Search Results (420)

Regulatory T cells (Tregs) play a pivotal role in maintaining immune homeostasis by exerting precise control over immune activation, suppressing excessive responses, and facilitating tissue repair. These specialized CD4+ T cells, characterized by FOXP3 expression, function as key regulators that prevent pathogen-directed immune responses from progressing to deleterious autoimmunity or chronic inflammation. Tregs mediate suppression via secretion of cytokines such as IL-10 and TGF-β, metabolic disruption, and direct modulation of effector immune cells, thereby maintaining equilibrium between protective immunity and peripheral tolerance. Both thymically derived natural Tregs (nTregs) and peripherally induced Tregs (pTregs) exhibit phenotypic plasticity, adapting to diverse inflammatory milieus and tissue microenvironments through an array of suppressive mechanisms that orchestrate immune regulation and facilitate tissue repair. This functional heterogeneity manifests across lymphoid and non-lymphoid tissues, wherein Tregs dynamically adapt to distinct microenvironments to mount tailored responses to infection, tissue injury, and inflammatory insults. Conversely, Tregs may promote disease progression in malignancies and persistent infections by attenuating antitumor and antimicrobial immune effector responses. Treg activity is essential for averting autoimmune pathologies, tempering inflammatory cascades, and fostering tissue regeneration, thereby rendering them indispensable for upholding both systemic and tissue-specific immune homeostasis. Elucidation of Treg immunobiology unveils substantial therapeutic prospects across a diverse array of pathologies; targeted modulation of Treg frequency and functionality offers promise for ameliorating autoimmunity, mitigating transplant rejection, and combating malignancy. This narrative review delineates the multifaceted roles of Tregs in immune homeostasis, elucidates emerging insights into their mechanistic underpinnings, and evaluates prospective applications in next-generation immunotherapeutic interventions. Full article

Major histocompatibility complex class II (MHC-II) expression by intestinal epithelial cells (IECs) has emerged as a critical mechanism regulating mucosal immune homeostasis at the interface between the intestinal microbiota, epithelial barrier, and immune system. Beyond professional antigen-presenting cells, IEC-intrinsic MHC-II shapes CD4⁺ T-cell responses, influencing tolerance to commensal microorganisms, immunity to enteric pathogens, and maintenance of barrier integrity. Recent studies have revealed that epithelial MHC-II expression is dynamically regulated by cytokines, the gut microbiota, dietary factors, and microbiota-derived metabolites, linking environmental signals to local adaptive immune responses. Dysregulation of epithelial antigen presentation has been implicated in chronic intestinal inflammation, including inflammatory bowel disease (IBD). This review summarizes current knowledge regarding the molecular regulation, spatial organization, and immunological functions of epithelial MHC-II and discusses its emerging role in host–microbiota interactions, mucosal barrier homeostasis, and intestinal disease. Full article

Lotus corniculatus L. can spontaneously colonize metal-contaminated areas like the old Zn-Pb calamine tailings. This study compared two L. corniculatus ecotypes collected from metal-contaminated (HM) and non-contaminated (NM) sites to identify physiological adaptations to long-term metal exposure. The results indicated that HM ecotype accumulates Zn, Pb, and Cd in shoots without showing any toxic symptoms at the ultrastructural level. The HM ecotype exhibited a different composition of photosynthetic pigments, lower lipid peroxidation, and oxidative stress levels and increased the efficiency of the antioxidant defense system and antioxidant activity compared to the NM ecotype. Leaf antioxidant enzymes such as SOD, CAT, POX, and GPX were more active in the shoots of the HM ecotype, while GR and APX showed lower activity compared to the NM ecotype. In addition, the HM ecotype was characterized by higher glutathione and total phenolics content (mainly catechin, rutin, ferulic, and salicylic acids); however, these non-enzymatic metabolites primarily function in metal chelation alongside their role in oxidative stress mitigation. The results showed that calamine Lotus plants exhibit effective adaptation to long-term metal exposure by keeping metals away from metabolically active compartments and strengthening antioxidant defenses. These coordinated mechanisms reduce oxidative stress and contribute to the enhanced metal tolerance of calamine plants. Full article

The bearingless induction motor (BIM) relies on accurate displacement feedback to maintain stable magnetic suspension, but sensor faults, degradation, and noise can distort feedback and induce transients during branch switching. This paper proposes a confidence-fusion-based fault-tolerant displacement measurement method for the BIM suspension feedback chain. A four-channel asymmetric redundant sensor configuration is developed, and channel state evaluation functions are constructed from sampling-difference terms and geometric-consistency residuals. A decreasing Sigmoid mapping with first-order smoothing generates continuous confidence coefficients to represent channel health. Combined with discrete fault flags of the primary channels, four reconstruction branches, AB, BC, AC, and CD, are adaptively weighted to obtain the reconstructed displacement, which is connected to the original suspension controller through a smooth feedback access mechanism. A MATLAB/Simulink closed-loop suspension model is used to evaluate the method under fault-free operation, an abrupt fault of primary channel A, simultaneous and sequential faults of primary channels A and B, abrupt and gradual degradation, constant bias, intermittent signal dropouts, and noise disturbance of primary channel B. Results show that the method identifies abnormal primary channels, redistributes reconstruction weights according to sensor conditions, and maintains a fallback path through the CD branch under dual-primary-channel failure. Under channel-B degradation, the confidence coefficient tracks the deterioration and supports the subsequent AB-to-AC branch transfer, whereas under noise disturbance, the fault flag remains inactive and unnecessary branch switching is avoided. The method improves feedback continuity without changing the main suspension controller. Full article

Pancreatic β-cells maintain glucose homeostasis through tightly regulated insulin biosynthesis, storage, and secretion. To prevent pathological accumulation of excess or aging secretory granules (SGs), β-cells use crinophagy, a selective lysosomal degradation pathway in which mature insulin-containing granules fuse directly with lysosomes to form hybrid organelles termed crinosomes. Crinophagy was historically considered a simple mechanism for discarding obsolete, aged SGs. The acidic, protease-rich environment of crinosomes is proposed to generate unconventional insulin-derived epitopes through cathepsin-mediated proteolysis and transpeptidation reactions. These cryptic epitopes, which include hybrid insulin peptides (HIPs) resulting from the covalent fusion of insulin fragments with peptides from co-resident granule proteins, are largely absent from the thymic epitope repertoire. This creates a “peripheral–thymic mismatch” that allows autoreactive CD4+ T cells to escape central tolerance, ultimately driving β-cell destruction in type 1 diabetes (T1D). Recent studies demonstrate that pharmacological or genetic inhibition of crinophagy reduces crinosome abundance, narrows the pathogenic epitope repertoire, and delays the onset of diabetes in preclinical models. In type 2 diabetes (T2D), a related pathway termed stress-induced nascent granule degradation (SINGD) diverts newly synthesized insulin granules to lysosomes under glucolipotoxic conditions, contributing to insulin depletion and progressive β-cell failure. This review summarizes the current understanding of the molecular mechanisms behind crinophagy. It discusses its two main functions: maintaining physiological quality control and generating pathological antigens. Additionally, the review explores how crinophagy interacts with other cellular stress pathways and highlights new therapeutic strategies aimed at targeting this process to protect pancreatic β-cell function and potentially prevent or delay diabetes. Full article

Background/Objectives: Estrogen deficiency is associated with metabolic disturbances and impaired glucose homeostasis. Morin, a natural flavonol, has shown promising hypoglycemic and antioxidant properties, but its effects under hypoestrogenic diabetic conditions remain poorly understood. The aim of this study was to evaluate the effects of morin on body weight, fasting blood glucose, glucose tolerance, and selected serum biochemical markers in an experimental model of diabetes under estrogen-deficient conditions (ovariectomized diabetic female mice). Methods: Female CD1 mice underwent sham surgery or ovariectomy (OVX), and each surgical condition was further divided into non-diabetic and diabetic subgroups treated with vehicle, glibenclamide (10 mg/kg), or morin (30 mg/kg). Body weight and fasting blood glucose were monitored over a 15-day treatment period. Oral glucose tolerance was assessed on day 15, and serum biochemical markers, including glucose, cholesterol, triglycerides, uric acid, blood urea nitrogen, creatinine, ALT, and AST, were measured thereafter. Results: Ovariectomy aggravated diabetes-associated hyperglycemia, impaired glucose tolerance, and triglyceride elevation. Morin treatment reduced fasting blood glucose and improved glucose tolerance in diabetic mice, including ovariectomized animals. Morin also attenuated the increase in serum triglycerides and blood urea nitrogen in ovariectomized diabetic mice, although it did not significantly improve cholesterol, uric acid, creatinine, ALT, or AST levels. Compared with glibenclamide, morin showed relevant glucose-lowering activity but had a more limited effect on the overall biochemical profile. Conclusions: These findings suggest that morin may partially improve glycemic control and selected metabolic alterations in experimental diabetes associated with estrogen deficiency. Further studies are required to clarify its mechanisms of action, long-term efficacy, and translational relevance. Full article

The fruit of Crataegi fructus (CF) is a traditional “medicine food” herb widely used for its lipid-lowering properties, but its active ingredients and mechanisms against metabolic dysfunction-associated fatty liver disease (MAFLD) remain poorly understood. This study employed an integrated multi-omics approach, combining serum metabolomics, liver transcriptomics, weighted gene co-expression network analysis (WGCNA), network pharmacology, and molecular docking, to systematically investigate the effects of CF extract (CFE) in a high-fat diet (HFD)-induced mouse model of MAFLD. Our analysis revealed that CFE treatment significantly reduced body weight gain (p < 0.01), improved glucose tolerance and insulin sensitivity (p < 0.01), and alleviated hepatic steatosis, as evidenced by reduced lipid accumulation and decreased NAS scores (p < 0.001). Metabolomics analysis showed that CFE reversed HFD-induced disturbances in serum fatty acids, glycerophospholipids, and bile acid metabolites. Transcriptomics further revealed that the AMPK and PPAR signalling pathways were critically involved in the regulation of lipid metabolism by which CFE alleviated MAFLD. Consistently, CFE treatment resulted in significant upregulation of AMPK and PPARα expression (p < 0.001) and downregulation of CD36 and DPP4 (p < 0.001), as confirmed by Western blotting and qPCR. Furthermore, integration of WGCNA and network pharmacology pinpointed chlorogenic acid (CA), ursolic acid (UA), and oleanolic acid (OA) as the primary bioactive components, and their lipid-lowering effects were validated in FFA-treated THLE-2 cells. In conclusion, this study offers preliminary insights into the lipid-lowering mechanisms of CFE via regulation of the AMPK/PPARα/CD36/DPP4 signalling pathway and support its further development as a functional food ingredient for MAFLD prevention. Full article

Co-contamination with dibenzofuran (DBF) and cadmium (Cd(II)) poses a major challenge in environmental remediation. While Burkholderia sp. can degrade polycyclic aromatic hydrocarbons and tolerate heavy metals, the coordinated mechanism governing DBF degradation under high Cd(II) stress remains elusive. Here, we characterize Burkholderia sp. FM-2, which optimally degrades 600 mg/L DBF at pH 6.0 and 25 °C, achieving 91.8% removal within 48 h. FM-2 exhibits exceptional Cd(II) tolerance, with a minimum inhibitory concentration of 2000 mg/L. UPLC-MS/MS confirms DBF degradation via dioxygenase-mediated hydroxylation and sequential enzymatic reactions. Transcriptomics reveals, for the first time, concurrent upregulation of genes encoding RND efflux pumps, ABC transporters, P-type ATPases, and core DBF-degrading enzymes under high Cd(II) stress, enabling the synergistic maintenance of intracellular Cd(II) homeostasis and efficient DBF degradation. Collectively, FM-2 remediates DBF-Cd(II) co-contamination via coordinated transcriptional regulation of degradation and detoxification pathways, offering a promising strain resource and molecular basis for the bioremediation of co-contaminated environments. Full article

Cadmium (Cd) toxicity poses a significant threat to crop production and food safety. Although proline is known to enhance plant tolerance to Cd, the molecular mechanisms regulating Cd detoxification through proline accumulation remain unclear. This study identifies the proline transporter TaPROT2 as a crucial positive regulator of Cd tolerance in wheat. We demonstrate that overexpression of TaPROT2 directly promotes proline accumulation in transgenic wheat while simultaneously activating the antioxidant enzyme system, thereby reducing both Cd accumulation and translocation. Using electrophoretic mobility shift assays (EMSA), yeast one-hybrid (Y1H) assays, and luciferase reporter assays, we confirmed that TaERF3 directly binds to the GCC-box element in the TaPROT2 promoter, thereby activating its transcription. Furthermore, overexpression of TaERF3 enhances the expression of TaPROT2, leading to increased proline accumulation and decreased Cd content. In summary, our study reveals a novel TaERF3-TaPROT2 module that promotes proline accumulation, reduces Cd accumulation, and enhances Cd tolerance, providing a promising target for breeding low-Cd wheat. Full article

Cadmium (Cd) is one of the most toxic heavy metals in the environment, and it severely represses photosynthesis, growth, development and nutrient uptake in photosynthetic organisms. Excessive cadmium (Cd) taken up by plants seriously threatens global food security and human health. Therefore, designing an eco-friendly and sustainable strategy that can reduce the accumulation of Cd in plants is a major challenge. Phosphorus (P), as an essential nutrient for plant growth, has been shown to play a pivotal role in mediating Cd-induced stress response. However, the molecular mechanisms underlying the crosstalk between phosphate signaling and Cd stress response remain largely uncharacterized, especially the role of the core phosphate homeostasis regulator Phosphate Starvation Response 1 (PSR1). Here, we used the model green microalga Chlamydomonas reinhardtii to investigate the physiological and transcriptomic responses to Cd stress in wild type (WT, CC-125) and PSR1 loss-of-function mutant (Crpsr1, CC-4267). Our results showed that the Crpsr1 mutant exhibited significantly enhanced Cd tolerance compared with WT under P-sufficient conditions, with a better growth phenotype and a significantly lower Cd accumulation. Transcriptome analysis revealed distinct gene expression profiles between WT and the Crpsr1 mutant in response to Cd treatment. Gene Ontology (GO) enrichment analysis showed that differentially expressed genes (DEGs) were mainly involved in primary metabolism, protein kinase activity, ion binding and transmembrane transport, which are critical processes for mitigating Cd stress. Notably, key genes associated with iron uptake and homeostasis were significantly upregulated in the Crpsr1 mutant under Cd stress, indicating a potential regulatory link between PSR1, iron homeostasis and Cd tolerance. Taken together, our findings establish a functional association between the central phosphate signaling regulator PSR1 and Cd stress response in green microalgae, and provide novel candidate genes and regulatory networks for developing engineered microalgae with enhanced Cd phytoremediation capacity. Full article

Soil cadmium (Cd) pollution has emerged as one of the key environmental issues threatening the safety of agricultural products worldwide, yet clean and low-cost intervention strategies that reduce Cd accumulation in edible crops without disrupting agricultural production remain scarce. Grafting onto tolerant rootstocks represents an emerging clean agronomic technology that achieves in situ Cd risk reduction within a single growing season. However, the molecular mechanisms by which rootstocks regulate scion phenotypes remain poorly understood. MicroRNAs (miRNAs) act as critical long-distance signals in plants, yet their roles in rootstock-mediated growth promotion and Cd reduction remain largely unclear. In this study, we used Solanum torvum as rootstock and purple eggplant (Solanum melongena) as scion to investigate growth, fruit quality, Cd accumulation, and miRNA-mediated regulatory mechanisms. Grafting significantly increased plant height (by 18%), stem diameter (by 12%), and yield without obvious effects on fruit quality. Under Cd stress, the Cd content in grafted eggplant fruits was reduced by 76%, whereas leaf potassium (K), calcium (Ca), and magnesium (Mg) contents were elevated by 21%, 17%, and 10%, respectively. High-throughput sequencing and quantitative real-time polymerase chain reaction identified five key differentially expressed miRNAs, including miR164a and miR166b, four of which were related to Cd stress. Gene Ontology (GO) enrichment analyzes that their target genes were mainly involved in hormone signal transduction and ion transport. Further validation suggested that grafting improved growth and reduced Cd accumulation by regulating genes of the NAC, SPL, and HD-ZIP III families. These results suggested that suitable rootstocks can enhance crop productivity and reduce toxic metal accumulation in edible parts through miRNA-mediated regulation. Full article

Maize (Zea mays L.), a typical thermophilic crop originating from tropical regions, exhibits an inherent sensitivity to low-temperature stress. Cold stress severely restricts maize seed germination, seedling growth, the physiological metabolism, and the final grain yield, which greatly limits its geographical cultivation range and sustainable industrial development. Elucidating the molecular regulatory mechanisms underlying maize cold tolerance and excavating cold-resistant functional genes are essential for the molecular breeding of cold-tolerant maize varieties and expanding maize planting areas in high-latitude and low-temperature-prone regions. In this study, using the strongly cold-tolerant maize inbred line B144 as the experimental material, we cloned the ZmMAPKKKA gene (NCBI accession: LOC103651289) and systematically screened and verified its cold-stress-specific interacting proteins via multiple molecular biological assays. The full-length coding sequence (CDS) of ZmMAPKKKA is 1134 bp, encoding a 377-amino-acid protein with a predicted molecular weight of 40.37 kDa. The quantitative real-time PCR (qRT-PCR) results demonstrated that the ZmMAPKKKA expression was significantly upregulated by 16.56-fold in maize roots after 12 h of low-temperature treatment, indicating a tissue-specific and robust cold response in root tissues. A total of 25 interacting proteins were identified through yeast two-hybrid screening, among which three stress-responsive proteins, including a protein kinase (LOC100286253), a protein phosphatase 2C (PP2C) (LOC542176), and a NAC transcription factor (LOC118474710), were selected for subsequent verification. The Pull-Down, Co-immunoprecipitation (Co-IP), and bimolecular fluorescence complementation (BiFC) assays consistently confirmed that ZmMAPKKKA specifically interacts with these three proteins both in vitro and in vivo under cold stress conditions. This study is the first to construct a ZmMAPKKKA-centered protein interaction module in the maize mitogen-activated protein kinase (MAPK) cascade under cold stress, establishing a novel kinase–phosphatase–transcription factor regulatory cascade that improves the current understanding of cold signal transduction mechanisms in maize. Homologous genes of ZmMAPKKKA in gramineous crops including rice (Oryza sativa) and sorghum (Sorghum bicolor) have been proven to participate in diverse abiotic stress responses, suggesting the conserved functional roles of MAPKKK family genes across gramineous species. Collectively, our findings provide comprehensive insights into the molecular mechanism of the maize MAPK signaling pathway mediating cold stress adaptation and supply valuable functional gene resources for cold-tolerant maize germplasm innovation and molecular breeding. Full article

Constant light (LL) exposure is an established environmental risk factor for metabolic diseases, in which the whitening of brown adipose tissue (BAT) plays a critical role. This study aimed to elucidate the molecular mechanisms through which cordycepin counteracts LL-induced BAT whitening and improves metabolic function. We established an LL-exposed mouse model and employed an integrative approach combining pharmacological, metabolic, molecular, and computational (docking) assays to define cordycepin’s effects and targets. Cordycepin treatment significantly improved cold tolerance and attenuated BAT whitening in LL mice. Mechanistically, cordycepin directly bound to and enhanced the activity of the NAD⁺-dependent deacetylase SIRT1. This activation mitigated LL-induced impairments in mitochondrial biogenesis, dynamics, and autophagy. Furthermore, SIRT1 activation rebalanced fatty acid metabolism by downregulating CD36 and upregulating CPT1, thereby restoring the coupling of fatty acid uptake to oxidation. All beneficial effects of cordycepin were abolished by the selective SIRT1 inhibitor EX-527. In summary, our work provides strong evidence that cordycepin directly interacts with SIRT1 and enhances its deacetylase activity, thereby restoring mitochondrial function and fatty acid oxidative homeostasis in BAT to counteract constant LL-induced metabolic dysfunction. These findings position cordycepin as a promising natural compound targeting the SIRT1 pathway for metabolic disorders. Full article

N6-methyladenosine (m⁶A) is a dynamic and reversible RNA modification governed by the tripartite machinery of writers, erasers, and readers, which plays crucial roles in plant adaptation to environmental stresses. However, the repertoire and function of m⁶A machinery in pepper (Capsicum chinense) remain uncharacterized. Here, we performed a genome-wide identification of m⁶A regulators in pepper (Ccm⁶As), revealing 20 high-confidence genes, comprising 6 writers, 7 erasers, and 7 readers. Comprehensive analysis of their phylogeny, conserved domains, and promoter cis-elements revealed structural conservation and a transcriptional architecture highly enriched in stress-responsive elements. Notably, in silico analysis revealed that the core catalytic writer CcMTA, the essential adaptor CcFIP37A, and the paralog CcMTB1 exhibited strong interactions, suggesting the formation of a functional methyltransferase complex. Using a comparative approach with cadmium-tolerant (CdRes-1) and cadmium-sensitive (CdSen-1) genotypes, we found that Cd stress induced a genotype-specific transcriptional reprogramming of the m⁶A machinery. In the tolerant genotype CdRes-1, eight regulators were significantly upregulated, whereas only CcMTA showed a modest induction in the sensitive CdSen-1. Subcellular localization experiments confirmed dual nuclear and cytoplasmic localization of CcMTA. Our findings provide a foundational epitranscriptomic resource for future functional investigations into the molecular mechanisms underlying cadmium stress responses in pepper. Full article

Cadmium (Cd) is a major environmental pollutant due to its high mobility and persistence in soils, facilitating entry into the food chain and threatening ecosystems and human health. However, the mechanisms that enable Salix species, well adapted for Cd remediation, to both tolerate and accumulate Cd remain elusive. Here, two Salix genotypes with contrasting Cd tolerance were examined under control and Cd stress using integrated physiological, transcriptomic, and metabolomic analyses of roots and leaves. The Cd-tolerant genotype (Salix suchowensis P294) maintained biomass under Cd stress, whereas the Cd-sensitive genotype (Salix sinopurpurea × Salix integra P646) showed a ~17% reduction. P294 accumulated more Cd in its stems (132.76 mg kg⁻¹) and leaves (122.25 mg kg⁻¹) than P646 (93.54 and 56.24 mg kg⁻¹). Transcriptomics responses were stronger in roots, with 896 DEGs in P294 and 462 in P646, enriched in nitrogen metabolism, phenylpropanoid biosynthesis, and metal transport, whereas only 167 and 176 DEGs were detected in leaves for P294 and P646, respectively. Metabolomics revealed more altered metabolites in roots (125 in P294, 89 in P646), mainly organic acids, amino acids, and flavonoids, compared with leaves (46 and 66). RT-qPCR validated the root-specific upregulation of key detoxification and transport genes (ABCA7, PRX72, GSTU1, GSTU4, ZIP1). These results reveal a root-centered regulatory network underlying Cd accumulation and tolerance, integrating detoxification, redox homeostasis, and structural reinforcement, as well as providing valuable targets for genetic improvement of phytoremediation efficiency. Full article