RESUMO

Excessive inflammation caused by bacterial infection is the primary cause of implant failure. Antibiotic treatment often fails to prevent peri-implant infection and may induce unexpected drug resistance. Herein, a non-antibiotic strategy based on the synergy of silver ion release and macrophage reprogramming is proposed for preventing infection and bacteria-induced inflammation suppression by the organic-inorganic hybridization of silver nanoparticle (AgNP) and quercetin (Que) into a polydopamine (PDA)-based coating on the 3D framework of porous titanium (SQPdFT). Once the planktonic bacteria (e.g., Escherichia coli, Staphylococcus aureus) reach the surface of SQPdFT, released Que disrupts the bacterial membrane. Then, AgNP can penetrate the invading bacterium and kill them, which further inhibits the biofilm formation. Simultaneously, released Que can regulate macrophage polarization homeostasis via the peroxisome proliferators-activated receptors gamma (PPARγ)-mediated nuclear factor kappa-B (NF-κB) pathway, thereby terminating excessive inflammatory responses. These advantages facilitate the adhesion and osteogenic differentiation of bone marrow-derived mesenchymal stem cells (BMSCs), concomitantly suppressing osteoclast maturation, and eventually conferring superior mechanical stability to SQPdFT within the medullary cavity. In summary, owing to its excellent antibacterial effect, immune remodeling function, and pro-osteointegration ability, SQPdFT is a promising protective coating for titanium-based implants used in orthopedic replacement surgery.

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Glycolytic metabolic reprogramming in cancer is regulated by both cancer intrinsic variations like isocitrate dehydrogenase 1 (IDH1) status and non-cancerous microenvironment components like tumor associated macrophages (TAMs). However, the detailed mechanism remains elusive. Here, we identify hexosaminidase B (HEXB) as a key regulator for glycolysis in glioblastoma (GBM). HEXB intercellularly manipulates TAMs to promote glycolysis in GBM cells, while intrinsically enhancing cancer cell glycolysis. Mechanistically, HEXB elevation augments tumor HIF1α protein stability through activating ITGB1/ILK/YAP1; Subsequently, HIF1α promotes HEXB and multiple glycolytic gene transcription in GBM cells. Genetic ablation and pharmacological inhibition of HEXB elicits substantial therapeutic effects in preclinical GBM models, while targeting HEXB doesn't induce significant reduction in IDH1 mutant glioma and inhibiting IDH1 mutation-derived 2-hydroxyglutaric acid (2-HG) significantly restores HEXB expression in glioma cells. Our work highlights a HEXB driven TAMs-associated glycolysis-promoting network in GBM and provides clues for developing more effective therapies against it.

Assuntos

Neoplasias Encefálicas , Carcinogênese , Glioblastoma , Glicólise , Subunidade alfa do Fator 1 Induzível por Hipóxia , Isocitrato Desidrogenase , beta-N-Acetil-Hexosaminidases , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Isocitrato Desidrogenase/genética , Isocitrato Desidrogenase/metabolismo , Linhagem Celular Tumoral , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/genética , Carcinogênese/genética , Camundongos , beta-N-Acetil-Hexosaminidases/metabolismo , beta-N-Acetil-Hexosaminidases/genética , Microambiente Tumoral/imunologia , Regulação Neoplásica da Expressão Gênica , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/imunologia , Integrina beta1/metabolismo , Integrina beta1/genética , Glutaratos/metabolismo , Mutação , Proteínas de Sinalização YAP/metabolismo

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The benefits of exercise on neuropathic pain (NP) have been demonstrated in numerous studies. In recent studies, inflammation, neurotrophins, neurotransmitters, and endogenous opioids are considered as the main mechanisms. However, the role of exercise in alleviating NP remains unclear. Neuroglia, widely distributed in both the central and peripheral nervous systems, perform functions such as support, repair, immune response, and maintenance of normal neuronal activity. A large number of studies have shown that neuroglia play an important role in the occurrence and development of NP, and exercise can alleviate NP by regulating neuroglia. This article reviewed the involvement of neuroglia in the development of NP and their role in the exercise treatment of NP, intending to provide a theoretical basis for the exercise treatment strategy of NP.

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Sonodynamic therapy (SDT) is gaining popularity in cancer treatment due to its superior controllability and high tissue permeability. Nonetheless, the efficacy of SDT is severely diminished by the transient generation of limited reactive oxygen species (ROS). Herein, we introduce an acid-activated nanosonosensitizer, CaO2@PCN, by the controllable coating of porphyrinic metal-organic frameworks (PCN-224) on CaO2 to induce cascaded oxidative stress in tumors. The PCN-224 doping can generate ROS during SDT to induce intracellular oxidative stress and abnormal calcium channels. Meanwhile, the ultrasound also promotes extracellular calcium influx. In addition, CaO2@PCN sequentially degrades in the tumor cell lysosomes, releasing Ca2+ and H2O2 to induce further abnormal calcium channels and elevate the levels of Ca2+. Insufficient catalase (CAT) in tumor cells promotes intracellular calcium overload, which can induce persistent ROS generation and mitochondrial dysfunction through ion interference therapy (IIT). More importantly, PCN-224 also protects CaO2 against significant degradation under neutral conditions. Hence, the well-designed CaO2@PCN produces synergistic SDT/IIT effects and persistent ROS against cancer. More notably, the acidity-responsive biodegradability endows CaO2@PCN with excellent biosafety and promising clinical potential.

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Family history (FH) of cancer and polygenic risk scores (PRS) are pivotal for cancer risk assessment, yet their combined impact remains unclear. Participants in the UK Biobank (UKB) were recruited between 2006 and 2010, with complete follow-up data updated until February 2020 for Scotland and January 2021 for England and Wales. Using UKB data (N = 442,399), we constructed PRS and incidence-weighted overall cancer PRS (CPRS). FH was assessed through self-reported standardized questions. Among 202,801 men (34.6% with FH) and 239,598 women (42.0% with FH), Cox regression was used to examine the associations between FH, PRS, and cancer risk. We found a significant dose-response relationship between FH of cancer and corresponding cancer risk (Ptrend < .05), with over 10 significant pairs of cross-cancer effects of FH. FH and PRS are positively correlated and independent. Joint effects of FH of cancer (multiple cancers) and PRS (CPRS) on corresponding cancer risk were observed: for instance, compared with participants with no FH of cancer and low PRS, men with FH of cancer and high PRS had the highest risk of colorectal cancer (hazard ratio [HR]: 3.69, 95% confidence interval [CI]: 3.01-4.52). Additive interactions were observed in prostate and overall cancer risk for men and breast cancer for women, with the most significant result being a relative excess risk of interaction (RERI) of 2.98, accounting for ~34% of the prostate cancer risk. In conclusion, FH and PRS collectively contribute to cancer risk, supporting their combined application in personalized risk assessment and early intervention strategies.

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OBJECTIVE: This study aims to investigate the optimal exercise intensity, type, and weekly duration for improving glycated haemoglobin (HbA1c) and fasting blood glucose (FBG) levels in older people individuals with diabetes. MATERIALS AND METHODS: PubMed, EMBASE, Web of Science and other databases were searched to identify randomised controlled trials (RCTs) starting from January 2000 to February 2024 that reported improved effects on fasting glucose and glycated haemoglobin after different exercises in middle-aged and elderly diabetic patients. Meta-analyses Review Manager V.5.3 was used. RESULTS: Meta-analysis showed that moderate- and high-intensity exercise had a significant effect on HbA1c levels, with a mean difference (MD) of -0.34 (95 % CI: -0.44 ∼ -0.24, p < 0.01) for moderate-intensity exercise and -0.54 (95 % CI: -0.78 ∼ -0.3, p < 0.001) for high-intensity exercise.. Both moderate-intensity and high-intensity exercise demonstrated statistical significance in lowering fasting blood glucose levels (p < 0.001). Additionally, there was no significant difference between aerobic and resistance exercise forms (p= 0.72). Furthermore, for reducing HbA1c levels, engageing in weekly exercise for at least 2.5 hours showed a MD of-0.44(95 % CI:-0.63∼0.25;p<0.001). CONCLUSIONS: In summary, in terms of exercise intensity, medium and high-intensity exercise can significantly reduce HbA1c and FBG levels in middle-aged and older people diabetic patients; in terms of exercise form, the effects of different exercise forms within medium and high-intensity on HbA1c and FBG are not statistically significant; and in terms of exercise time, in moderate-intensity aerobic exercise, older people exercising for more than 2.5 h per week are more beneficial.

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One issue that always strands the scaling-up development of perovskite photovoltaics is the significant efficiency drop when enlarging the device area, which is caused by the inhomogeneous distribution of defected sites1-3. In the narrow band gap formamidinium lead iodide (FAPbI3), the native impurities of PbI2 and δ-FAPbI3 non-perovskite could induce unfavored non-radiative recombination, as well as inferior charge transport and extraction 4,5.Here, we develop an impurity-healing interface engineering strategy to well address the issue both in small-area solar cell and large-scale submodule. With the introduction of a functional cation, 2-(1-cyclohexenyl)ethyl ammonium, two-dimensional (2D) perovskite with high mobility is rationally constructed on FAPbI3 to horizontally cover the film surface and vertically penetrate to the grain boundaries of 3D perovskites. Such unique configuration not only comprehensively transforms the PbI2 and δ-FAPbI3 impurities into stable 2D perovskite and realize a uniform defect passivation, but also provides interconnecting channels for efficient carrier transport. As a result, the FAPbI3-based small-area (0.085 cm2) solar cells achieve a champion efficiency over 25.86% with a notably high fill factor (FF) of 86.16%. More encouragingly, the fabricated submodules with the aperture area of 715.1 cm2 obtain a certified record efficiency of 22.46% with a good FF of 81.21%, showcasing the feasibility and effectualness of the impurity-healing interface engineering for scaling-up promotion with well-preserved photovoltaic performance.

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Objects: Ketamine is a drug of abuse worldwide and current treatments for ketamine abuse are inadequate. It is an urgent need to develop novel anti-addictive strategy. Since gut microbiota plays a crucial role in drug abuse, the present study investigates the impact and mechanisms of the gut microbiota in addictive behaviors induced by ketamine addiction. Methods: Conditioned place preference (CPP) was employed to assess addiction, followed by 16S rRNA gene sequencing to elucidate alterations in the gut microbiota. Furthermore, qRT-PCR, ELISA, and immunohistochemistry were conducted to evaluate the expression levels of crucial genes and proteins associated with the gut-brain axis. Additionally, we investigated whether ketamine addiction is regulated through the gut microbiota by orally administering antibiotics to establish pseudo-germ-free mice. Results: We found that repeated ketamine administration (20 mg/kg) induced CPP and significantly altered gut microbiota diversity and composition, as revealed by 16S rRNA gene sequencing. Compared to the control group, ketamine exposure exhibited differences in the relative abundance of 5 microbial families, with 4 (Lachnospiraceae, Ruminococcaceae, Desulfovibrionaceae and Family-XIII) showing increases, while one (Prevotellaceae) displayed a decrease. At the genus level, five genera were upregulated, while one was downregulated. Furthermore, COG analysis revealed significant differences in protein functionality between the two groups. Additionally, axis series studies showed that ketamine dependence reduced levels of tight junction proteins, GABA and GABRA1, while increasing BDNF and 5-HT. Moreover, an oral antibiotic cocktail simulating pseudo germ-free conditions in mice did not enhance the addictive behavior induced by ketamine. Conclusion: Our study supports the hypothesis that ketamine-induced CPP is mediated through the gut microbiota. The present study provides new insights into improvement of efficient strategy for addiction treatment.

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Radical polymerization is a powerful technique for producing a variety of polymeric materials. However, the chain transfer reaction impedes the formation of polymers from many common α-olefins such as propene and 1-butene using this method. Consequently, poly(α-olefins) are predominantly produced via coordination polymerization. To address this limitation, we have devised a strategy involving group transfer radical polymerization (GTRP) to facilitate the radical homopolymerization to access carbon-chain poly(α-olefins). This approach enables the precise construction of a diverse array of carbon-chain poly(α-olefins) with high molecular weights. Furthermore, by using nonconventional monomers, we extend the applicability of this technique to the copolymerization of α-olefins with acrylonitrile, paving the way for the synthesis of copolymers with different monomers. To investigate the properties of the polymers obtained by this method, one of the poly(α-olefins) is studied as an interphase layer material in anode-free Li metal batteries, and the results indicate the potential of the polymer in energy storage applications.

RESUMO

Pathogen-host competition for manganese and intricate immunostimulatory pathways severely attenuates the efficacy of antibacterial immunotherapy against biofilm infections associated with orthopaedic implants. Herein, we introduce a spatiotemporal sono-metalloimmunotherapy (SMIT) strategy aimed at efficient biofilm ablation by custom design of ingenious biomimetic metal-organic framework (PCN-224)-coated MnO2-hydrangea nanoparticles (MnPM) as a metalloantibiotic. Upon reaching the acidic H2O2-enriched biofilm microenvironment, MnPM can convert abundant H2O2 into oxygen, which is conducive to significantly enhancing the efficacy of ultrasound (US)-triggered sonodynamic therapy (SDT), thereby exposing bacteria-associated antigens (BAAs). Moreover, MnPM disrupts bacterial homeostasis, further killing more bacteria. Then, the Mn ions released from the degraded MnO2 can recharge immune cells to enhance the cGAS-STING signaling pathway sensing of BAAs, further boosting the immune response and suppressing biofilm growth via biofilm-specific T cell responses. Following US withdrawal, the sustained oxygenation promotes the survival and migration of fibroblasts, stimulates the expression of angiogenic growth factors and angiogenesis, and neutralizes excessive inflammation. Our findings highlight that MnPM may act as an immune costimulatory metalloantibiotic to regulate the cGAS-STING signaling pathway, presenting a promising alternative to antibiotics for orthopaedic biofilm infection treatment and pro-tissue repair.

Assuntos

Biofilmes , Compostos de Manganês , Óxidos , Oxigênio , Biofilmes/efeitos dos fármacos , Animais , Camundongos , Compostos de Manganês/química , Compostos de Manganês/farmacologia , Oxigênio/metabolismo , Óxidos/farmacologia , Óxidos/química , Antibacterianos/farmacologia , Peróxido de Hidrogênio/metabolismo , Imunoterapia/métodos , Humanos , Terapia por Ultrassom/métodos , Nanopartículas/química , Transdução de Sinais/efeitos dos fármacos , Antígenos de Bactérias/imunologia , Staphylococcus aureus/efeitos dos fármacos , Feminino

RESUMO

OBJECTIVE: Subjective cognitive complaints have been reported in women during perimenopause and the Everyday Memory Questionnaire - Revised (EMQ-R) has been recently evaluated as a standardized instrument to measure subjective cognitive changes. The purpose of this study was to identify potential cut-off points for the EMQ-R retrieval subscale and attentional subscale, and to assess the validity of these cut-off points in detecting objective cognitive changes associated with reported subjective cognitive complaints. METHOD: After screening, 232 perimenopausal women were included in the analyses. The supervised classification and regression tree was applied to identify optimal cut-off points. Its performance was evaluated by the value of the receiver operating characteristics curve, sensitivity and specificity. RESULTS: Findings revealed that the optimal cut-off point for the attentional subscale was 7, and for the retrieval subscale was 13. Both cut-off points presented acceptable discrimination performance. An independent t-test indicated that both cut-off points were associated with significant differences in scores on neuropsychological measures of retrieval (episodic memory and verbal fluency) as well as neuropsychological measures of higher-level attention (working memory). CONCLUSION: The identified cut-off points may be helpful for women to track or quantify their subjective experiences of brain fog or cognitive symptoms during the menopause transition.

RESUMO

OBJECTIVES: Cognitive symptoms are frequently reported by women during the menopause transition years. The aim of this research was to codesign and evaluate a fact sheet resource to help women understand and manage cognitive symptoms that may occur during menopause. METHODS: This study adopted a codesign approach involving women during the menopause transition years as well as professionals to develop and evaluate a fact sheet, with a focus on acceptability and safety. Four phases (discover, define, develop, deliver) were conducted to develop, refine, and evaluate the fact sheet using a mixed-methods approach of focus groups, interviews, and surveys. RESULTS: The discover phase identified a need for online educational resources for women in premenopause, perimenopause, and postmenopause to learn about menopause-related topics. The define and develop phases, relying on focus group sessions with perimenopausal and postmenopausal women, revealed common themes related to the experience of cognitive symptoms and a desire for management tips to optimize cognitive functioning. Structured interviews with professionals highlighted a desire for more concrete examples of cognitive symptoms. The results of the deliver phase found strong acceptability for the fact sheet, alongside requests for additional information on menopausal hormone therapy from premenopausal, perimenopausal, and postmenopausal women. CONCLUSIONS: The study reported a wide range of cognitive symptoms among women during the menopause transition years. This study showed broad agreement on the fact sheet's acceptability and safety in addressing menopausal cognitive symptoms. Feedback on menopausal hormone therapy and management tips underscores the demand for more research on effective interventions.

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The goal of our research is to elucidate and better assess placental function in rats with preeclampsia through an innovative application of ultrasound-based radiomics. Using a rat model induced with L-NAME, we carefully investigated placental dysfunction via microstructural analysis and immunoprotein level assessment. Employing the Boruta feature selection method on ultrasound images facilitated the identification of crucial features, consequently enabling the development of a robust model for classifying placental dysfunction. Our study included 12 pregnant rats, and thorough placental evaluations were conducted on 160 fetal rats. Distinct alterations in placental microstructure and angiogenic factor expression were evident in rats with preeclampsia. Leveraging high-throughput mining of quantitative image features, we extracted 558 radiomic features, which were subsequently used to construct an impressive evaluation model with an area under the receiver operating curve (AUC) of 0.95. This model also exhibited a remarkable sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 88.7%, 91.5%, 90.2%, 90.4%, and 90.0%, respectively. Our findings highlight the ability of ultrasound-based radiomics to detect abnormal placental features, demonstrating its potential for evaluating both normative and impaired placental function with high precision and reliability.

Assuntos

Modelos Animais de Doenças , Placenta , Pré-Eclâmpsia , Gravidez , Feminino , Pré-Eclâmpsia/diagnóstico por imagem , Pré-Eclâmpsia/fisiopatologia , Animais , Placenta/diagnóstico por imagem , Ratos , Ultrassonografia/métodos , Ratos Sprague-Dawley , Curva ROC , Ultrassonografia Pré-Natal/métodos , Radiômica

RESUMO

Hepatotoxicity caused by the anticancer medication oxaliplatin (OXA) significantly restricts its clinical use and raises the risk of liver damage. Huaier, a fungus found in China, has been demonstrated to have various beneficial effects in adjuvant therapy for cancer. However, the preventive impact of Huaier against OXA-induced hepatotoxicity is still unknown. The potential molecular pathways behind the hepatoprotective activity of Huaier against OXA-induced hepatotoxicity were investigated in the current study Mice were intraperitoneally injected with 10 mg/kg of OXA once a week for six consecutive weeks to establish a liver injury model. Huaier (2 g/kg, 4 g/kg, and 8 g/kg) was administered weekly to mice by gavage for six weeks. Commercial kits were used to determine the contents of glutathione, catalase, superoxide dismutase, and malondialdehyde. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to assess the impact of Huaier therapy on the expression of the PI3K pathway. Huaier exhibited a good protective effect on OXA-induced hepatotoxicity in a dose-dependent manner, which was connected to the suppression of oxidative stress, according to the results of biochemical index detection and histological staining analysis. In addition, Huaier could counteract the OXA-induced suppression of the PI3K/AKT signaling pathway. Moreover, the hepatoprotective effect and PI3K activation of Huaier were eradicated by LY294002. These findings imply that by decreasing oxidative stress, Huaier can minimize OXA-induced liver injury, establishing the groundwork for Huaier to lessen chemotherapy-induced hepatotoxicity in clinical practice.

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Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide, with the gut microbiota and its metabolites are important regulators of its progression. Trimethylamine N-oxide (TMAO), a metabolite of the gut microbiota, has been closely associated with various metabolic diseases, but its relationship with NAFLD remains to be elucidated. In this study, we found that fecal TMAO levels correlated with NAFLD severity. Moreover, TMAO promoted lipid deposition in HepG2 fatty liver cells and exacerbated hepatic steatosis in NAFLD rats. In the colon, TMAO undermined the structure and function of the intestinal barrier at various levels, further activated the TLR4/MyD88/NF-κB pathway, and inhibited the WNT/ß-catenin pathway. In the liver, TMAO induced endothelial dysfunction with capillarization of liver sinusoidal endothelial cells, while modulating macrophage polarization. In conclusion, our study suggests that gut microbiota metabolite TMAO promotes NAFLD progression by impairing the gut and liver and that targeting TMAO could be an alternative therapeutic strategy for NAFLD.

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A zinc-mediated cross-electrophile coupling of benzyl sulfonium salts with thiosulfonates via C-S bond cleavage was achieved. The reductive thiolation proceeded well under transition metal-free conditions to afford the desired benzyl sulfides in good yields, exhibiting both broad substrate scope and good functionality tolerance. In addition, the reaction could be applied to the use of selenosulfonate as an effective selenylation agent and be subjected to scale-up synthesis.

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Midlife has been suggested to be a crucial time to introduce interventions for improving cognitive functions. The effects of cognitive training (CT) in healthy middle-aged populations and more specifically during the menopausal transition have not been systematically investigated. To investigate the effects of CT on cognition in healthy middle-aged adults and specifically in females during the menopause transition, literature was searched inception to July 2023 and studies were included that examined the effects of CT on a defined cognitive outcome. The improvement on cognitive performance following CT was the main outcome measured as mean difference (from baseline to immediate post) estimates with corresponding 95% confidence intervals (CI) in meta-analysis and was discussed with the support of subgroup analysis based on outcome type (i.e., far or near-transfer) and cluster tabulations. Nineteen articles were included in the qualitative synthesis with a total of 7765 individuals, and eight articles were included in the meta-analyses. CT was categorized into six type clusters: Game-based CT, General CT, Speed of Processing Training, Working Memory Training, Strategy-based CT, and Cognitive Remediation. Cognitive outcome was divided into six clusters: working memory, verbal memory, language, executive function, attention/processing speed, and visual memory. Meta-analysis reported significant improvement in the domain of executive function (0.48, 95% CI 0.08-0.87), verbal memory (0.22, 95% CI 0.11-0.33), and working memory (0.16, 95% CI 0.05-0.26). CT confers benefits on various cognitive domains, suggesting a potential role of CT to promote optimal cognitive functioning in the midlife and specifically in women during the menopause transition.

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Controllable transformation is a prerequisite to the in-depth understanding of structure evolution mechanisms and structure-property correlations at the atomic level. Most transformation cases direct the directional evolution of nanocluster sizes, i.e., size-maintained, size-increased, or size-reduced transformation, while size disproportionation was rarely reported. Here, we report the Au-doping-induced size disproportionation of nanocluster transformation. Slight Au-doping on the bimetallic (AgCu)43 nanocluster produced its trimetallic derivative, (AuAgCu)43, following a size-maintained transformation. By comparison, the (AgCu)43 nanocluster underwent a size-disproportionation transformation under heavy Au alloying, leading to the formation of size-reduced (AuAgCu)33 and size-increased (AuAgCu)56 nanoclusters simultaneously. Such a size disproportionation among the nanocluster transformations was verified by the thin-layer chromatography analysis. This work presented a novel nanocluster transformation case with a size disproportionation characteristic, expected to provide guidance for the understanding of cluster size evolutions.