Wu Y, Tao Z, Qin Z
… +4 more, Li Y, Zhao M, Zhao S, Wu J
Sci China Life Sci
· 2026 May · PMID 42189387
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Biotic stress is a major constraint on global crop productivity and a persistent challenge to sustainable agriculture. The ubiquitin-proteasome system (UPS) serves as a central post-translational regulatory hub coordinat...Biotic stress is a major constraint on global crop productivity and a persistent challenge to sustainable agriculture. The ubiquitin-proteasome system (UPS) serves as a central post-translational regulatory hub coordinating plant growth, stress adaptation, and immune responses. Within this system, E3 ubiquitin ligases confer substrate specificity by recognizing and ubiquitinating target proteins, thereby shaping immune signaling networks at multiple levels. Recent studies have revealed that plant E3 ligases regulate both pattern-triggered and effector-triggered immunity by controlling the stability of immune receptors, signaling intermediates, and transcriptional regulators, while also playing crucial roles in antiviral defense and resistance to herbivorous insects. In parallel, diverse pathogen effectors have evolved to target, hijack, or mimic host E3 ligases, illustrating an intense coevolutionary arms race centered on ubiquitin-mediated regulation. Building on these mechanistic insights, emerging research hotspots, including structural dissection of E3-substrate interactions, genome editing, promoter engineering, and allelic variation mining, are opening new avenues to fine-tune immunity while minimizing growth penalties. This review synthesizes current advances in E3 ligase-mediated plant defense, highlights pathogen strategies that exploit ubiquitination pathways, and discusses future perspectives for leveraging E3 ligases in resistance breeding and sustainable crop protection.
Type 2 diabetic osteoporosis (T2DOP) is a significant complication of type 2 diabetes, characterized by an increased risk of fractures. While dysregulated bone cell glucose metabolism is implicated, its specific mechanis...Type 2 diabetic osteoporosis (T2DOP) is a significant complication of type 2 diabetes, characterized by an increased risk of fractures. While dysregulated bone cell glucose metabolism is implicated, its specific mechanisms are unclear. This research combined bioinformatics with experimental validation to examine glycolysis-related genes in T2DOP. We merged osteoporosis and type 2 diabetes datasets, then applied differential expression analysis, WGCNA, and machine learning (113 algorithms) to identify core biomarkers. Functional enrichment, immune infiltration, and scRNA-seq analyses elucidated their roles. L1000FWD screened potential drugs, validated by molecular docking and in a T2D mouse model. We identified eight key biomarkers (ATN1, PDLIM7, PLD3, ACADSB, PDZK1, RAPGEF4, MYBPC3, BSG) with high diagnostic value (AUC > 0.75). They were enriched in glucose metabolism and osteoclast pathways. Immune analysis revealed altered infiltration, and scRNA-seq indicated their primary influence on osteoblasts, mesenchymal stem cells, and osteoclasts. Calcifediol (25(OH)D₃) was the top drug candidate, showing strong binding affinity. In vivo, 25(OH)D₃ treatment ameliorated bone loss, improved metabolic parameters, and modulated key biomarker expression. Our research identifies eight glycolysis-related genes as candidate diagnostic and therapeutic targets with biological and causal plausibility for T2DOP. Calcifediol demonstrates promise as a preclinical therapeutic candidate for T2DOP, with the potential to enable simultaneous management of diabetic hyperglycemia and osteoporosis, and its clinical value requires further verification in subsequent studies.
Acute lung injury (ALI) triggered by inhaled nanoparticles represents a growing clinical concern, yet the molecular mechanisms governing pulmonary vascular endothelial injury remain poorly defined. Here, we investigate t...Acute lung injury (ALI) triggered by inhaled nanoparticles represents a growing clinical concern, yet the molecular mechanisms governing pulmonary vascular endothelial injury remain poorly defined. Here, we investigate the role of the MiT/TFE transcription factor family, the master regulators of autophagy-lysosomal biogenesis, in orchestrating endothelial adaptive responses to copper oxide nanoparticles (CuONPs). In human umbilical vein endothelial cells (HUVECs), CuONPs exposure induced lysosomal membrane permeabilization and oxidative stress, which triggered robust nuclear translocation of MiT/TFE factors, particularly TFE3. This activation drove a transcriptional program of autophagy-lysosomal biogenesis, promoting the clearance of damaged lysosomes and mitigating CuONPs-induced cell death. Notably, genetic silencing of TFE3 abrogated this adaptive response, exacerbating oxidative damage and cytotoxicity, while overexpression of TFE3 conferred significant protection. In a mouse model of intratracheal CuONPs instillation, pulmonary exposure activated the TFE3 pathway in vivo. Genetic ablation of Tfe3 in mice resulted in exacerbated pulmonary vascular barrier disruption, heightened inflammation, and aggravated lung injury. Conversely, pharmacological activation of autophagy-lysosomal biogenesis with the mTOR inhibitor Torin1 alleviated CuONPs-induced endothelial damage and lung inflammation, recapitulating the protective effect of TFE3 signaling. Collectively, our findings identify TFE3 as a critical regulator of endothelial homeostasis against nanoparticle-induced injury, acting through the transcriptional control of autophagy-lysosomal homeostasis. Targeting this pathway may represent a novel therapeutic strategy for nanoparticle-associated ALI.
AIMS: Diabetic cardiomyopathy (DCM) is a serious complication driven by diabetes-associated oxidative stress and ferroptosis. This study compared the cardioprotective efficacy of metformin and empagliflozin in streptozot...AIMS: Diabetic cardiomyopathy (DCM) is a serious complication driven by diabetes-associated oxidative stress and ferroptosis. This study compared the cardioprotective efficacy of metformin and empagliflozin in streptozotocin (STZ)-induced diabetic rats, focusing on ferroptosis-related mechanisms. MATERIALS AND METHODS: Forty adult male Sprague-Dawley rats were divided into a control group (n = 10) and a diabetic group induced by STZ (55 mg/kg; n = 30). Following successful induction, the surviving diabetic rats were subdivided into untreated, metformin-treated (200 mg/kg/day), and empagliflozin-treated (10 mg/kg/day) subgroups (n = 8 each). After 12 weeks, biochemical, molecular, and histological analyses were conducted. KEY FINDINGS: Diabetic rats showed a 6.4-fold increase in fasting blood glucose (FBG) and a 3.9-fold rise in lactate dehydrogenase (LDH). These systemic changes were accompanied by marked myocardial oxidative stress imbalance and a 1.5-fold increase in cardiac iron. BTB and CNC homology 1 (BACH1) mRNA expression was upregulated 2.2-fold, coupled with suppression of heme oxygenase 1 (HO-1) and glutathione peroxidase 4 (GPX4) to 0.5 and 0.7-fold, respectively. Histological analysis revealed a 4-fold increase in the percentage area of collagen fibers, alongside a 6.2-fold and 4.5-fold increase in Yes-associated protein 1 (YAP1) and programmed death ligand 1 (PD-L1), respectively, and a 0.3-fold reduction in nuclear factor erythroid 2-related factor 2 (NRF2) expression, accompanied by ultrastructural damage characteristic of ferroptosis. Empagliflozin significantly improved antioxidant status, molecular and immunohistochemical marker expression, and myocardial integrity more effectively than metformin. SIGNIFICANCE: Empagliflozin demonstrated greater cardioprotective effects than metformin in STZ-induced DCM, though further clinical studies are needed to confirm the translational relevance.
AIMS: Toll-like receptor 8 (TLR8) is implicated in systemic sclerosis (SSc) pathogenesis, but its precise cellular mechanisms remain elusive. This study elucidates TLR8's role in monocyte-endothelial crosstalk and evalua...AIMS: Toll-like receptor 8 (TLR8) is implicated in systemic sclerosis (SSc) pathogenesis, but its precise cellular mechanisms remain elusive. This study elucidates TLR8's role in monocyte-endothelial crosstalk and evaluates the therapeutic potential of targeting the TLR8/AP-1 axis in SSc. MATERIALS AND METHODS: TLR expression in peripheral blood mononuclear cells (PBMC) from SSc patients and healthy controls was assessed via flow cytometry. Single-cell RNA-sequencing datasets were analyzed for monocyte TLR8 profiling. In vitro, CD14+ monocytes and human dermal microvascular endothelial cells (HDMC) were co-cultured using specific pharmacological modulators (TLR8 agonist VTX-2337; AP-1 inhibitor T5224). In vivo efficacy of AP-1 inhibition was evaluated in a bleomycin-induced SSc mouse model. KEY FINDINGS: TLR8 was predominantly expressed and significantly upregulated in SSc CD14+ monocytes, positively correlating with vascular manifestations like Raynaud's phenomenon. In vitro, VTX-2337-mediated TLR8 activation induced inflammatory cytokines and adhesion molecules (ITGB1/ITGB2) in monocytes via AP-1. These activated monocytes enhanced monocyte-endothelial adhesion, accelerated endothelial migration, disrupted tube formation, and induced endothelial-to-mesenchymal transition (EndoMT). Crucially, AP-1 inhibition with T5224 abrogated these pathogenic interactions. In vivo, T5224 significantly ameliorated endothelial injury, dermal inflammation, and skin fibrosis in bleomycin-treated mice. SIGNIFICANCE: The TLR8/AP-1 axis drives monocyte-mediated endothelial injury in SSc. Pharmacological AP-1 inhibition disrupts this pathogenic monocyte-endothelial crosstalk, offering a promising therapeutic strategy against SSc skin inflammation and fibrosis.
AIMS: Paclitaxel-induced peripheral neuropathy (PIPN) is a significant, dose-limiting side effect of chemotherapy characterized by neuronal dysfunction stemming from mitochondrial damage. This study investigates the ther...AIMS: Paclitaxel-induced peripheral neuropathy (PIPN) is a significant, dose-limiting side effect of chemotherapy characterized by neuronal dysfunction stemming from mitochondrial damage. This study investigates the therapeutic potential of mitochondria transplantation for mitigating PIPN. MATERIALS AND METHODS: PIPN was induced in rats via intraperitoneal paclitaxel injections (2 mg/kg, four doses). Allogeneic mitochondria from donor soleus muscles were injected into the vastus lateralis muscle of recipient rats. Sensory and motor functions were evaluated using behavioral tests. Mitochondrial biodistribution was tracked utilizing MitoTracker™ dye and lentiviral Mito-GFP labeling. Mechanistic evaluations included mitochondrial complex I-V activity assays, biogenesis marker quantification (TFAM, Nrf2), and histological assessments of sciatic nerve myelination, intraepidermal nerve fibers (IENFs), and neuromuscular junctions (NMJs). KEY FINDINGS: Exogenous mitochondria successfully underwent retrograde transport from the muscle into the sciatic nerve and spinal cord, significantly alleviating paclitaxel-induced neuropathic pain and motor impairments. Mechanistically, transplantation restored mitochondrial complex activities and biogenesis markers in the peripheral nervous system, improved neuronal redox balance, and reduced microglial infiltration. Furthermore, mitochondrial transplantation promoted sciatic nerve remyelination and normalized target-tissue innervation by rescuing IENF and NMJ densities. SIGNIFICANCE: Intramuscular mitochondria transplantation effectively counteracts paclitaxel-induced mitochondrial damage, suppresses neuroinflammation, and restores neuronal homeostasis, offering a promising therapeutic strategy for managing PIPN.
The hERG channel (Kv11.1 potassium channel) is the main carrier of the cardiac rapid delayed rectifier potassium current (Iₖᵣ), which plays a crucial role in the repolarization of the cardiac action potential. This study...The hERG channel (Kv11.1 potassium channel) is the main carrier of the cardiac rapid delayed rectifier potassium current (Iₖᵣ), which plays a crucial role in the repolarization of the cardiac action potential. This study investigates the effect of intracellular Ca signaling on the expression and function of the hERG channel. The results show that Ca significantly upregulates hERG mRNA expression and I or Iₖᵣ current density with pharmacological evidence implicating Ca/calmodulin-dependent kinase (CaMK) and mitogen-activated protein kinase kinase-extracellular signal-regulated kinase (MEK-ERK) signaling, while the effects of calcineurin and nuclear factor of activated T-cells (NFAT) signaling on this process are negligible. Based on the results of inhibitor experiments, the regulation is dependent on gene transcription and protein translation processes. This study provides pharmacological evidence suggesting that CaMK- and MEK-ERK-related pathways may be involved in Ca-mediated modulation of hERG channel activity, providing new insights into arrhythmia-related ion channel regulation.
AIMS: Serelaxin (RLX), the drug form of human gene-2 relaxin, has potent anti-fibrotic properties that are currently being clinically-evaluated for the treatment of heart failure (HF). Whilst these effects can potentiall...AIMS: Serelaxin (RLX), the drug form of human gene-2 relaxin, has potent anti-fibrotic properties that are currently being clinically-evaluated for the treatment of heart failure (HF). Whilst these effects can potentially be antagonised by angiotensin receptor blocker co-administration, this study determined if RLX was a suitable adjunct therapy to angiotensin converting enzyme inhibitor (ACEi) treatment. In particular, the anti-fibrotic effects of RLX were compared to or combined with the clinically-used ACEi, perindopril, in murine models of isoprenaline (ISO)-induced cardiomyopathy and surgically-induced myocardial infarction (MI). METHODS: The dose-response effects of perindopril (1, 2 or 4 mg/kg/day) on systolic blood pressure (SBP) and left ventricular (LV) fibrosis were first assessed in ISO-injured mice, after 7- or 14-days of treatment. The therapeutic effects of RLX (0.5 mg/kg/day) on SBP, LV fibrosis and LV functional parameters (ejection fraction, fractional shortening, stroke volume, cardiac output) were then compared to or combined with perindopril (2 mg/kg/day) pre-treatment (7-days prior) or co-administration (over 7-days) in ISO-injured mice; or perindopril co-administration (over 21-days) in MI-injured mice. KEY FINDINGS: Perindopril attenuated the ISO-induced LV fibrosis at 2 or 4 mg/kg/day, but induced significant hypotension at 4 mg/kg/day. RLX reduced the ISO- or MI-induced LV fibrosis, and restored measures of LV dysfunction, to a greater extent than perindopril (2 mg/kg/day), in the absence of BP regulation. These effects were maintained in the presence of perindopril pre-treatment or co-administration. SIGNIFICANCE: These findings confirmed that RLX had greater anti-fibrotic potential than perindopril, but could be applied as a rapidly-acting adjunct therapy to ACEi.
Current therapies for diabetes mellitus, a highly prevalent chronic metabolic disorder, rarely achieve etiological intervention and are limited by poor patient compliance and significant side effects. Extracellular vesic...Current therapies for diabetes mellitus, a highly prevalent chronic metabolic disorder, rarely achieve etiological intervention and are limited by poor patient compliance and significant side effects. Extracellular vesicles (EVs), nanoscale carriers of intercellular communication, offer a promising therapeutic alternative due to their high biocompatibility, low immunogenicity, and inherent capacity for delivering biomolecules to specific targets. This review systematically synthesizes recent progress in EV-based strategies for diabetes. First, we examine how mammalian-derived EVs (such as from mesenchymal stem cells and immune cells) directly protect and restore pancreatic β-cells, restore immune tolerance, and ameliorate systemic insulin resistance. Second, we highlight the emerging potential of plant-derived EVs, which allow for oral administration and modulate metabolism via gut-organ axes. We further discuss the engineering of EVs into targeted drug delivery systems, with a focus on breakthroughs in oral insulin delivery and their applications in treating diabetic complications, including nephropathy, chronic wounds, and liver-brain axis-related disorders. Finally, we outline the key challenges of standardization, scalable production, and clinical translation, proposing a roadmap for future research. This comprehensive analysis underscores the potential of EVs to provide transformative strategies for diabetes management through multifaceted mechanisms and innovative engineering strategies.
Cardiac rehabilitation (CR), centered on structured exercise training, improves exercise capacity, cardiac function, and quality of life in patients with cardiovascular disease (CVD). However, its benefits are still desc...Cardiac rehabilitation (CR), centered on structured exercise training, improves exercise capacity, cardiac function, and quality of life in patients with cardiovascular disease (CVD). However, its benefits are still described mainly by functional outcomes, whereas the underlying molecular basis remains less clearly integrated. This review summarizes the major mechanisms of exercise-induced cardioprotection in CR, including modulation of inflammation and oxidative stress, enhancement of mitochondrial biogenesis and quality control, improvement of endothelial function, regulation of epigenetic pathways, and release of exercise-derived factors. These interconnected responses influence cardiac remodeling, metabolic homeostasis, endothelial repair, and cell survival. We further integrate these mechanisms into a conceptual framework and discuss how different exercise stimuli may preferentially engage distinct biological pathways, supporting a mechanism-informed approach to individualized exercise prescription. A better understanding of these molecular networks may help advance CR from functional rehabilitation toward a more precise and biology-guided strategy.
Acute myeloid leukemia (AML) involves immune dysregulation and evasion, in which tryptophan catabolism via the kynurenine pathway (KP) is central. Leukemic blasts often overexpress indoleamine 2,3-dioxygenase-1 (IDO1) an...Acute myeloid leukemia (AML) involves immune dysregulation and evasion, in which tryptophan catabolism via the kynurenine pathway (KP) is central. Leukemic blasts often overexpress indoleamine 2,3-dioxygenase-1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), driving excess L-kynurenine (Kyn) production. Kyn activates the aryl hydrocarbon receptor (AhR), inducing interleukin-6 (IL-6) secretion and STAT3 phosphorylation with NF-κB co-activation, sustaining chronic inflammation. Concomitantly, KP activation is immunosuppressive: Kyn biases T cells toward FoxP3+ regulatory phenotypes, drives exhaustion of T and NK cells, and impairs dendritic and B-cell function, yielding an immunosuppressive milieu rich in IL-10 and IL-35. Together, these actions link chronic inflammation to immune tolerance in AML. By contrast, while upstream enzymes (IDO1/TDO2) are well studied, downstream KP metabolites remain poorly characterized in AML. In other systems, kynurenic acid (KYNA) mediates anti-inflammatory GPR35/AhR signaling, whereas 3-hydroxykynurenine (3-HK) and quinolinic acid (QUIN) generate reactive oxygen species, activate NF-κB-dependent cytokine cascades, and induce T-cell apoptosis. Collectively, the extended KP emerges as a nexus linking inflammatory signaling and immunosuppression in AML, with implications for disease progression, immune escape, and resistance, warranting further investigation.
Exosomes are nanosized extracellular vesicles (30-150 nm) secreted by most cell types, carrying various biomolecules that reflect the physiological or pathological state of their cells of origin. Owing to their molecular...Exosomes are nanosized extracellular vesicles (30-150 nm) secreted by most cell types, carrying various biomolecules that reflect the physiological or pathological state of their cells of origin. Owing to their molecular diversity and stability in bodily fluids, exosomes have emerged as promising tools in precision medicine. Diabetic kidney disease (DKD), affecting approximately 30-40% of individuals with diabetes, remains the leading cause of end-stage kidney disease worldwide. Current diagnostic tools, including albuminuria and estimated glomerular filtration rate, lack sensitivity and specificity for early detection and dynamic monitoring of disease activity. Emerging evidence indicates that urinary exosomes derived from glomerular cells, particularly podocytes, provide an insight into intrarenal pathobiology, reflecting real-time cellular injury and key disease-associated changes. Given the central role of podocytes in maintaining the glomerular filtration barrier and their early involvement in DKD, podocyte-derived urinary exosomes hold potential and may enable earlier intervention and more personalized therapeutic strategies. Beyond their biomarker potential, exosomal protein and microRNA cargo such as Regucalcin, Elf3, PHYD1, miR-155, miR-21, miR-29, actively participate in key pathogenic processes, including inflammation, fibrosis, oxidative stress, and metabolic dysregulation, thereby contributing to DKD progression. This review synthesizes current evidence providing mechanistic insights on urinary exosomes and their cargo as emerging biomarkers in DKD, highlighting their translational potential in advancing precision nephrology. In addition, we also discuss the current challenges in clinical implementation of exosome-based biomarkers into routine clinical practice for the diagnosis of DKD.
Hou C, Sun W, Wang L
… +6 more, Ge X, Tu Q, Guo H, Zhou T, Yan L, Xiong W
Sci China Life Sci
· 2026 May · PMID 42168477
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Outer membrane vesicles (OMVs) derived from Akkermansia muciniphila (A. muciniphila) are known to have immunomodulatory properties; however, their role in allergic asthma remains largely unexplored. In this study, we iso...Outer membrane vesicles (OMVs) derived from Akkermansia muciniphila (A. muciniphila) are known to have immunomodulatory properties; however, their role in allergic asthma remains largely unexplored. In this study, we isolated OMVs from A. muciniphila and conjugated them with polymyxin B (PMB) to neutralize membrane-associated lipopolysaccharide (LPS). In a murine asthma model, both PMB-conjugated A. muciniphila OMVs (PMB-A. muciniphila OMVs) and native OMVs alleviated asthma symptoms, with PMB-A. muciniphila OMVs exhibiting superior efficacy. The enhanced therapeutic effect of PMB-A. muciniphila OMVs was attributable to a more potent suppression of alternative macrophage polarization (M2). Mechanistically, PMB-A. muciniphila OMVs disrupt oxidative phosphorylation and inhibit the AP-1 transcription complex and downstream PI3K/AKT signaling, which are essential for M2 polarization. In conclusion, our findings demonstrate that PMB conjugation augments the therapeutic potential of A. muciniphila OMVs against allergic asthma by specifically targeting M2 macrophage polarization via metabolic reprogramming and suppression of AP-1/PI3K/AKT signaling. These findings suggest that PMB-A. muciniphila OMVs present a novel and promising microbiota-derived therapeutic strategy for asthma.
Sci China Life Sci
· 2026 Jun · PMID 42165924
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Nanoplastics (NPs), pervasive environmental pollutants with elevated toxicity and stability, present critical remediation challenges due to the inefficiency of conventional methods. Here, we reveal a protozoan biofloccul...Nanoplastics (NPs), pervasive environmental pollutants with elevated toxicity and stability, present critical remediation challenges due to the inefficiency of conventional methods. Here, we reveal a protozoan bioflocculation pathway in Tetrahymena that effectively sequesters NPs and fundamentally reshapes their environmental fate. Upon NP exposure, Tetrahymena activates a Ca-dependent mucus secretion mechanism, driving nano-scale aggregation that reduces aqueous NP concentrations by 41.6%-44.8% and enriches sedimentary sinks. Critically, this biotic process mitigates atmospheric dispersion risks, compelling revision of current NP fate models that neglect biological interactions. Multi-omics analyses identify Ca-mediated GRL secretion dynamics associated with this bioflocculation response in Tetrahymena. This mechanism represents a Ca-mediated defensive response observed in Tetrahymena, which may also occur in related species but requires further investigation across other protist taxa. These findings underscore the critical, underappreciated role of protozoa in pollutant mitigation and necessitate updates to global frameworks for projecting NP transport, abundance and ecological risk.
Li H, Huang ZYX, Lan J
… +6 more, Hu L, Wang Z, Wang Y, Santini L, Becker DJ, Xu Y
Sci China Life Sci
· 2026 Jul · PMID 42165921
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Wild small mammals represent critical sources of zoonotic infections due to their high diversity, global distribution, and proximity to humans. Nevertheless, significant knowledge gaps persist in characterizing pan-taxon...Wild small mammals represent critical sources of zoonotic infections due to their high diversity, global distribution, and proximity to humans. Nevertheless, significant knowledge gaps persist in characterizing pan-taxonomic microbial richness and sharing dynamics, particularly regarding ecologically critical yet understudied Eulipotyphla (true insectivores). Here, we take a macroecological approach to compare how microbial hosting and sharing dynamics differ across insectivores, rodents, and bats, and what ecological factors drive such disparities. We find that insectivores host comparable microbial richness to rodents and bats while exhibiting superior connectivity in microbe-sharing networks, suggesting a higher potential for intra- and cross-order microbial transmission. Urban adaptation, geographic range area, and longevity are shared drivers of microbial richness and sharing across these host orders, while greater body mass and shorter gestation time specifically are positive predictors of these outcomes within insectivores. Climate change projections identify insectivores as primary transmission hosts in new high-latitude hotspots by 2035, including parts of the US, Canada, and Russia, posing greater zoonotic threats than rodents or bats. Our findings challenge the prevailing paradigm that prioritizes rodents and bats as special zoonotic reservoirs, establishing insectivores as critical but overlooked players in disease ecology. Collective proactive surveillance of insectivores, rodents, and bats is imperative for forecasting emerging zoonotic threats and informing global risk assessment frameworks.