Journal of advanced research最新文献

Introduction: Adipose tissue (AT) immune cells regulate metabolic functions in obesity through both inflammatory and non-inflammatory pathways. However, the specific roles and mechanisms of individual AT immune cell types in glycemic control remain poorly understood.

Objective: This study investigates the function of myeloid-derived Zbtb46⁺ cells, a major subset of peripheral dendritic cells (DCs), in established obesity.

Methods: Chimeric Zbtb46-DTR mice were generated by transplanting bone marrow from Zbtb46-DTR donors into wild-type recipients with distinct congenic markers. Obesity was induced with a high-fat diet (HFD; 60% kcal from fat), and myeloid-derived Zbtb46⁺ cells were selectively depleted in obese mice via diphtheria toxin (DT) injection. DC-specific Dpp4 knockout (DC-Dpp4KO) mice were generated using the Cre-loxP system and subsequently challenged with the HFD.

Results: Inducible depletion of myeloid-derived Zbtb46⁺ cells improves glucose homeostasis and reduces body weight in obese mice. Notably, these effects were observed even in weight-matched mice and under conditions of increased ATM accumulation, suggesting benefits independent of weight loss or AT inflammation. The improvement in glucose homeostasis was primarily mediated by elevated GLP-1 levels, which enhanced insulin secretion and decreased food intake. Increased GLP-1 was associated with decreased DPP4 activity, attributed to the depletion of ATDCs, a key contributor to circulating DPP4. Consistently, DC-specific Dpp4 deficiency confirmed that ATDC-derived DPP4 regulates GLP-1-induced insulin secretion in obesity.

Conclusions: These findings uncover a novel, non-inflammatory role for ATDCs in glucose regulation via the DPP4/GLP-1/GLP-1R axis, positioning them as promising therapeutic targets for obesity and related metabolic diseases.

Introduction: Optimal ovarian stimulation (OS) selection is critical for IVF success, but expert-based decisions often lack consistency in outcomes, cost-efficiency, and personalization, highlighting the need for more individualized and data-driven approaches.

Objectives: This study propose an artificial intelligence (AI) system that analyzes extensive IVF-ET cycles to uncover OS-pregnancy outcome relationships, enabling personalized treatment recommendations while improving success rates and minimizing unnecessary costs.

Methods: This study analyzed anonymized data from 17,791 patients undergoing OS and IVF/ICSI at Tongji Hospital between May 2015 and May 2019. An adaptive AI model was developed to predict key indicators-including progesterone (P), number of oocytes retrieved (NOR), estradiol (E2), and endometrial thickness (EMT) on the hCG day-by integrating personal characteristics, ovarian reserve, and etiological factors. This model facilitated personalized OS selection, pregnancy outcome grading, and the development of an AI-driven clinical decision support system (CDSS).

Results: The key indicators-progesterone (P), number of oocytes retrieved (NOR), estradiol (E2), and endometrial thickness (EMT) on the hCG day-were used to establish a pregnancy grading system. Pregnancy rates are stratified as follows: Level IV (Total Score 15-16), 0.55; Level III (Total Score 13-14), 0.44; Level II (Total Score 11-12), 0.24; and Level I (Total Score 4-10), 0.07. After OS optimization, 1,355 patients who were initially at level I were elevated to a better level. Of the 2,341 patients initially in level II, 2,290 improved, and of the 3,839 initially in level III, 1,448 improved. Patients elevated to level IV accounted for 80 percent of all cases. The CDSS prioritized a GnRH antagonist regimen for 54.64 % of patients, resulting in per-patient time savings of 15.39-33.48 days and cost reductions of ¥989-¥2,623 compared to non-optimal to antagonist. Scaled to China's > 1 million ART cycles annually, this corresponds to projected direct savings of approximately ¥0.54-1.43 billion per year. In the new evaluation datasets (n = 4,251), implementation of CDSS recommendations increased the clinical pregnancy rate from 0.452 to 0.512 (p < 0.001) and reduced mean per-cycle cost from ¥7,385 to ¥7,242 (p = 0.018), demonstarting cost-effectiveness dominance with ICER saving of ¥2,383 per additional clinical pregnancy.

Conclusion: This AI-assisted CDSS streamlines clinicians' decision-making by enabling efficient and accurate initial judgments on OS, standardizing and personalizing recommendations, and optimizing OS for effectiveness and cost-efficiency.

Introduction: As an emerging natural nanomedicine, traditional Chinese medicine-derived exosome-like nanovesicles have shown unique potential in the treatment of chronic non-healing wounds due to their advantages such as good biocompatibility, high safety and large-scale production. However, at present, there are relatively few studies on different states and extraction processes of traditional Chinese medicine, which restricts its clinical transformation process.

Objective: This study aims to systematically compare the properties and biological activities of Portulaca oleracea L. (Purslane) derived exosome-like nanovesicles (Po-DENs) extracted from fresh and dried Purslane by using ultracentrifugation and polyethylene glycol extraction methods. The key functional metabolites and proteins were identified through multi-omics analysis, and their therapeutic potential in diabetic wound healing was verified both in vivo and in vitro.

Method: Fresh and dried Portulaca oleracea L. samples were treated by ultracentrifugation and polyethylene glycol precipitation methods, and four kinds of plant nanovesicles were separated. Their physical properties such as particle size were characterized. The composition of the vesicles was determined through metabolomics and proteomics. The proliferation, antioxidant, anti-apoptotic and anti-inflammatory effects of four types of vesicles on skin keratinocytes and fibroblasts were investigated, and the mechanism was analyzed through proteomics. And it was finally verified in the wound healing model of diabetic mice to confirm its therapeutic activity and biological safety.

Result: The results demonstrated that fresh Purslane-derived nanovesicles isolated by ultracentrifugation (F-Po-UC) exhibited superior bioactivity compared to other extraction methods and dried material preparations. Omics analyses further revealed that F-Po-UC is enriched with a wide range of metabolites and proteins, which act through signaling pathways related to tissue regeneration. Subsequent vivo studies demonstrated that dressings based on Purslane-derived vesicles significantly accelerated wound healing in a diabetic mouse model, confirming their potential as an innovative therapeutic strategy.

Conclusion: Fresh Purslane-derived nanovesicles demonstrate exceptional therapeutic potential for diabetic wound healing through their potent proliferative, antioxidant, and anti-inflammatory effects, supported by multi-omics characterization and robust in vivo validation.

Introduction: Plant-microbe collaborative remediation is a highly promising heavy metal remediation strategy. However, its remediation efficiency for manganese (Mn) tailings and its underlying mechanism remain inadequately explored.

Objectives: This study aimed to screen microbial strains capable of remediating Mn contamination and evaluate the potential of these strains to enhance the remediation of heavy metal-contaminated soils through plant-microbe interactions.

Methods: Bacterial strains with both Mn resistance and plant growth-promoting characteristics were isolated from the rhizosphere of plants in Mn tailings. Two selected strains were inoculated to the rhizosphere of 2-year-old Koelreuteria paniculata seedlings in non-polluted soil or in Mn tailings. The effectiveness of the strains in remediating Mn tailings was evaluated by measuring the growth, photosynthetic characteristics, antioxidant enzyme activity, Mn accumulation capacity of K. paniculata, and overall soil remediation effect.

Results: This study selected two Mn resistance and plant growth-promoting bacteria, including Bacillus cereus (EA-1) and Priestia megaterium (BN-4). Functioanl groups identified by Fourier transform infrared spectroscopy (FTIR), such as hydroxyl and phosphate groups, are essential for Mn adsorption on the bacterial surface. In Mn tailings, inoculation with the BN-4 strain significantly increased superoxide dismutase (SOD) and catalase (CAT) activities in the leaves of K. paniculata by 201.57% and 34.48%, respectively, compared to the uninoculated treatment. However, inoculation with the EA-1 strain enhanced the root, stem, and leaf biomass, net photosynthetic rate, stomatal conductance, Mn accumulation, and bioconcentration factor (BCF) of K. paniculata by 72.70%, 47.82%, 51.32%, 81.38 %, 86.05%, 113.09% and 76.19%, respectively, compared to the uninoculated treatment.

Conclusion: Considering the growth of K. paniculata and its capacity for Mn accumulation and BCF, inoculation with the EA-1 strain is a more favorable approach for remediation of Mn tailings.

Introduction: Efforts are being made to design a brain-like intelligence due to its robustness, synaptic modification (i.e., learning and memory), analog synaptic multiplication, multi-state storage, ultra-low power consumption, and parallel computation. However, current bioelectronic and biomedical technologies have yet to fully replicate brain-like intelligence. In particular, devices that can emulate both homosynaptic and heterosynaptic plasticity remain extremely limited.

Objectives: This work presents a neuromemristive synapse capable of replicating key biological features, including homosynaptic and heterosynaptic plasticity. The proposed synapse uses a memristor, a promising candidate for achieving bio-realistic features of synapse due to its low power consumption, multi-state operation, analog behavior, high data storage durability, and CMOS compatibility.

Methods: The artificial synapse is designed as a composite 1-port structure consisting of a memristor (M) and a controlled capacitor (CCon). The memristor is responsible for emulating synaptic plasticity in response to distinct brainwave patterns, while the capacitor modulates the discharge rate through the memristor. During the active input phase (synaptic potentiation), the composite 1-port charges up. During the inactive phase (synaptic depression), CCon governs the discharging of the memristor, enabling full or partial discharging through memory fading or homosynaptic and heterosynaptic depression pathways.

Results: We designed the proposed synapse in SPICE and validated its bio-functionalities through various simulations. The proposed synapse demonstrates low power consumption and replicates key neurobiological processes for learning and memory such as heterosynaptic homeostasis, modular input specificity, associativity, and homosynaptic long-term and short-term potentiation and depression (LTP, LTD, STF, STD), along with memory fading effect (MFE), and strong stimulation (SST).

Conclusion: The proposed synapse bio-realistically mimics synaptic plasticity, neurotransmitter dynamics, and neuronal responses. Implemented using off-the-shelf components, it supports both volatile and non-volatile modes, making it suitable for CMOS integration. This enables advancements in spiking neural networks, brain function analysis, and scalable neuromorphic computing systems.

Background: Urinary system tumors, including bladder, kidney, and prostate cancers, impose a substantial health burden worldwide and exhibit significant molecular and genetic heterogeneity.

Aim: of Review: This review delves into the intricate landscape of targeted therapy for urinary system tumors and its pivotal role in advancing precision medicine. Key Scientific Concepts of Review: Urinary system tumors include kidney cancer, bladder cancer, and prostate cancer. They exhibit remarkable heterogeneity at the molecular level, which challenges the effectiveness of conventional treatments. Compared with conventional therapy, precision medicine is a tailored approach that customizes treatments for individual patients on the basis of their unique genetic, molecular, and clinical profiles. In general, precision medicine discovers targets through multiomics data, and targeted therapy develops drugs on the basis of these targets. Targeted therapy focuses on the discernment of specific molecular or genetic aberrations that are distinct to cancer cells, thereby demarcating them from their healthy counterparts. Several molecular targets driving these malignancies are summarized among the current state of approved targeted therapies. Limitations include the emergence of resistance mechanisms and the potential for adverse effects. In the pursuit of precision medicine, this review scrutinizes innovative approaches, including biomarker utilization, genomics, and personalized treatments, which demonstrate potential in customizing therapies to individual patients. In conclusion, this review illuminates the pivotal role of targeted therapy in the context of heterogeneous urinary system tumors and underscores its potential to drive the precision medicine paradigm forward.

Introduction: Some fruits are vulnerable to chilling lignification during cold storage. However, the active polymerization cell regions of guaiacyl (G) and sinapyl (S) lignin units in fruit flesh during lignification and their dynamic change patterns are unclear. We have visualized G-unit lignin in fruit flesh cells, but there is no method for imaging the active polymerization regions of S monolignol.

Objective: This work aims to understand the cell dynamics mechanism of newly synthesized G- and S-unit lignin in fruit flesh during postharvest lignification from both accumulation and inhibition perspectives.

Methods: A bioorthogonal chemical labeling method to label S-unit lignin in fruit flesh cells was established. Then, using loquat fruit as the research object, and the newly synthesized G- and S-unit lignin in loquat fruit flesh during postharvest lignification was visualized. Moreover, for the inhibition study, we prepared methyl jasmonate (MeJA) hydrogel beads that could continuously inhibit the lignification during postharvest storage.

Results: The polymerization of G monolignol tended to be active in the middle lamella of the parenchyma cells during early storage, whereas the polymerization of S monolignol tended to be active in the cell corner during late storage. Besides, the change patterns of vascular bundles and lignified cells were different from the parenchyma cells. Furthermore, a hydrogel bead capable of continuously releasing MeJA was prepared and used to inhibit the lignification. Results demonstrated that the inhibitory effects on G- and S-unit lignin were concentrated on the parenchyma cells, and there were also spatiotemporally specific, whereas the effects on vascular bundles and lignified cells were limited.

Conclusion: The newly synthesized S-unit lignin in fruit flesh was visualized for the first time. Distinct spatiotemporal polymerization patterns of G- and S-unit lignin were found during postharvest lignification and its inhibition, and the corresponding cellular model was proposed.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) exhibits aggressive perineural invasion (PNI), a hallmark of poor prognosis observed in 70-100% of cases. Schwann cells (SCs), key components of the tumor microenvironment, drive PNI via multiple pathways, yet the underlying mechanisms remain unclear.

Objectives: This study investigates the hypothesis that PDAC cells and SCs establish a glutamine-glutamate metabolic symbiosis to fuel PNI.

Methods: Integrated approaches, including LC-MS metabolomics, isotopic tracing, co-culture systems, and in vivo models, were employed to analyze bidirectional metabolite exchange. Molecular assays and functional studies elucidated signaling pathways. The therapeutic potential of targeting glutamine transporters (SLC1A5/SLC7A5) and glutamate receptor NR2A was tested using inhibitors V9302 and PEAQX.

Results: SCs secreted glutamine, which PDAC cells internalized via SLC1A5 and converted to glutamate. Glutamate activated SCs through NR2A, inducing ROS/NRF2-expression and upregulating glutamine synthetase (GS) and GLT-1, thereby regenerating glutamine to sustain the metabolic loop. KRAS-ACTN4-p65 signaling amplified this cycle by transcriptionally activating SLC1A5/SLC7A5 and GLS, while leucine uptake via SLC7A5 activated mTORC1 to promote invasion and PNI. In vivo, dual inhibition of SLC1A5/SLC7A5 (V9302) and NR2A (PEAQX) synergistically reduced tumor growth, PNI length, and improved sciatic nerve function in mice.

Conclusion: This study identifies a reciprocal glutamine-glutamate metabolic symbiosis between PDAC cells and SCs as a driver of PNI, orchestrated by KRAS-ACTN4-NF-κB signaling and glutamate-NR2A-ROS-NRF2 pathways. Disrupting this axis with V9302 and PEAQX offers a novel therapeutic strategy to target PDAC's metabolic adaptability and neurotrophic microenvironment.

Background: Bioengineered bacteria have emerged as versatile, programmable platforms for in vivo drug delivery. By integrating gene editing, synthetic gene circuits, targeted surface modifications, and environment‑responsive triggers, these living vectors can home to specific tissues and dynamically release therapeutic molecules in response to local cues. Recent advances have demonstrated their potential across oncology, immunomodulation, infectious disease control, and inflammatory disorders, yet challenges in stability, biosafety, and regulatory approval remain.

Aim of review: This review synthesizes the latest developments in programmable microbial therapeutics, focusing on engineering strategies and delivery system designs that enhance precision, efficacy, and safety. We evaluate proof‑of‑concept applications in disease models and identify critical bottlenecks hindering clinical translation, with the goal of guiding future research toward robust, personalized microbial interventions.

Key scientific concepts of review: This review centers on four main areas. First, programmable gene circuits and biosensors enable conditional drug release only when desired. Second, targeting strategies-such as adhesion molecules and microenvironmental cues-guide bacteria to disease sites. Third, delivery system designs (e.g., encapsulation and surface coating) improve bacterial survival and payload stability. Fourth, expression-optimization methods fine-tune therapeutic output levels. We also discuss biosafety measures like kill-switches and auxotrophy, and outline future directions including intelligent feedback loops, multifunctional circuits, and streamlined regulatory pathways.

Introduction: The physiological functions of p70 S6 kinase 1 (S6K1) have been extensively studied in S6K1-deficient mice. However, there is limited evidence demonstrating the influence of S6K1 deletion on human brain development.

Objectives: In this study, we identify the role of S6K1 in human brain development utilizing genetically engineered human embryonic stem cell-derived brain organoids.

Methods: Dorsal forebrain organoids generated from S6K1-depleted human embryonic stem cells (hESCs) were analyzed through single-cell RNA sequencing at early (5 weeks) and late (14 weeks) stages. In addition, the brain organoids derived from co-cultured S6K1-deleted and wild-type hESCs were subjected to ATAC-sequencing.

Results: Genetic deletion of S6K1 significantly decreases the size of the dorsal forebrain organoids in the early stages. Single-cell RNA sequencing analysis shows an abnormal emergence of retinal cell lineages in S6K1-deleted brain organoids, which diverges from cortical neurons in the early stage, eventually leading to a decrease in the proportion of mature cortical neurons. The chromatin accessibility analysis of co-cultured brain organoids shows that retinal specification in S6K1 knockout organoids was due to non-cell-autonomous function, whereas incomplete maturation of neurons results from cell-autonomous function.

Conclusion: Depletion of S6K1 signaling in the early stage of human brain development drives the formation of retinal cells distinct from cortical neurons. Our findings demonstrate that S6K1 signaling fine-tunes neuronal and retinal lineage specification during brain development.