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Flowering time is an important agronomic trait affecting crop yield. FCS-LIKE ZINC FINGER (FLZ) proteins are plant-specific regulatory proteins that are involved in multiple biological processes. However, their roles in plant flowering time control have not been clarified. Here, we report that OsFLZ2 is a negative regulator of rice flowering time. OsFLZ2 delays flowering by repressing the expression of key floral integrator genes. Biochemical assays showed OsFLZ2 physically interacts with OsMADS51, a flowering activator under short-day (SD) conditions. Both OsFLZ2 and OsMADS51 are highly expressed in rice leaves before floral transition under natural SD conditions, and their proteins are colocalized in the nucleus. Co-expression of OsFLZ2 can destabilize OsMADS51 and weaken its transcriptional activation of the downstream target gene Early heading date 1 (Ehd1). Taken together, these results indicate that OsFLZ2 can interfere with the function of OsMADS51 to fine-tune rice flowering time.
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Oryza , Oryza/genética , Oryza/metabolismo , Flores/metabolismo , Regulação da Expressão Gênica de Plantas , Fotoperíodo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMO
In middle to late 2023, a sublineage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron XBB, EG.5.1 (a progeny of XBB.1.9.2), is spreading rapidly around the world. We performed multiscale investigations, including phylogenetic analysis, epidemic dynamics modeling, infection experiments using pseudoviruses, clinical isolates, and recombinant viruses in cell cultures and experimental animals, and the use of human sera and antiviral compounds, to reveal the virological features of the newly emerging EG.5.1 variant. Our phylogenetic analysis and epidemic dynamics modeling suggested that two hallmark substitutions of EG.5.1, S:F456L and ORF9b:I5T are critical to its increased viral fitness. Experimental investigations on the growth kinetics, sensitivity to clinically available antivirals, fusogenicity, and pathogenicity of EG.5.1 suggested that the virological features of EG.5.1 are comparable to those of XBB.1.5. However, cryo-electron microscopy revealed structural differences between the spike proteins of EG.5.1 and XBB.1.5. We further assessed the impact of ORF9b:I5T on viral features, but it was almost negligible in our experimental setup. Our multiscale investigations provide knowledge for understanding the evolutionary traits of newly emerging pathogenic viruses, including EG.5.1, in the human population.
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ZFP57 is a master regulator of genomic imprinting. It has both maternal and zygotic functions that are partially redundant in maintaining DNA methylation at some imprinting control regions (ICRs). In this study, we found that DNA methylation was lost at most known ICRs in Zfp57 mutant embryos. Furthermore, loss of ZFP57 caused loss of parent-of-origin-dependent monoallelic expression of the target imprinted genes. The allelic expression switch occurred in the ZFP57 target imprinted genes upon loss of differential DNA methylation at the ICRs in Zfp57 mutant embryos. Specifically, upon loss of ZFP57, the alleles of the imprinted genes located on the same chromosome with the originally methylated ICR switched their expression to mimic their counterparts on the other chromosome with unmethylated ICR. Consistent with our previous study, ZFP57 could regulate the NOTCH signaling pathway in mouse embryos by impacting allelic expression of a few regulators in the NOTCH pathway. In addition, the imprinted Dlk1 gene that has been implicated in the NOTCH pathway was significantly down-regulated in Zfp57 mutant embryos. Our allelic expression switch models apply to the examined target imprinted genes controlled by either maternally or paternally methylated ICRs. Our results support the view that ZFP57 controls imprinted expression of its target imprinted genes primarily through maintaining differential DNA methylation at the ICRs.
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Alelos , Impressão Genômica , Proteínas Repressoras/genética , Animais , Metilação de DNA/genética , Embrião de Mamíferos/metabolismo , Feminino , Camundongos , RNA-Seq , Receptores Notch/metabolismo , Proteínas Repressoras/metabolismo , Transdução de Sinais/genéticaRESUMO
BACKGROUND: Base editors (BEs) display diverse applications in a variety of plant species such as Arabidopsis, rice, wheat, maize, soybean, and cotton, where they have been used to mediate precise base pair conversions without the collateral generation of undesirable double-stranded breaks (DSB). Studies of single-nucleotide polymorphisms (SNPs) underpinning plant traits are still challenging, particularly in polyploidy species where such SNPs are present in multiple copies, and simultaneous modification of all alleles would be required for functional analysis. Allotetraploid cotton has a number of homoeologous gene pairs located in the A and D sub-genomes with considerable SNPs, and it is desirable to develop adenine base editors (ABEs) for efficient and precise A-to-G single-base editing without DSB in such complex genome. RESULTS: We established various ABE vectors based on different engineered adenosine deaminase (TadA) proteins fused to Cas9 variants (dCas9, nCas9), enabling efficient A to G editing up to 64% efficiency on-target sites of the allotetraploid cotton genome. Comprehensive analysis showed that GhABE7.10n exhibited the highest editing efficiency, with the main editing sites specifically located at the position A5 (counting the PAM as positions 21-23). Furthermore, DNA and RNA off-target analysis of cotton plants edited with GhABE7.10n and GhABE7.10d by whole genome and whole-transcriptome sequencing revealed no DNA off-target mutations, while very low-level RNA off-target mutations were detected. A new base editor, namely GhABE7.10dCpf1 (7.10TadA + dCpf1), that recognizes a T-rich PAM, was developed for the first time. Targeted A-to-G substitutions generated a single amino acid change in the cotton phosphatidyl ethanolamine-binding protein (GhPEBP), leading to a compact cotton plant architecture, an ideotype for mechanized harvesting of modern cotton production. CONCLUSIONS: Our data illustrate the robustness of adenine base editing in plant species with complex genomes, which provides efficient and precise toolkit for cotton functional genomics and precise molecular breeding.
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Gossypium , Oryza , Adenina/metabolismo , Sistemas CRISPR-Cas , Edição de Genes , Gossypium/genética , Gossypium/metabolismo , Oryza/genética , RNARESUMO
Rice black-streaked dwarf virus disease (RBSDVD) and southern rice black-streaked dwarf virus disease (SRBSDVD) are the most destructive viral diseases in rice. Progress is limited in breeding due to lack of resistance resource and inadequate knowledge on the underlying functional gene. Using genome-wide association study (GWAS), linkage disequilibrium (LD) decay analyses, RNA-sequencing, and genome editing, we identified a highly RBSDVD-resistant variety and its first functional gene. A highly RBSDVD-resistant variety W44 was identified through extensive evaluation of a diverse international rice panel. Seventeen quantitative trait loci (QTLs) were identified among which qRBSDV6-1 had the largest phenotypic effect. It was finely mapped to a 0.8-1.2 Mb region on chromosome 6, with 62 annotated genes. Analysis of the candidate genes underlying qRBSDV6-1 showed high expression of aspartic proteinase 47 (OsAP47) in a susceptible variety, W122, and a low resistance variety, W44. OsAP47 overexpressing lines exhibited significantly reduced resistance, while the knockout mutants exhibited significantly reduced SRBSDVD and RBSDVD severity. Furthermore, the resistant allele Hap1 of OsAP47 is almost exclusive to Indica, but rare in Japonica. Results suggest that OsAP47 knockout by editing is effective for improving RBSDVD and SRBSDVD resistance. This study provides genetic information for breeding resistant cultivars.
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Ácido Aspártico Proteases , Oryza , Viroses , Estudo de Associação Genômica Ampla , Oryza/genética , Peptídeo Hidrolases , Melhoramento Vegetal , Doenças das Plantas/genética , ReoviridaeRESUMO
After the merger of the former Taxodiaceae and Cupressaceae s.s., currently the conifer family Cupressaceae (sensu lato) comprises seven subfamilies and 32 genera, most of which are important components of temperate and mountainous forests. With the exception of a recently published genus-level phylogeny of gymnosperms inferred from sequence analysis of 790 orthologs, previous phylogenetic studies of Cupressaceae were based mainly on morphological characters or a few molecular markers, and did not completely resolve the intergeneric relationships. In this study, we reconstructed a robust and well-resolved phylogeny of Cupressaceae represented by all 32 genera, using 1944 genes (Orthogroups) generated from transcriptome sequencing. Reticulate evolution analyses detected a possible ancient hybridization that occurred between ancestors of two subclades of Cupressoideae, including Microbiota-Platycladus-Tetraclinis (MPT) and Juniperus-Cupressus-Hesperocyparis-Callitropsis-Xanthocyparis (JCHCX), although both concatenation and coalescent trees are highly supported. Moreover, divergence time estimation and ancestral area reconstruction indicate that Cupressaceae very likely originated in Asia in the Triassic, and geographic isolation caused by continental separation drove the vicariant evolution of the two subfamilies Cupressoideae and Callitroideae in the northern and southern hemispheres, respectively. Evolutionary analyses of some morphological characters suggest that helically arranged linear-acicular leaves and imbricate bract-scale complexes represent ancestral states, and the shift from linear-acicular leaves to scale-like leaves was associated with the shift from helical to decussate arrangement. Our study sheds new light on phylogeny and evolutionary history of Cupressaceae, and strongly suggests that both dichotomous phylogenetic and reticulate evolution analyses be conducted in phylogenomic studies.
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Cupressaceae , Juniperus , Cupressaceae/anatomia & histologia , Cupressaceae/genética , Cycadopsida , Hibridização Genética , FilogeniaRESUMO
Phylogenies of an increasing number of taxa have been resolved with the development of phylogenomics. However, the intergeneric relationships of Podocarpaceae, the second largest family of conifers comprising 19 genera and approximately 187 species mainly distributed in the Southern Hemisphere, have not been well disentangled in previous studies, even when genome-scale data sets were used. Here we used 993 nuclear orthologous groups (OGs) and 54 chloroplast OGs (genes), which were generated from 47 transcriptomes of Podocarpaceae and its sister group Araucariaceae, to reconstruct the phylogeny of Podocarpaceae. Our study completely resolved the intergeneric relationships of Podocarpaceae represented by all extant genera and revealed that topological conflicts among phylogenetic trees could be attributed to synonymous substitutions. Moreover, we found that two morphological traits, fleshy seed cones and flattened leaves, might be important for Podocarpaceae to adapt to angiosperm-dominated forests and thus could have promoted its species diversification. In addition, our results indicate that Podocarpaceae originated in Gondwana in the late Triassic and both vicariance and dispersal have contributed to its current biogeographic patterns. Our study provides the first robust transcriptome-based phylogeny of Podocarpaceae, an evolutionary framework important for future studies of this family.
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Magnoliopsida , Traqueófitas , Cycadopsida , Magnoliopsida/genética , Filogenia , Traqueófitas/genética , TranscriptomaRESUMO
Although it is known that rice 14-3-3 family genes are involved in various defense responses, the functions of OsGF14f in response to diseases have not been reported. Here, we showed that the transcription of OsGF14f was significantly induced by leaf blast infection, and the overexpression of OsGF14f quantitatively enhanced resistance to leaf blast and bacterial blight in rice. Further analysis showed that the expression levels of salicylic acid (SA) pathway-associated genes (PAL1, NH1, PR1a and PR10) in the OsGF14f-overexpressing plants, were higher than those in wild-type plants after inoculation with the blast isolate (Magnaporthe oryzae Barr). In addition, the expression level of OsGF14f was significantly induced after SA treatment, and higher endogenous SA levels were observed in the OsGF14f-overexpressing plants compared with that in wild-type plants, especially after blast challenge. Taken together, these results suggest that OsGF14f positively regulates leaf blast and bacterial blight resistance in rice via the SA-dependent signaling pathway.
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Magnaporthe , Oryza , Resistência à Doença/genética , Regulação da Expressão Gênica de Plantas , Magnaporthe/fisiologia , Oryza/metabolismo , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Folhas de Planta/metabolismo , Proteínas de Plantas/metabolismo , Ácido Salicílico/metabolismoRESUMO
A novel lateral flow strip assay has been developed for rapid on-site detection of tobramycin. In this assay, unique dual-functional platinum-decorated gold nanoparticles (Au@Pt NPs) are synthesized by covering conventional gold nanoparticles (AuNPs) with an ultra-thin Pt film. Au@Pt NPs retain the plasmon activity of AuNPs and exhibit ultra-high catalytic activity that the Pt skin can achieve. The aptamer (Apt) specific for tobramycin and its complementary DNA (cDNA) are loaded on Au@Pt NPs as a duplex probe through the thiol group modified at the 5' end of the cDNA. When tobramycin is present, it binds specifically to the aptamer, resulting in its dehybridization from the cDNA and detachment from the surface of Au@Pt NPs. Then Au@Pt NPs can be captured by the fixed probe (DNA1) on the test zone (T zone) of the lateral flow strip through the hybridization between DNA1 and cDNA. The dual-functional Au@Pt NPs provide two different detection modes: one is based on the color of AuNPs (low sensitivity mode) and the other is based on the chromogenic reaction catalyzed by the Pt nanozyme (high sensitivity mode). The strip can complete the visual detection process of tobramycin within 10 min, and the cutoff values for the naked eye detection in the two modes are 60 nM and 5 nM, respectively. Furthermore, using a portable scanning reader and ImageJ software, quantitative detection can be achieved. The limits of detection (LOD) of the two modes are 0.09 nM and 0.02 nM, respectively. The strip has been successfully applied to detect tobramycin in different food samples. Therefore, Au@Pt NPs and the strip provide a highly sensitive, rapid and economical way for in-spot detection of tobramycin residues. The strip can be run in two modes, which can realize the on-demand adjustment of the detection performance and offer wider application prospects in diverse scenarios.
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Ouro , Nanopartículas Metálicas , Limite de Detecção , Platina , TobramicinaRESUMO
There is a long-standing debate on whether visual consciousness is confined to cognitive access measured by reportability, or whether it is rich and overflows reportability. Much of the debate in previous studies concentrated on whether information outside attentional focus could be consciously experienced and reportable. This study sought to address the debate from a new perspective, through testing whether fully attended supraliminal information is necessarily reportable with a variation of attribute amnesia. Participants were asked to judge the parity of a single number or whether a Chinese character referred to furniture. After several trials, they were unexpectedly asked to report the stimulus identity. The results consistently showed that participants could not correctly report the identity, indicating that fully attended information that was consciously perceived could sometimes overflow report. In addition to providing novel overflow evidence, these findings also have crucial implications in understanding the relationship between consciousness and working memory.
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Atenção , Estado de Consciência , Amnésia , Humanos , Memória de Curto PrazoRESUMO
Our conscious perception of the world is not an instantaneous, moment-by-moment construction. Rather, our perception of an event is influenced, over time, by information gained after the event; this is known as a postdictive effect. A recent study reported that this postdictive effect could occur even in choice. The present study sought to test whether the striking postdictive effect of choice reflects the modulation of attention on choice, by directly and systematically manipulating attention in two experiments. Specifically, Experiment 1 revealed that the robust postdictive effect of choice was almost completely eliminated when attentional bias was removed. More important, Experiment 2 demonstrated that the postdictive effect of choice could be modulated by directly manipulating participants' attention with a spatial cue, in particular, when the cue appeared at short time delays. These results suggest that choice could be considerably postdictively influenced by attention and this effect was most pronounced within a short time window wherein decision making was most likely in progress. The current study not only enables clarification of the mechanism of the newly discovered postdictive effect of choice, but also extends evidence of the modulation of attention on decision making.
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Atenção/fisiologia , Comportamento de Escolha/fisiologia , Ilusões/fisiologia , Adulto , Estado de Consciência , Sinais (Psicologia) , Feminino , Humanos , Masculino , Percepção do Tempo , Adulto JovemRESUMO
Although the regulatory function of miRNAs and their targets have been characterized in model plants, a possible underlying role in the cotton response to herbivore infestation has not been determined. To investigate this, we performed small RNA and degradome sequencing between resistant and susceptible cotton cultivar following infestation with the generalist herbivore whitefly. In total, the 260 miRNA families and 241 targets were identified. Quantitative-PCR analysis revealed that several miRNAs and their corresponding targets exhibited dynamic spatio-temporal expression patterns. Moreover, 17 miRNA precursors were generated from 29 long intergenic non-coding RNA (lincRNA) transcripts. The genome-wide analysis also led to the identification of 85 phased small interfering RNA (phasiRNA) loci. Among these, nine PHAS genes were triggered by miR167, miR390, miR482a, and two novel miRNAs, including those encoding a leucine-rich repeat (LRR) disease resistance protein, an auxin response factor (ARF) and MYB transcription factors. Through combined modeling and experimental data, we explored and expanded the miR390-tasiARF cascade during the cotton response to whitefly. Virus-induced gene silencing (VIGS) of ARF8 from miR390 target in whitefly-resistant cotton plants increased auxin and jasmonic acid (JA) accumulation, resulting in increased tolerance to whitefly infestation. These results highlight the provides a useful transcriptomic resource for plant-herbivore interaction.
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Resistência à Doença/genética , Gossypium/genética , Hemípteros , Herbivoria , MicroRNAs/metabolismo , RNA Interferente Pequeno/metabolismo , Animais , Ciclopentanos/metabolismo , Resistência à Doença/fisiologia , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Ontologia Genética , Inativação Gênica , Gossypium/metabolismo , Hemípteros/crescimento & desenvolvimento , Hemípteros/metabolismo , Ácidos Indolacéticos/metabolismo , Isoleucina/análogos & derivados , Isoleucina/metabolismo , Proteínas de Plantas/metabolismo , Estabilidade de RNA/genética , RNA Longo não Codificante/metabolismo , RNA de Plantas/genética , RNA de Plantas/metabolismo , RNA Interferente Pequeno/genética , Transdução de Sinais/genética , TranscriptomaRESUMO
Quantum mechanics provides the means of generating genuine randomness that is impossible with deterministic classical processes. Remarkably, the unpredictability of randomness can be certified in a manner that is independent of implementation devices. Here, we present an experimental study of device-independent quantum random number generation based on a detection-loophole-free Bell test with entangled photons. In the randomness analysis, without the independent identical distribution assumption, we consider the worst case scenario that the adversary launches the most powerful attacks against the quantum adversary. After considering statistical fluctuations and applying an 80 Gb×45.6 Mb Toeplitz matrix hashing, we achieve a final random bit rate of 114 bits/s, with a failure probability less than 10^{-5}. This marks a critical step towards realistic applications in cryptography and fundamental physics tests.
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BACKGROUND/AIMS: Abnormal apoptosis of granulosa cells (GCs) is thought to involve in the pathogenesis of polycystic ovary syndrome (PCOS); however, the associated cellular and molecular mechanisms remain unclear. METHODS: Primary GCs were obtained from healthy women and women with PCOS. The cell proliferation and apoptosis were analyzed in insulin-stimulated and insulin receptor gene (INSR) siRNA-transfected GCs. The protein expression of Akt-mTOR-S6K1 signal molecules was measured by Western blot. RESULTS: This study showed that 1 nM of insulin significantly stimulated cell proliferation, induced cell apoptosis, and decreased the telomerase activity in GCs from both the healthy women and PCOS patients (p < 0.001), but silencing of INSR expression blocked the effects of insulin. Insulin induced significantly more apoptosis in GCs from PCOS patients than from healthy women (p < 0.01). Insulin significantly increased the ratio of p-Akt/Akt, the expression of mTOR protein, and the ratio of p-S6K1/S6K1 in GCs from normal control than in cells from PCOS patients (p < 0.001). CONCLUSION: Insulin-induced apoptosis of GCs, less activation of Akt-mTOR signaling, and reduction of telomerase activity may be associated with the pathogenesis of PCOS.
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Apoptose/fisiologia , Proliferação de Células/fisiologia , Células da Granulosa/metabolismo , Síndrome do Ovário Policístico/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Adulto , Feminino , Humanos , Adulto JovemRESUMO
Quantum repeaters play a significant role in achieving long-distance quantum communication. In the past decades, tremendous effort has been devoted towards constructing a quantum repeater. As one of the crucial elements, entanglement has been created in different memory systems via entanglement swapping. The realization of j-hierarchy entanglement swapping, i.e., connecting quantum memory and further extending the communication distance, is important for implementing a practical quantum repeater. Here, we report the first demonstration of a fault-tolerant two-hierarchy entanglement swapping with linear optics using parametric down-conversion sources. In the experiment, the dominant or most probable noise terms in the one-hierarchy entanglement swapping, which is on the same order of magnitude as the desired state and prevents further entanglement connections, are automatically washed out by a proper design of the detection setting, and the communication distance can be extended. Given suitable quantum memory, our techniques can be directly applied to implementing an atomic ensemble based quantum repeater, and are of significant importance in the scalable quantum information processing.
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Secret sharing of a quantum state, or quantum secret sharing, in which a dealer wants to share a certain amount of quantum information with a few players, has wide applications in quantum information. The critical criterion in a threshold secret sharing scheme is confidentiality: with less than the designated number of players, no information can be recovered. Furthermore, in a quantum scenario, one additional critical criterion exists: the capability of sharing entangled and unknown quantum information. Here, by employing a six-photon entangled state, we demonstrate a quantum threshold scheme, where the shared quantum secrecy can be efficiently reconstructed with a state fidelity as high as 93%. By observing that any one or two parties cannot recover the secrecy, we show that our scheme meets the confidentiality criterion. Meanwhile, we also demonstrate that entangled quantum information can be shared and recovered via our setting, which shows that our implemented scheme is fully quantum. Moreover, our experimental setup can be treated as a decoding circuit of the five-qubit quantum error-correcting code with two erasure errors.
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We report the first experimental demonstration of quantum entanglement among ten spatially separated single photons. A near-optimal entangled photon-pair source was developed with simultaneously a source brightness of â¼12 MHz/W, a collection efficiency of â¼70%, and an indistinguishability of â¼91% between independent photons, which was used for a step-by-step engineering of multiphoton entanglement. Under a pump power of 0.57 W, the ten-photon count rate was increased by about 2 orders of magnitude compared to previous experiments, while maintaining a state fidelity sufficiently high for proving the genuine ten-particle entanglement. Our work created a state-of-the-art platform for multiphoton experiments, and enabled technologies for challenging optical quantum information tasks, such as the realization of Shor's error correction code and high-efficiency scattershot boson sampling.
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Entanglement, the essential resource in quantum information processing, should be witnessed in many tasks such as quantum computing and quantum communication. The conventional entanglement witness method, relying on an idealized implementation of measurements, could wrongly conclude a separable state to be entangled due to imperfect detections. Inspired by the idea of a time-shift attack, we construct an attack on the conventional entanglement witness process and demonstrate that a separable state can be falsely identified to be entangled. To close such detection loopholes, based on a recently proposed measurement-device-independent entanglement witness method, we design and experimentally demonstrate a measurement-device-independent entanglement witness for a variety of two-qubit states. By the new scheme, we show that an entanglement witness can be realized without detection loopholes.
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OBJECTIVES: This study aims to investigate the high-risk factors for osteonecrosis of the femoral head (ONFH) after internal fixation with multiple cannulated compression screws for adult femoral neck fractures and to construct a prediction model. PATIENTS AND METHODS: Between from January 2012 and December 2020, a total of 268 patients (138 males, 130 females; mean age: 53±10 years; range, 23 to 70 years) with ONFH who had complete follow-up data were included. Closed reduction in combination with open reduction were performed. All patients received internal fixation with multiple cannulated compression screws and were assigned to ONFH and non-ONFH groups. Logistic regression model was utilized to identify independent risk factors for postoperative ONFH, followed by constructing a nomogram prediction model. The predictive ability of the model was evaluated by receiver operating characteristic curve, Hosmer-Lemeshow test, and calibration curve. RESULTS: Multivariate analysis revealed that older age (odds ratio [OR]: 2.307, 95% confidence interval [CI]: 1.295-4.108], Charlson Comorbidity Index (CCI) ≥2 (OR: 2.214, 95% CI: 1.035-4.739), fracture displacement (OR: 2.426, 95% CI: 1.122-5.247), unsatisfactory reduction (OR: 2.629, 95% CI: 1.275-5.423), postoperative removal of internal fixation implant (OR: 2.200, 95% CI: 1.051-4.604) were independent risk factors for postoperative ONFH (p<0.05). The nomogram prediction model constructed based on these clinical characteristics showed high predictive value (AUC=0.807) and consistency (p>0.05). CONCLUSION: Age, comorbidity index, fracture type, reduction quality and postoperative removal of internal fixation implant are of utmost importance for postoperative ONFH in patients with femoral neck fractures. The established nomogram prediction model can accurately predict the occurrence of postoperative ONFH.
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Fraturas do Colo Femoral , Osteonecrose , Masculino , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Cabeça do Fêmur , Osteonecrose/etiologia , Osteonecrose/cirurgia , Fatores de Risco , Fraturas do Colo Femoral/cirurgia , Fixação Interna de Fraturas/efeitos adversosRESUMO
BACKGROUND: Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease that affects multiple organs and cause a wide range of severe clinical manifestations, including lupus nephritis (LN), which is a major risk factor for morbidity and mortality in individual with SLE. Ursolic acid (UA) is a natural compound with favorable anti-inflammatory properties and has been employed to treat multiple disease, including inflammatory diseases, diabetes, and Parkinson's disease. However, its therapeutic potential on LN and the underlying mechanisms remains unclear. PURPOSE: This aim of this study was to investigate the impact of UA on LN and its underlying mechanism. METHODS: MRL/lpr lupus-prone mouse model was used and UA was administered orally for 8 weeks. Dexamethasone was used as a positive control. After 8 weeks of administration, the spleen-to-body-weight ratio, renal function, urine albumin excretion, cytokines levels, and the deposition of immune complex were measured. The primary mouse glomerular mesangial cells (GMCs) and SV40-MES-13 were stimulated by lipopolysaccharide (LPS), either alone or in combination with nigericin, to establish an in vitro model. The activation of NLRP3 inflammasome were investigated both in vivo and in vitro using qRT-PCR, immunoblotting, and immunofluorescence. RESULTS: Our results revealed that UA prominently alleviated LN in MRL/lpr lupus-prone mice, leading to a significant reduction in proteinuria production, infiltration of immune cells infiltration, and histopathological damage in the renal tissue. In addition, UA exerted inhibitory effects on the secretion of IL-1ß, IL-18, and caspase-1, pyroptosis, and ASC speck formation in primary mouse GMCs and SV40-MES-13 cells. Furthermore, UA facilitated the degradation of NLRP3 by suppressing SUMO1-mediated SUMOylation of NLRP3. CONCLUSION: UA possess a therapeutical effect on LN in MRL/lpr mice by enhancing the degradation of NLRP3 through inhibition of SUMO1-mediated SUMOylation of NLRP3. Our findings provide a basis for proposing UA as a potential candidate for the treatment of LN.