDs, showing great potential. Our research gives new insights into the characteristics of multiple wavelength ultraviolet, and provides scientific basis for the selection of new light sources in the field of ultraviolet disinfection.

Left-behind cumulative risk and academic adjustment in Chinese middle school students: The moderating effect of growth mindset.

Left-behind children, as a large-scale disadvantaged group, encounter an array of risk factors that impede their academic development because of parental migration. The current study aimed at investigating the roles of left-behind cumulative risk and growth mindset on academic adjustment and exploring whether growth mindset moderated the association between left-behind cumulative risk and academic adjustment in left-behind middle school students. A total of 1184 left-behind middle school students (615 males; 12-16 years) participated in the study. Results indicated that left-behind cumulative risk is negatively associated with academic adjustment in middle school students (ß = -.199, t(1183) = -7.229, p < .001). Besides, growth mindset has a protective effect on left-behind middle school students' academic adjustment (ß = .386, t(1183) = 14.070, p < .001) and a moderating effect on the relationship between left-behind cumulative risk and academic adjustment (ß = .394, t(1182) = 4.057, p < .001, ΔR2 = .012). These findings suggest that family risk factors related to left-behind status affect the academic adjustment of left-behind middle school students in a superposition way, while the positive individual factor of growth mindset could protect the negative impact caused by parental migration.

Deep reinforcement learning navigation via decision transformer in autonomous driving.

In real-world scenarios, making navigation decisions for autonomous driving involves a sequential set of steps. These judgments are made based on partial observations of the environment, while the underlying model of the environment remains unknown. A prevalent method for resolving such issues is reinforcement learning, in which the agent acquires knowledge through a succession of rewards in addition to fragmentary and noisy observations. This study introduces an algorithm named deep reinforcement learning navigation via decision transformer (DRLNDT) to address the challenge of enhancing the decision-making capabilities of autonomous vehicles operating in partially observable urban environments. The DRLNDT framework is built around the Soft Actor-Critic (SAC) algorithm. DRLNDT utilizes Transformer neural networks to effectively model the temporal dependencies in observations and actions. This approach aids in mitigating judgment errors that may arise due to sensor noise or occlusion within a given state. The process of extracting latent vectors from high-quality images involves the utilization of a variational autoencoder (VAE). This technique effectively reduces the dimensionality of the state space, resulting in enhanced training efficiency. The multimodal state space consists of vector states, including velocity and position, which the vehicle's intrinsic sensors can readily obtain. Additionally, latent vectors derived from high-quality images are incorporated to facilitate the Agent's assessment of the present trajectory. Experiments demonstrate that DRLNDT may achieve a superior optimal policy without prior knowledge of the environment, detailed maps, or routing assistance, surpassing the baseline technique and other policy methods that lack historical data.

Degradation of reactive red (B-3BF) dye wastewater using UV irradiation (254/185 nm) with sodium persulfate in a pilot UV device.

Two low-pressure ultraviolet (UV) lamps at 185/254 nm with sodium persulfate in a pilot UV device were utilized for the degradation of reactive red (B-3BF) dye wastewater compared with two UV lamps at 185/185 nm and two UV lamps at 254/254 nm. The degradation performances of UV irradiation (254/185 nm) with sodium persulfate under different degradation times, flow rates, initial pH, initial Na2S2O8 concentrations and initial dye concentrations were investigated. The experimental results illustrated that the degradation percentage of B-3BF dye could reduce to 90.42% with the energy consumption of 85.1 kWh/kg and the residual dye concentration of 1.92 mg/L by UV irradiation (254/185 nm) with initial Na2S2O8 concentration of 1.5 mmol/L and initial dye concentration of 20 mg/L. In addition, degradation performance of B-3BF dye wastewater by UV irradiation (254/185 nm) with sodium persulfate was more effective than those of UV irradiation (254/254 nm) and UV irradiation (185/185 nm). Therefore UV irradiation (254/185 nm) with sodium persulfate was promising for the degradation of B-3BF dye wastewater.

Effects of clarithromycin exposure on the growth of Microcystis aeruginosa and the production of algal dissolved organic matter.

Antibiotics are commonly found in the aquatic environment, which can affect microbial community compositions and activities, and even have potential adverse impacts on human and ecosystem health. The current understanding of the effects of antibiotics on microalgae growth and algal dissolved organic matter (DOM) remains indistinct. To understand the toxic effects of antibiotics on the microalgae, Microcystis aeruginosa was exposed to clarithromycin (CLA) in this study. Cell density determination, chlorophyll content determination, and organic spectrum analysis were conducted to show the effect of CLA exposure on the growth, photosynthetic activity, and organic metabolic processes of Microcystis aeruginosa. The findings revealed that the physiological status of algae could be significantly influenced by CLA exposure in aquatic environments. Specifically, exposure to 1 µg/L CLA stimulated the growth and photosynthetic activity of algal cells. Conversely, CLA above 10 µg/L led to the inhibition of algal cell growth and photosynthesis. Notably, the inhibitory effects intensified with the increasing concentration of CLA. The molecular weight of DOM produced by Microcystis aeruginosa increased when exposed to CLA. Under the exposure of 60 µg/L CLA, a large number of algal cells ruptured and died, and the intracellular organic matter was released into the algal liquid. This resulted in an increase in high molecular weight substances and soluble microbial-like products in the DOM. Exposure to 1 and 10 µg/L CLA stimulated Microcystis aeruginosa to produce more humic acid-like substances, which may be a defense mechanism against CLA. The results were useful for assessing the effects of antibiotic pollution on the stability of the microalgae population and endogenous DOM characteristics in aquatic ecosystems.

Metagenomic insights into effects of carbon/nitrogen ratio on microbial community and antibiotic resistance in moving bed biofilm reactor.

This study investigated the effects of carbon/nitrogen (C/N) ratio on microbial community in moving bed biofilm reactor (MBBR) using metagenomic analysis, and the dynamic changes of relevant antibiotic resistance genes (ARGs) were also analyzed. The results showed that under low C/N ratio, MBBR exhibited average removal rates of 98.41 % for ammonia nitrogen and 75.79 % for total nitrogen. Metagenomic analysis showed low C/N ratio altered the structure of biofilm and water microbiota, resulting in the detachment of bacteria such as Actinobacteria from biofilm into water. Furthermore, sulfamethazine (SMZ)-resistant bacteria and related ARGs were released into water under low C/N ratio, which lead to the increase of SMZ resistance rate to 90%. Moreover, most dominant genera are potential hosts for both nitrogen cycle related genes and ARGs. Specifically, Nitrosomonas that carried gene sul2 might be released from biofilm into water. These findings implied the risks of antibiotic resistance dissemination in MBBR under low C/N ratio.

Transient responses of double core-holes generation in all-attosecond pump-probe spectroscopy.

Double core-holes (DCHs) show remarkable and sensitive effects for understanding electron correlations and coherence. With advanced modulation of x-ray free-electron laser (XFEL) facility, we propose the forthcoming all-attosecond XFEL pump-probe spectroscopy can decipher the hidden photon-initiated dynamics of DCHs. The benchmark case of neon is investigated, and norm-nonconserving Monte-Carlo wavefunction method simulates non-Hermitian dynamics among vast states, which shows superiority in efficiency and reliability. In our scheme, population transfer to DCHs is sequentially irradiated by pump and probe laser. By varying time delay, Stark shifts and quantum path interference of resonant lines sensitively emerge at specific interval of two pulses. These ubiquitous multi-channel effects are also observed in phase-fluctuating pulses, derived from extra phases of impulsive Raman processes by pump laser. Non-perturbation absorption/emission verifies the uniquely interchangeable role of two pules in higher intensity. Our results reveal sensitive and robust responses on pulse parameters, which show potential capacity for XFEL attosecond pulse diagnosis and further attosecond-timescale chemical analysis.

An allosteric mechanism for potent inhibition of SARS-CoV-2 main proteinase.

The main proteinase (Mpro) of SARS-CoV-2 plays a critical role in cleaving viral polyproteins into functional proteins required for viral replication and assembly, making it a prime drug target for COVID-19. It is well known that noncompetitive inhibition offers potential therapeutic options for treating COVID-19, which can effectively reduce the likelihood of cross-reactivity with other proteins and increase the selectivity of the drug. Therefore, the discovery of allosteric sites of Mpro has both scientific and practical significance. In this study, we explored the binding characteristics and inhibiting process of Mpro activity by two recently reported allosteric inhibitors, pelitinib and AT7519 which were obtained by the X-ray screening experiments, to probe the allosteric mechanism via molecular dynamic (MD) simulations. We found that pelitinib and AT7519 can stably bind to Mpro far from the active site. The binding affinity is estimated to be -24.37 ± 4.14 and - 26.96 ± 4.05 kcal/mol for pelitinib and AT7519, respectively, which is considerably stable compared with orthosteric drugs. Furthermore, the strong binding caused clear changes in the catalytic site of Mpro, thus decreasing the substrate accessibility. The community network analysis also validated that pelitinib and AT7519 strengthened intra- and inter-domain communication of Mpro dimer, resulting in a rigid Mpro, which could negatively impact substrate binding. In summary, our findings provide the detailed working mechanism for the two experimentally observed allosteric sites of Mpro. These allosteric sites greatly enhance the 'druggability' of Mpro and represent attractive targets for the development of new Mpro inhibitors.

Graphene Quantum Dots Nanoantibiotic-Sensitized TiO2- x Heterojunctions for Sonodynamic-Nanocatalytic Therapy of Multidrug-Resistant Bacterial Infections.

The exploration of sonodynamic therapy (SDT) as a possible replacement for antibiotics by creating reactive oxygen species (ROS) is suggested as a non-drug-resistant theranostic method. However, the low-efficiency ROS generation and complex tumor microenvironment which can deplete ROS and promote tumor growth will cause the compromised antibacterial efficacy of SDT. Herein, through an oxygen vacancy engineering strategy, TiO2- x microspheres with an abundance of Ti3+ are synthesized using a straightforward reductant co-assembly approach. The narrow bandgaps and Ti3+/Ti4+-mediated multiple-enzyme catalytic activities of the obtained TiO2- x microspheres make them suitable for use as sonosensitizers and nanozymes. When graphene quantum dot (GQD) nanoantibiotics are deposited on TiO2- x microspheres, the resulting GQD/TiO2- x shows an increased production of ROS, which can be ascribed to the accelerated separation of electron-hole pairs, as well as the peroxidase-like catalytic activity mediated by Ti3+, and the depletion of glutathione mediated by Ti4+. Moreover, the catalytic activities of TiO2- x microspheres are amplified by the heterojunctions-accelerated carrier transfer. In addition, GQDs can inhibit Topo I, displaying strong antibacterial activity and further enhancing the antibacterial activity. Collectively, the combination of GQD/TiO2- x-mediated SDT/NCT with nanoantibiotics can result in a synergistic effect, allowing for multimodal antibacterial treatment that effectively promotes wound healing.

Exportin XPO6 upregulation activates the TLR2/MyD88/NF-κB signaling by facilitating TLR2 mRNA nuclear export in COPD pulmonary monocytes.

Chronic obstructive pulmonary disease (COPD) poses a significant health threat characterized by lung inflammation primarily triggered by pulmonary monocytes. Despite the centrality of inflammation in COPD, the regulatory mechanisms governing this response remain elusive, presenting a challenge for anti-inflammatory interventions. In this study, we assessed the expression of exportins in COPD mouse models, revealing a notable upregulation of XPO6 in the mouse lung (P = 0.0011). Intriguingly, we observed a consistent upregulation of XPO6 in pulmonary monocytes from both human and mouse COPD subjects (P < 0.0001). Furthermore, in human lung tissue, XPO6 expression exhibited a positive correlation with TLR2 expression (P = 0). In vitro investigations demonstrated that XPO6 enhances TLR2 expression, activating the MyD88/NF-κB inflammatory signaling pathway. This activation, in turn, promotes the secretion of pro-inflammatory cytokines such as TNFα, IL-6, and IL-1ß in monocytes. Mechanistically, XPO6 facilitates the nuclear export of TLR2 mRNA, ensuring its stability and subsequent protein expression in monocytes. In conclusion, our findings unveil that the upregulation of XPO6 in COPD pulmonary monocytes activates the MyD88/NF-κB inflammatory signaling pathway by facilitating the nuclear export of TLR2 mRNA, thereby identifying XPO6 as a promising therapeutic target for anti-inflammatory interventions in COPD.

Amphiphilic amidines as potential plasmic membrane-targeting antifungal agents: synthesis, bio-activities and QSAR.

BACKGROUND: Cationic antimicrobial peptides (AMPs) possess broad-spectrum biological activities with less inclination to inducing antibiotic resistance. Herein a battery of amphiphilic amidines were designed by mimicking the characteristics of AMPs. The antifungal activities and the effects to the hyphal morphology and membrane permeability were investigated. RESULTS: The results indicated the inhibitory rates of ten compounds were over 80% to Botrytis cinerea and ten compounds over 90% to Valsa mali Miyabe et Yamada at 50 mg L-1. The half maximal effective concentration (EC50) values of compound 5g and 6g to V. mali were 1.21 and 1.90 mg L-1 respectively. The protective rate against apple canker of compound 5g reached 93.4% at 100 mg L-1 on twigs, superior to carbendazim (53.3%). When treated with 5g, the cell membrane permeability and leakage of content of V. mali increased, accompanied with the decrease of superoxide dismutase (SOD) and catalase (CAT) level. Concurrently, the mycelial hyphae contracted, wrinkled, and collapsed, providing evidence of membrane perturbation. A three-dimensional quantitative structure-activity relationship (3D-QSAR) between the topic compounds and the EC50 to V. mali was established showing good predictability (r2 = 0.971). CONCLUSION: Amphiphilic amidines can acquire antifungal activities by acting on the plasmic membrane. Compound 5g could be a promising lead in discovering novel fungicidal candidates. © 2024 Society of Chemical Industry.

Targeting Liver Xor by GalNAc-siRNA Is an Effective Strategy for Hyperuricemia Therapy.

Hyperuricemia, i.e., increased plasma uric acid concentration, is a common problem in clinical practice, leading to gout or nephrolithiasis, and is associated with other disorders, such as metabolic syndrome, cardiovascular disease, and chronic renal disease. Xanthine oxidoreductase (XOR) is a critical rate-limiting enzyme involved in uric acid synthesis and a promising target for hyperuricemia therapy. However, XOR inhibitors currently face clinical problems such as a short half-life and side effects. Here, we found that specifically targeting liver Xor with GalNAc-siRNAs had a good therapeutic effect on hyperuricemia. First, siRNAs were designed to target various sites in the homologous region between Homo sapiens and Mus musculus Xor mRNA and were screened in primary mouse hepatocytes. Then, the siRNAs were modified to increase their stability in vivo and conjugated with GalNAc for liver-specific delivery. The effects of GalNAc-siRNAs were evaluated in three hyperuricemia mouse models, including potassium oxonate and hypoxanthine administration in WT and humanized XDH mice and Uox knockout mice. Febuxostat, a specific XOR inhibitor used for hyperuricemia treatment, was used as a positive control. Targeting liver Xor with GalNAc-siRNAs by subcutaneous administration reduced plasma uric acid levels, uric acid accumulation in the kidney, renal inflammation, and fibrosis, thereby alleviating kidney damage in hyperuricemia mouse models without hepatoxicity. The results demonstrated that targeting liver Xor with GalNAc-siRNAs was a promising strategy for hyperuricemia therapy.