Search Results (5,061)

Atopic dermatitis (AD) is a chronic inflammatory dermatosis driven by skin barrier impairment and immune dysregulation. This study aimed to investigate the anti-inflammatory and barrier-related effects of the ethanol extract of Bidens bipinnata L. fruits (EEBB) in a calcipotriol (MC903)-induced AD-like dermatitis mouse model and lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. In vivo, repeated topical application of EEBB (60, 180, and 600 μg/day) significantly attenuated MC903-induced AD-like clinical symptoms, skin weight, and erythema index. Notably, EEBB significantly improved skin hydration-related parameters, including relative skin hydration readings and the post-application moisture retention profile, and partially restored filaggrin and loricrin expression in lesional skin, whereas dexamethasone showed limited effects on these hydration-related parameters under the present conditions. Histopathologically, EEBB ameliorated epidermal lesions and reduced inflammatory cell infiltration. Mechanistically, EEBB suppressed the levels of pro-inflammatory (TNF-α, IFN-γ) and Th2 (IL-4, IL-5) cytokines in lesional skin. In vitro, EEBB significantly inhibited the production of nitric oxide (NO) and prostaglandin E₂ (PGE₂), and downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression in RAW 264.7 cells. These effects were associated with inhibited phosphorylation of JNK and p38 MAPK, with no marked effect on ERK phosphorylation under the present conditions. In conclusion, EEBB effectively alleviated AD-like dermatitis, accompanied by improved skin hydration and restoration of barrier-related protein expression, attenuation of local inflammatory responses, and targeted inhibition of the MAPK signaling pathway. Full article

Renal cell carcinoma (RCC) is a biologically heterogeneous malignancy characterized by variable clinical behavior and diverse molecular phenotypes. Although immune checkpoint inhibitors and targeted therapies have transformed the treatment landscape of advanced RCC, clinically validated biomarkers capable of improving risk stratification, therapeutic-decision making and disease monitoring remain lacking. Kidney injury molecule-1 (KIM-1), also known as hepatitis A virus cellular receptor-1 (HAVCR1) or T-cell immunoglobulin and mucin domain-containing protein-1 (TIM-1), has emerged as a biologically compelling investigational biomarker e because of its close relationship to proximal tubular epithelial injury and renal carcinogenesis. KIM-1 is a transmembrane glycoprotein minimally expressed in normal kidney tissue but markedly upregulated in dedifferentiated proximal tubular epithelial cells following injury, and in clear cell RCC, where its extracellular domain can be shed into plasma and urine. Beyond its role as a marker of tubular injury, KIM-1 participates in immune regulation, phagocytosis, inflammatory signaling and tissue remodeling, supporting its potential relevance to tumor biology. Clinical studies have demonstrated associations between elevated circulating KIM-1 levels and RCC diagnosis, recurrence risk, and survival outcomes, particularly in localized and postoperative disease settings. KIM-1 has additionally been investigated as a therapeutic target through antibody–drug conjugate approaches. Despite promising translational data, important limitations yet remain. Current evidence is predominantly prognostic rather than predictive, and substantial analytical and biological challenges continue to limit implementation. Assay standardization, clinically meaningful cutoffs, specimen selection, timing of sampling, and confounding by chronic kidney disease or nonmalignant renal injury remain incompletely resolved. Furthermore, evidence supporting incremental value beyond established clinicopathologic models remains limited. This review critically evaluates the biological rationale, analytical considerations and clinical evidence supporting KIM-1 in RCC. Particular emphasis is placed on distinguishing prognostic, predictive, pharmacodynamic, and therapeutic applications, as well as defining the evidentiary gaps that must be addressed before clinical implementation. Current evidence is derived predominantly from retrospective and exploratory analyses, and important limitations remain regarding assay standardization, biological specificity, chronic kidney disease-related confounding, and prospective validation. The review concludes with a summary of the evolving landscape of KIM-1-directed biomarker strategies in RCC, which may ultimately contribute to improved biologic risk stratification and biomarker-driven clinical investigation in RCC. Full article

Fruit color is a key quality indicator for apples and directly influences their market value. The process of fruit ripening encompasses various physiological and biochemical changes, such as the breakdown of chlorophyll and the buildup of anthocyanins and carotenoids. This study investigated the mechanism of chlorophyll degradation in apple peels using ‘Granny Smith’ varieties. The experiments involving the treatment with methyl jasmonate (MeJA) indicated that a concentration of 10 µM MeJA led to a reduction in chlorophyll degradation, while a higher concentration of 1500 µM MeJA enhanced this degradation, which aligned with the variations observed in the expression of genes associated with chlorophyll degradation. The key chlorophyll degradation gene MdSGR1 was cloned and found to be induced by methyl jasmonate. MdSGR1 encodes a 283-amino-acid protein belonging to the stay-green superfamily. The promoter possesses inducible cis-acting elements that respond to methyl jasmonate, low temperature and light, while the protein is localized to chloroplasts. Overexpression and silencing vectors were constructed. Overexpression of MdSGR1 induced chlorosis in tobacco leaves and ‘Granny Smith’ apple peels, decreased chlorophyll content, and upregulated related gene expression. Conversely, silencing MdSGR1 produced opposite effects. Arabidopsis thaliana plants overexpressing MdSGR1 exhibited low chlorophyll content, reduced photosynthetic rate, upregulated expression of genes associated with chlorophyll degradation. The results of yeast one-hybrid and dual-luciferase reporter assays indicated that the MdMYC2 transcription factor interacts with the promoter region of MdSGR1. In conclusion, MdSGR1 is crucial for the degradation of chlorophyll in apple peel, and it is regulated both by the MdMYC2 transcription factor and different concentrations of MeJA. This study preliminarily elucidated the regulatory mechanism of methyl jasmonate on chlorophyll degradation in fruit peel, and these findings provide an important theoretical basis for controlling degreening and color quality in apple fruit. Full article

The gastric endocrine population comprises functionally distinct cell types that exhibit both neuronal and endocrine characteristics; however, their molecular markers remain incompletely defined. Here, we identify growth differentiation factor 9 (GDF9), nephrin (NPHS1), and rearranged during transfection (RET) as novel markers of gastric endocrine cells. A co-immunofluorescence (IF) analysis demonstrated that GDF9, NPHS1, and RET are co-expressed with chromogranin A (CHGA), a well-known marker of gastrointestinal endocrine cells. Further Co-IF analysis revealed that GDF9-expressing cells were negative for ghrelin and somatostatin, whereas NPHS1 was co-expressed with both hormones. A subpopulation of RET-positive cells co-expressed ghrelin but not somatostatin. Notably, GDF9- and RET-positive cells co-expressed dopamine decarboxylase (DDC), consistent with enrichment in enterochromaffin-like (ECL) cells. Revisitation of our previous mRNA-sequencing data revealed reduced transcript levels of Gdf9, Nphs1, and Ret in CA-PKA mice, which express constitutively active protein kinase A (PKA) and develop gastric preneoplastic lesions. Co-IF and cellular quantification showed a localized reduction in the density of GDF9 and CHGA-positive endocrine cells, together with altered abundance of NPHS1- and RET-expressing cells in CA-PKA stomachs. These changes occurred in the context of extensive hyperplasia of the surrounding epithelium, indicating that the observed alterations reflect localized reduction and non-cell-autonomous effects of epithelial expansion. Notably, we observed RET misexpression outside the endocrine compartment in CA-PKA mice, suggesting that aberrant RET signaling may contribute to lesions by promoting abnormal glandular branching. Together, these findings identify GDF9, NPHS1, and RET as novel markers of gastric endocrine cells and their potential role in gastric homeostasis. Full article

Drought stress is one of the most prevalent abiotic stressors and severely impairs plant growth and productivity. Therefore, identifying functional genes associated with drought tolerance is essential for the molecular breeding of drought-resistant crops. The RD22 (Responsive to Desiccation 22) gene family encodes conserved BURP domain-containing proteins that participate in plant responses to drought stress. In this study, two RD22 homologs, DsRD22a and DsRD22b, were isolated and characterized from the drought-tolerant ornamental species Dianthus spiculifolius. Sequence analysis showed that both proteins contain a conserved BURP domain and are typical members of the RD22 family. Tissue-specific expression analysis revealed that both genes were predominantly expressed in leaves and stems. Abiotic stress assays demonstrated that the expression levels of DsRD22a and DsRD22b were significantly induced by abscisic acid (ABA), osmotic stress, and salt stress, whereas their transcriptional responses to relatively low-temperature and oxidative stress were relatively weak. Subcellular localization analysis indicated that DsRD22a and DsRD22b proteins are localized in the cytoplasm. Heterologous overexpression assays showed that transgenic Arabidopsis thaliana lines overexpressing DsRD22a or DsRD22b exhibited significantly enhanced tolerance to salt and osmotic stresses compared with wild-type (WT) plants. Soil drought assays further confirmed that the transgenic lines had higher soluble protein contents and improved drought tolerance than WT plants. These findings suggest that DsRD22a and DsRD22b positively regulate plant responses to drought stress, potentially by promoting soluble protein accumulation. Collectively, DsRD22a and DsRD22b represent valuable candidate genes for the genetic improvement of drought tolerance in plants. Full article

Strigolactones (SLs), as a class of novel plant hormones, play important roles in the regulation of plant branching. However, their function in branch development of wintersweet remains unclear. In this study, a gene involved in SLs biosynthesis, CpD27, was identified and isolated from wintersweet. The sequence characteristics, expression patterns, subcellular localization, and functional analysis through heterologous expression in Arabidopsis thaliana were investigated. Multiple sequence alignment showed that CpD27 contains the conserved D27 protein domain DUF4033. Quantitative real-time PCR analysis revealed that CpD27 is expressed in various vegetative organs of wintersweet, with the highest expression in leaves, followed by axillary buds. It is also expressed in all floral organs, with the highest expression level in the outer petals. CpD27 expression is induced by hormones (ABA and ACC) and low temperature (4 °C). Subcellular localization analysis indicated that CpD27 is localized in the chloroplasts of Arabidopsis. Heterologous expression of CpD27 in Arabidopsis delayed bolting. The number of both rosette branches and cauline branches in transgenic plants was reduced compared with wild-type plants. In addition, the expression of AtBRC1 was significantly upregulated in transgenic lines, suggesting that CpD27 has a function similar to that of its homolog in Arabidopsis. Overall, these results indicate that CpD27 plays a conserved role in the SLs-mediated branching pathway, which regulates branch development in wintersweet. This study provides a molecular and theoretical basis for further understanding branch development in wintersweet. Full article

Ventricular remodeling occurring in heart failure (HF) involves structural disarray of the sarcolemma T-tubule (TT)–sarcoplasmic reticulum (SR) dyad junctions, thereby disrupting the close apposition of L-type Ca²⁺ channels (Ca_V1.2) with ryanodine receptors (RyR2) that trigger SR Ca²⁺ release and myofilament contraction. In a rat ischemic heart failure model expressing low thyroid hormone (TH) function, we used 3D stochastic optical reconstruction microscopy (STORM) to image RyR2 clusters with Ca_V1.2 channels, and the associated protein junctophilin-2 (Jph2). We tested whether treatment with T3, the biologically active form of TH, throughout progression of the disease would preserve T-tubule structure and dyadic ion channel organization. Confocal microscopy of isolated cardiomyocytes (CMs) stained with ANEPPS membrane dye showed significantly decreased TT density in diseased CMs while T3 treatment attenuated TT disorganization. 3D STORM images of dyadic ion channels labeled with fluorescent-tagged antibodies to RyR-Dylight550, Jph-CF647 and Ca_V1.2/IgG-Dylight488 were captured. A density-based algorithm defined RyR2 clusters, and a 400 nm spherical 3D volume of interest around each RyR2 cluster’s centroid determined the number of Ca_V1.2 and Jph2 localizations associated with each RyR2 cluster. Analysis revealed significant reduction in RyR2 cluster size and number with reduced co-localized Jph2 in failing CMs. T3 treatment increased RyR2 cluster numbers and cluster volumes albeit non-significantly, with increased co-clustering of Jph2. The number of Ca_V1.2 co-localized with RyR2 clusters trended lower in the failing CMs. These results support maintaining TH homeostasis in optimizing the nanoscale organization of Ca²⁺ ion channels in triggering Ca²⁺ release and myofibrillar contraction in patients with heart disease. Full article

The Popeye domain-containing protein 1 (Popdc1), also known as Bves, plays a crucial role in maintaining skeletal muscle homeostasis, with its variants leading to limb–girdle muscular dystrophy type R25. Skeletal muscles of patients with the homozygous missense variant of Bves exhibit impaired membrane trafficking, while skeletal muscle fibers in bves^S191F homozygous mutant zebrafish are significantly reduced and disorganized. However, the mechanism by which the absence of bves induces skeletal muscle atrophy remains unclear. In this study, we discovered a novel mechanism whereby bves deficiency drives skeletal muscle atrophy by disrupting mitochondrial structure and function. Our findings indicate that bves knockout leads to a significant decrease in zebrafish’s ability to swim, atrophy of skeletal muscle tissue, loss of cell membrane localization signals, and abnormalities in mitochondrial structure and function. After an 8-week intervention of regular aerobic exercise, the symptoms of skeletal muscle atrophy in bves knockout zebrafish were significantly alleviated, and the expression levels of genes and proteins related to mitochondrial were effectively rescued. These findings establish a connection between bves deficiency-induced disruption of mitochondrial structure and function and the onset and progression of skeletal muscle tissue atrophy symptoms, thereby laying a molecular foundation for exercise rehabilitation strategies in atrophic myopathy. Full article

1-Deoxy-D-xylulose-5-phosphate synthase (DXS) serves as the initial rate-limiting enzyme in the methylerythritol phosphate (MEP) pathway, governing the biosynthesis of precursors for photosynthetic pigments and terpenoids. In this study, the LaDXS2-2 gene was cloned and functionally characterized in lavender (Lavandula angustifolia). The full-length coding sequence (CDS) of LaDXS2-2 spans 2178 base pairs, encoding a protein of 725 amino acids. Phylogenetic analysis revealed that LaDXS2-2 is most closely related to the DXS from Salvia miltiorrhiza. Expression profiling demonstrated that LaDXS2-2 was highly expressed in flower buds, and its transcript levels were significantly upregulated (p < 0.05) in response to ethephon, high light intensity, and low temperature, while exhibiting tissue-specific responses to gibberellin application. Subcellular localization assays confirmed LaDXS2-2 is targeted to the chloroplast. Heterologous overexpression of LaDXS2-2 in tobacco resulted in a marked increase in photosynthetic pigment content, enhanced the actual photochemical efficiency of photosystem II [Y(II)], and reduced non-photochemical quenching (NPQ). Integrated transcriptomic and metabolomic analyses further revealed that LaDXS2-2 overexpression activated the diterpenoid biosynthesis pathway and upregulated amino acid metabolism as well as the TCA cycle, while competitively suppressing phenylpropanoid and flavonoid biosynthesis pathways. These findings indicate that LaDXS2-2 not only enhances photosynthetic efficiency by promoting the synthesis of photosynthetic pigments but also suggests a potential role in influencing primary carbon and nitrogen metabolism, as inferred from transcriptomic and metabolomic data. This functionality may ultimately influence plant growth and metabolic homeostasis. Overall, this study provides a theoretical foundation for the synergistic improvement of photosynthetic efficiency and secondary metabolism in crops. Full article

Citrus fruits are widely cultivated all over the world. Due to climatic conditions, citrus fruits are frequently exposed to periodic low temperatures, which poses a serious threat to their yield and quality. Cold not only restricts plant growth and deteriorates fruit quality but also leads to fruit abscission and tree mortality, posing severe constraints on large-scale citrus production. The TIFY family gene plays crucial roles in plant development and stress adaptation. However, the genome-wide identification and functional analysis of TIFY genes in cold stress adaptation of citrus plants remain largely unexplored. Here, we performed a systematic genome-wide analysis of the TIFY family in sweet orange (Citrus sinensis (L.) Osbeck) and identified 14 CsTIFY members. We conducted a comprehensive study on the protein characteristics, phylogenetic relationships, gene structure, chromosome distribution, promoter cis-acting elements, and subcellular localization of these genes. Phylogenetic analysis classified the CsTIFYs into ZML (ZML1–ZML4), JAZ (JAZ1–JAZ7), PPD (JAZ8, JAZ9), and TIFY (TIFY1) subfamilies, and they are distributed on seven chromosomes. Collinearity analysis revealed that segmental duplication is the primary driver for CsTIFY family expansion. Expression profiling under cold stress identified JAZ1, JAZ2, and JAZ3 as the most cold-inducible members. All three CsTIFY proteins are targeted to the nucleus, as confirmed by subcellular localization analysis. Overexpression of JAZ1, JAZ2, or JAZ3 in citrus calli significantly enhanced cold sensibility. Collectively, this study elucidates the gene function of CsTIFYs under cold stress and provides new insight for molecular breeding of cold-tolerant citrus varieties. Full article

Identifying cold-resistance genes is essential for improving the ability of apples (Malus × domestica) to tolerate low temperatures, as cold stress significantly limits their growth and productivity. The MdWRKY31 gene was cloned from apple, and its sequence characteristics, expression pattern, and biological function were systematically investigated. Bioinformatic analysis indicated that MdWRKY31 belongs to the group II WRKY transcription factors and is localized in the nucleus. Expression analysis revealed that MdWRKY31 transcript levels were markedly upregulated under low-temperature stress. To further explore its function, MdWRKY31 was heterologously overexpressed in tomato (Solanum lycopersicum). Following low-temperature treatment, transgenic tomato plants exhibited significantly reduced accumulation of reactive oxygen species, markedly enhanced activities of antioxidant enzymes (SOD, POD, and CAT), increased contents of proline and soluble protein, and a notable decrease in malondialdehyde levels. Additionally, transcript levels of SlCBF1, SlCBF2, SlCBF3, SlICE1, along with the ABA signaling-related genes SlNCED1 and SlABI5, were markedly elevated. Further molecular docking showed that the MdWRKY31 protein has strong binding affinity to the W-box elements in the promoters of SlCBF1 suggesting that it may regulate the expression of these genes through direct protein–DNA interactions. These findings indicate that MdWRKY31 improves plant cold tolerance by CBF-dependent pathways to modulate antioxidant defenses and osmotic balance. These findings identify candidate genetic resources for breeding cold-resistant apple cultivation. Full article

P. massoniana is an important native economic and ecological tree species in southern China, where seasonal drought has emerged as a critical factor limiting its productivity. The SAUR gene family, recognized as core early auxin-responsive genes, plays a crucial role in balancing plant growth, development, and stress adaptation; however, research related to this family in conifers remains limited. Utilizing the chromosome-level genome of P. massoniana, this study identified 73 SAUR genes (PmSAUR1~73) through bioinformatics methods, systematically analyzing the physicochemical properties of the encoded proteins, chromosomal localization, phylogenetic relationships, gene structures, and cis-acting elements. Combined with transcriptome sequencing and molecular experiments, the drought stress response patterns of these genes were further elucidated. The results indicated that PmSAUR genes predominantly encode alkaline proteins, primarily localized in mitochondria and nuclei, with an uneven distribution across nine chromosomes, where tandem duplication serves as the primary mechanism driving family expansion. Phylogenetic analysis classified these genes into seven subfamilies, which include both conserved clades homologous to angiosperms and branches specific to P. massoniana. All members contain the Auxin_inducible conserved domain, with motif1 identified as the core essential motif. Promoter regions were enriched with MeJA (methyl jasmonate)-responsive (56%), ABA-responsive, and drought stress-related cis-elements. Under drought stress, 38 PmSAUR genes exhibited diverse temporal expression patterns. Four key genes (PmSAUR14, PmSAUR28, PmSAUR54, and PmSAUR73), which are localized in the nucleus and exhibit high expression specifically in male cones or roots, were identified. These genes exhibit an expression pattern consistent with an auxin-negative response (i.e., repressed by IAA and induced by drought) and display a distinctive response pattern characterized by drought-induced upregulation coupled with IAA-mediated downregulation. This mechanism may contribute to the drought adaptation strategies of P. massoniana, involving regulatory processes for aboveground reproduction and adaptation of the underground root system. This study represents the first effort to elucidate the evolutionary characteristics and drought response patterns of the SAUR gene family in P. massoniana, thereby addressing the existing research gap regarding the functions of SAUR genes in coniferous trees. Furthermore, it offers candidate gene resources and theoretical support for the molecular breeding of stress resistance in P. massoniana. In addition, two auxin-induced SAUR genes (PmSAUR22 and PmSAUR37) were identified as contrasting examples, but the main focus of this study is on the four auxin-repressed genes. Full article

Alternative splicing (AS) is a major post-transcriptional regulatory mechanism that greatly expands transcriptomic and proteomic diversity in plants. Recent studies have demonstrated that AS dynamically regulates gene expression during plant development and under diverse environmental conditions through isoform-specific modulation of transcript stability, translation efficiency, protein localization, and signaling pathways. In this review, we summarize recent advances in understanding the roles of AS in plant development and abiotic stress responses. Mechanistically, splice site selection is regulated through coordinated interactions among cis-regulatory elements, RNA-binding proteins, RNA secondary structures, transcriptional kinetics, chromatin organization, and spliceosomal dynamics. AS plays critical roles in various developmental processes, including seed germination, vegetative growth, flowering transition, and senescence, while also contributing to plant adaptation to abiotic stresses such as osmotic, temperature, and oxidative stresses. Particular emphasis is placed on the diverse regulatory outcomes of AS, including isoform-specific protein functions, AS-coupled nonsense-mediated decay, transcript stability control, and context-dependent isoform switching. We further discuss the varying levels of experimental evidence supporting reported AS events, ranging from transcriptome-wide observations to genetically and biochemically validated isoform functions. Moreover, recent advances in long-read sequencing, single-cell transcriptomics, proteogenomics, and genome-engineering technologies are accelerating the functional characterization of splice isoforms and uncovering the complexity of AS-mediated regulatory networks. Collectively, these advances highlight AS as a central mechanism coordinating plant developmental plasticity and environmental adaptation. Full article

Background: Uridine diphosphate glucose (UDP-Glc) is one of the key substrates for the biosynthesis of gallotannins in plants. UDP-glucose dehydrogenase (UGD) catalyzes the irreversible oxidation of UDP-Glc to UDP-glucuronic acid (UDP-GlcA), thus affecting the biosynthesis and accumulation of gallotannins in the Chinese gallnut. Methods and Results: In this study, we identified three members of the RcUGD family from the Rhus chinensis genome. Protein sequence alignment revealed that all three RcUGDs possess the conserved NAD⁺ coenzyme binding motif GAGYVGG and the catalytic motif GFGGSCFQKDIL. qRT-PCR analysis revealed that the expression levels of RcUGD3 in stem and root tissues were respectively 10-fold and 13-fold greater than that in the leaves, in which gallotannin accumulation was higher. RcUGD3 expression level declined by 63% during early (24 d) gallnut development, suggesting an inverse relationship between RcUGD3 expression level and gallotannin biosynthesis. In addition, subcellular localization analysis using the tobacco transient transformation system showed that RcUGD proteins are broadly distributed throughout the cell. Moreover, an in vitro enzyme activity assay indicated that the recombinant RcUGD3 protein catalyzed UDP-Glc to produce UDP-GlcA as shown by HPLC. Taken together, our results suggested that RcUGD3 protein is responsible for UDP-Glc degradation and probably plays a regulatory role in gallotannin biosynthesis in the Chinese gallnut. Conclusions: This study lays a foundation for further elucidating the function and expression regulation mechanism of the RcUGD gene family and provides new insights for the super-accumulation mechanisms of gallotannins in Chinese gallnuts. Full article

Carbon monoxide (CO) is a gasotransmitter generated by heme oxygenase (HO) isoforms during heme catabolism. The inducible HO-1 produces CO under conditions of redox imbalance, such as oxidative stress and inflammation. On the other hand, HO-2 constitutively generates CO, primarily during the physiological turnover of heme. Extensive evidence indicates that CO exerts autocrine effects by targeting hemoproteins, including soluble guanylyl cyclase, cyclooxygenase, and cytochromes. Furthermore, CO regulates many biological processes within the brain, including mitochondrial biogenesis, potassium channel activity, mitogen-activated protein kinase and phosphatidylinositol-3-kinase/Akt signaling. It also controls the activity of transcription factors, such as hypoxia-inducible factor-1 and peroxisome proliferator-activated receptor-γ. Through these mechanisms, CO modulates inflammatory gene expression, promotes anti-apoptotic signaling, and contributes to local stress responses. Conversely, CO produced in the hypothalamus inhibits the stress-induced release of corticotropin-releasing hormone and arginine vasopressin under pro-inflammatory conditions, resulting in reduced adrenocorticotropin hormone release and cortisol secretion from the anterior pituitary and adrenal cortex, respectively. Moreover, hypothalamic CO acts in a paracrine manner to modulate glucocorticoid release during psychological stress, including restraint or water deprivation. Together, these findings support the view that endogenous CO is a key modulator of the stress axis, exerting pleiotropic effects that integrate neuroendocrine, immune, and metabolic responses. Full article