Published online Jun 7, 2026. doi: 10.3748/wjg.v32.i21.116337
Revised: January 13, 2026
Accepted: March 6, 2026
Published online: June 7, 2026
Processing time: 190 Days and 14.9 Hours
Inflammatory bowel disease, particularly ulcerative colitis (UC), represents a chronic relapsing intestinal disorder of complex pathogenesis. The inflammatory cascade characteristic of UC compromises both the architecture and physiological integrity of the enteric nervous system. Salidroside (Sal), a bioactive component with well-documented anti-inflammatory and tissue-protective properties, has emerged as a potential candidate for UC treatment, yet its specific effects on enteric glial cells (EGCs) behavior and the underlying mechanisms mediating its therapeutic potential in experimental colitis remain incompletely understood.
To investigate how Sal regulates EGCs activation and its therapeutic pathways in experimental colitis.
Colitis severity was quantified through disease activity scores, histological examination, and colonic length mea
Sal treatment significantly reduced disease activity index scores by (P < 0.0001), preserved colon length by 11.80% compared to dextran sulfate sodium salt (DSS) group (5.23 ± 0.16 cm vs 5.93 ± 0.17 cm, P = 0.0268), and decreased serum interleukin (IL)-1β by 78.17% [from 61.09 ± 0.90 pg/mL to 13.33 ± 0.68 pg/mL, P < 0.0001, 95% confidence interval (CI): 45.10%-50.40%], IL-6 by 64.13% (from 85.96 ± 1.73 pg/mL to 30.83 ± 0.84 pg/mL, P < 0.0001, 95%CI: 50.39%-59.87%), and tumor necrosis factor-α by 11.40% (from 91.06 ± 1.92 pg/mL to 80.68 ± 0.02 pg/mL, P = 0.0054, 95%CI: 3.57%-17.19%) in the DSS-induced colitis model. These beneficial outcomes correlated with modulatory effects on EGCs within the enteric nervous system. Integrated network pharmacology and transcriptomic investigations revealed that Sal operates through stimulation of the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) cascade, which underlies its anti-colitic pro
Through activation of the cAMP/PKA/CREB signaling cascade, Sal suppresses pathological EGCs activation, consequently attenuating intestinal inflammatory processes, preserving mucosal barrier integrity, and ameliorating experimental colitis.
Core Tip: Salidroside (Sal) exerts protective effects in dextran sulfate sodium-induced colitis by modulating enteric glial cell (EGC) activity. Sal suppresses pathological EGC activation, reducing inflammatory mediators such as interleukin (IL)-1β, IL-6, tumor necrosis factor-α, and nuclear factor kappa-B, while enhancing glial cell line-derived neurotrophic factor (GDNF) production. These effects restore mucosal barrier integrity, normalize intestinal permeability, and improve epithelial tight junction structure. Mechanistically, Sal activates the cyclic adenosine monophosphate (cAMP)/protein kinase A/cAMP-response element binding protein signaling pathway, linking EGC regulation to anti-inflammatory outcomes. This study highlights Sal as a promising therapeutic agent for ulcerative colitis, emphasizing the critical role of the enteric nervous system and EGCs in maintaining intestinal homeostasis.
- Citation: Li Y, Tao SS, Wang Y, Sun Q, Li MY, Zhang H, Li YQ. Salidroside mitigates experimental colitis through cyclic adenosine monophosphate pathway activation and suppression of enteric glial cell responses. World J Gastroenterol 2026; 32(21): 116337
- URL: https://www.wjgnet.com/1007-9327/full/v32/i21/116337.htm
- DOI: https://dx.doi.org/10.3748/wjg.v32.i21.116337
Ulcerative colitis (UC) is a chronic and recurrent form of inflammatory bowel disease (IBD). It manifests through symptoms such as abdominal pain, diarrhea, rectal bleeding, and mucopurulent bloody stool, which severely com
Recent investigations suggest that the enteric nervous system (ENS) exerts substantial regulatory influence on intestinal barrier function and immune homeostasis[7,8]. The ENS comprises enteric neurons and enteric glial cells (EGCs) distributed within the myenteric plexus (MP) and submucosal plexus (SP) throughout the intestinal wall[7]. Dysregulated activation of EGCs disrupts mucosal barrier integrity, enhances epithelial permeability, and provokes in
Salidroside (Sal), a natural phenolic glycoside isolated from the perennial herb Rhodiola rosea, exerts diverse biological effects, including antioxidant, anti-inflammatory, and neuroprotective activities[11,12]. Evidence demonstrates that Sal mitigates intestinal inflammation through modulation of immune cell function, gut microbiota composition, and multiple signaling pathways[11-13]. However, whether Sal confers tissue protection in UC via regulation of EGCs within the ENS, and the underlying molecular mechanisms, remains unresolved. The cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP-response element binding protein (CREB) pathway represents a classical intracellular signaling cascade[14]. Previous investigations have confirmed through in vitro experiments that activation of the cAMP/PKA/CREB signaling pathway can ameliorate LPS-induced inflammatory damage[15]. However, it remains unclear whether Sal alleviates intestinal inflammation by modulating the cAMP/PKA/CREB pathway and targeting EGCs.
In this study, a 3% dextran sulfate sodium salt (DSS)-induced colitis mouse model was employed. Colitis mice were administered either Sal or a selective PKA inhibitor. The specific mechanisms by which Sal regulates intestinal inflammatory responses by targeting EGCs were explored through integrated morphological, molecular biology, network pharmacology, and transcriptomic approaches. This study aimed to elucidate the ENS-dependent neuro-immune re
Male C57BL/6 mice (n = 56, 8 weeks old, body weight 21 ± 3 g) were procured from the Animal Center of The Fourth Military Medical University (FMMU). Throughout the experimental period, animals were maintained in specific pathogen-free housing with individual ventilation systems. Environmental parameters included ambient temperature of 21 ± 2 °C, relative humidity maintained between 40%-60%, and alternating 12-hour light-dark cycles. Standard laboratory chow and water were accessible ad libitum. All experimental procedures received ethical approval from the FMMU Animal Care and Use Committee and adhered to institutional guidelines for laboratory animal welfare.
The investigation consisted of two distinct experimental phases (Figure 1A). The first part of the experiment involved 24 mice. After a one-week adaptation period, the mice were randomly divided into 3 groups using a random number table method (n = 8 per group): Normal control (control), DSS-induced colitis (DSS), and DSS with Sal intervention (DSS + Sal). Colitis induction in designated groups utilized 3% DSS solution administered via drinking water for seven consecutive days. The DSS + Sal cohort simultaneously received oral gavage of Sal (10 mg/kg daily, catalog 10338-51-9, Med
Throughout the experimental timeline, daily monitoring encompassed general appearance, body weight fluctuations, fecal consistency, and hematochezia presence in all cohorts. Following established protocols, individual disease activity index (DAI) scores were calculated for each animal (Table 1). For DAI scores, investigators were blinded to group allocation throughout the evaluation process. Blinding was maintained by coding samples numerically, with group identities revealed only after all measurements were completed and recorded.
| Score | Body weight loss (%) | Fecal property | Presence of gross bleeding or bloodstain |
| 0 | None | Normal | Negative hemoccult |
| 1 | 1-5 | Soft but still formed | Weakly positive hemoccult |
| 2 | 5-10 | Soft | Positive hemoccult |
| 3 | 10-15 | Very soft | Blood traces in stool visible |
| 4 | ≥ 15 | Watery diarrhea | Gross rectal bleeding |
On experimental day 7, mice underwent 12-hour fasting followed by oral fluorescein isothiocyanate (FITC)-dextran administration (30 mg/kg). Four hours post-administration, tail vein blood collection was performed. Samples were maintained at ambient temperature for one hour, then subjected to centrifugation (3800 rpm, 1000 × g, 10 minutes) for serum isolation. Serum FITC-dextran concentrations were determined through fluorometric quantification.
Four mice per cohort received sodium pentobarbital anesthesia (120 mg/kg, intraperitoneal injection). Peripheral blood was harvested and processed for subsequent enzyme-linked immunosorbent assay (ELISA) analysis. Transcardial perfusion with phosphate-buffered saline (PBS) [0.01 M PBS, potential of hydrogen (pH) = 7.4] achieved vascular clearance. Following colonic excision, longitudinal measurements were recorded across cohorts. The intact colon was divided into four segments for differential processing: Segment one underwent fixation in 4% paraformaldehyde (w/v, 0.1 M phosphate buffer, pH = 7.4), ethanol dehydration series, and hematoxylin-eosin (HE) staining preparation. Segment two was preserved in Carnoy’s solution, dehydrated, and prepared for alcian blue-periodic acid Schiff (AB-PAS) staining. Segment three received 4% paraformaldehyde fixation (w/v, 0.1 M phosphate buffer) for immunofluorescence his
Following established protocols, colonic segments one and two underwent paraffin embedding and serial coronal sectioning at 5 μm thickness. HE and AB-PAS staining protocols were executed according to standardized methodologies. Histological index (HI) scoring (Table 2) and goblet cell enumeration were subsequently performed. The scoring and counting were performed with scorers remaining blinded to the group assignment.
| Score | Degree of inflammation | Extent of inflammation | Crypt damage |
| 0 | None | None | None |
| 1 | Slight | Mucosa | Basal 2/3 damaged |
| 2 | Medium | Mucosa and submucosa | Basal 2/3 damaged |
| 3 | Severe | Muscular or transmural | Only surface epithelium intact |
| 4 | Severe | Muscular or transmural | Entire crypt and epithelium lost |
Following published protocols, colonic preparations and tissue sections were obtained from segment three. Six pre
| Antigen | Host species | Dilution | Source | Catalog No. | |
| Immunofluorescent histochemical staining | Western blotting | ||||
| CREB | Rabbit | NA | 1: 1000 | Cell Signaling Technology (Danvers, MA, United States) | 9197 |
| GAPDH | Rabbit | NA | 1: 1000 | Sigma (Saint Louis, MO, United States) | G9545 |
| GDNF | Rabbit | NA | 1: 1000 | Abcam (Cambridge, United Kingdom) | AB176564 |
| GFAP | Chicken | 1: 500 | NA | Abcam (Cambridge, United Kingdom) | AB4674 |
| GFAP | Rabbit | NA | 1: 1000 | Abcam (Cambridge, United Kingdom) | AB7260 |
| Hu D + Hu C | Rabbit | 1: 500 | NA | Abcam (Cambridge, United Kingdom) | AB184267 |
| Occludin | Rabbit | 1: 500 | 1: 1000 | Servicebio (Wuhan, Hubei Province, China) | GB111401 |
| Phospho-CREB | Rabbit | NA | 1: 1000 | Cell Signaling Technology (Danvers, MA, United States) | 9198 |
| Phospho-PKA | Rabbit | NA | 1: 1000 | Cell Signaling Technology (Danvers, MA, United States) | 5661 |
| PKA | Rabbit | NA | 1: 1000 | Cell Signaling Technology (Danvers, MA, United States) | 4782 |
| ZO-1 | Rabbit | 1: 300 | 1: 2000 | Servicebio (Wuhan, Hubei Province, China) | GB15195 |
| Antigen | Conjugation | Dilution | Source | Catalog No. |
| Donkey anti-rabbit IgG | Alexa flour 488 | 1:1000 | Invitrogen (Carlsbad, CA, United States) | A21206 |
| Donkey anti-rabbit IgG | Alexa flour 594 | 1:1000 | Invitrogen (Carlsbad, CA, United States) | A21207 |
| Donkey anti-chicken IgG | Alexa flour 488 | 1:1000 | Jackson (Lancaster, PA, United States) | 703545155 |
| Goat anti-rabbit IgG | HRP | 1:5000 | Abcam (Cambridge, United Kingdom) | AB9655 |
A laser scanning confocal microscope system (FV-3000, Olympus, Tokyo, Japan) was employed to examine colonic preparations and tissue sections, utilizing specific laser wavelengths and detection filters: 510-530 nm emission with 488 nm excitation for Alexa 488, 590-615 nm emission with 543 nm excitation for Alexa 594, and 450-460 nm emission with 355 nm excitation for DAPI. Image-J software version 1.80 (NIH, Bethesda, MD, United States) facilitated quantitative analyses. Parameters evaluated included the density of Hu C/D-immunoreactive enteric neurons within individual ganglia across both MP and SP, alongside their spatial associations with glial fibrillary acidic protein (GFAP)-expressing EGC processes. Intestinal epithelial cells were assessed for occludin and zonula occludens-1 (ZO-1) mean fluorescence intensity. Each experimental group’s analysis encompassed a minimum of 6 randomly chosen microscopic fields per specimen. The histological analyzing of all the samples was performed in a blinded fashion.
Following established protocols, the fourth colonic segment received 0.1 M phosphate buffer rinsing, underwent 1.5-hour fixation in 1% osmium tetroxide, progressed through graded ethanol dehydration series, experienced acetone re
Colonic tissue specimens maintained on ice were subjected to lysis using radio immunoprecipitation assay buffer supplemented with protease and phosphatase inhibitor mixtures. The bicinchoninic acid methodology enabled protein concentration determination, with 30 μg total protein loaded onto 8%-10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis gels for electrophoretic separation. Following electrophoresis completion, electrotransfer procedures moved proteins onto polyvinylidene difluoride membranes, which then received two-hour blocking treatment in tris-buffered saline solution containing 0.1% tween-20 and 5% (w/v) non-fat milk. Primary antibody incubation proceeded overnight at 4 °C (Table 3), after which washing steps preceded two-hour room temperature incubation with secondary antibodies (Table 4). Chemiluminescent methodology enabled protein band visualization, with glyceraldehyde-3-phosphate dehydrogenase serving as the reference control for expression level normalization.
Whole blood samples collected from each experimental group underwent one-hour ambient temperature clotting, sub
GeneCards and OMIM databases provided UC-associated therapeutic target retrieval, whereas TCMSP and UniProt repositories yielded Sal-related target extraction. Venn diagram analysis of UC-related and Sal-associated targets revealed candidate molecules potentially mediating Sal’s therapeutic action in UC. The STRING database facilitated protein-protein interaction (PPI) network assembly with connectivity parameters requiring correlation coefficients ≥ 0.4. Gene Ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment evaluation of intersecting targets utilized the DAVID platform. Statistical significance criteria were established at Q < 0.05 for GO analyses and P < 0.05 for KEGG evaluations.
The Gene Expression Omnibus (GEO) repository provided transcriptomic dataset acquisition (GSE75214 and GSE92415 dataset identifiers). The limma package enabled differential gene expression determination using selection parameters of |log2 fold change| > 1 combined with P < 0.05. The DAVID database platform facilitated functional characterization via GO functional annotation and KEGG pathway enrichment evaluation.
SPSS software version 25.0 (SPSS Inc., Chicago, IL, United States) performed statistical computations, while GraphPad Prism version 9.5 (GraphPad Software Inc., San Diego, CA, United States) generated graphical representations. Mean ± SEM format expressed quantitative data. One-way analysis of variance enabled intergroup statistical evaluation. Tukey’s test facilitated post-hoc multiple comparisons for normally distributed data, whereas distribution-free methods with Dunn’s test addressed non-parametric datasets for multiple comparisons. P < 0.05 established the statistical significance threshold.
Body weight changes and fecal characteristics were utilized as key clinical indicators for colitis assessment (Figure 1C-G). Normal weight gain trajectory, regular stool formation, and absence of bleeding characterized the control group
HE and AB-PAS histological analyses (Figure 2A and B) revealed preservation of mucosal, submucosal, muscular, and serosal layers in controls, with normal architectural features and plentiful goblet cells [Figure 2A (A1 and A4) and Figure 2B (B1 and B4)]. The DSS group demonstrated extensive epithelial disruption or complete loss, profound glandular depletion, massive inflammatory cell infiltrates throughout mucosal and submucosal compartments, and dramatic goblet cell depletion [Figure 2A (A2 and A5) and Figure 2B (B2 and B5)]. Sal therapy ameliorated epithelial injury, diminished inflammatory infiltrates, and maintained goblet cell populations in colitic mice [Figure 2A (A3 and A6) and Figure 2B (B3 and B6)]. Relative to controls, the DSS + Sal group exhibited significant colonic HI score reduction alongside marked goblet cell preservation (P < 0.05) (Figure 2C and D).
GFAP-immunoreactive EGCs (green fluorescence) manifested stellate or fusiform soma with extensive processes, while their nuclei (blue fluorescence) appeared centrally located, ovoid, and occupied substantial cytoplasmic volume. In Figure 3, within the MP and SP of control animals, GFAP-expressing EGCs formed intimate associations with Hu C/D-immunoreactive enteric neurons (red fluorescence) (Figure 3A and D). DSS treatment induced substantial EGCs activation throughout both the MP and SP, with region-specific morphological characteristics distinguishing the activation patterns between plexuses. Within the MP, activated EGCs exhibited hypertrophic process terminals creating dense neuronal encirclement, see Figure 3B. Within the SP, activated EGCs displayed numerous elongated, extensively branched processes that not only proliferated throughout ganglia but also formed tight wrapping around neighboring enteric neurons (Figure 3E). Sal administration substantially reversed this activation across both regions. MP EGCs demonstrated process terminal thinning, while SP EGCs exhibited diminished branching with shortened extensions, approximating control morphology (Figure 3C and F). These morphological improvements aligned with decreased GFAP protein levels detected via Western blot analysis in the DSS + Sal group.
Quantitative assessment indicated comparable Hu C/D-immunoreactive enteric neuron numbers across all experimental groups (P > 0.05) (Figure 3G and I). Semi-quantitative measurement of GFAP-positive EGCs and Hu C/D-positive neuron overlapping regions showed substantial MP and SP overlap elevation in the DSS group vs controls (P < 0.05). This overlap underwent significant reduction in the DSS + Sal group relative to the DSS group (P < 0.05) (Figure 3H and J).
Intestinal epithelial integrity was assessed via tight junction protein expression patterns of occludin and ZO-1. Control animals demonstrated apical junction concentration of these proteins in colonic epithelial cells via immunofluorescent histochemical analysis. In Figure 4, these proteins exhibited grid-like, compact arrangement forming continuous filamentous networks with robust fluorescence intensity [Figure 4A (A1-A4), B (B1-B4), C and D]. The DSS group ma
The TCMSP database search identified 143 targets associated with Sal, and following duplicate removal and low-confidence entry exclusion, 2398 UC-related targets emerged from GeneCard and OMIM databases. Venn diagram analysis revealed 52 overlapping targets shared between Sal and UC (Figure 5A). PPI network construction identified IL-6 and additional markers as central nodes (Figure 5B). GO and KEGG enrichment analyses suggested that Sal may confer UC protection via cAMP pathway activation (Figure 5C and D). GEO dataset examination additionally identified differentially expressed genes (DEGs) distinguishing UC patients from healthy controls, revealing 638 downregulated genes and 329 upregulated genes (Figure 5E). GO functional annotation indicated strong associations between these DEGs and cAMP-related biological processes (Figure 5F). KEGG pathway analysis further demonstrated substantial cAMP signaling pathway downregulation in UC patient colonic tissues, a pathway involved in inflammatory modulation (Figure 5G-I). Taken together, these findings support cAMP/PKA/CREB signaling as a probable mechanistic foundation underlying Sal’s therapeutic efficacy in UC.
To determine whether Sal’s anti-inflammatory efficacy in DSS-induced colitis involves cAMP/PKA/CREB pathway regulation, mice received intraperitoneal Sal administration combined with the specific pathway inhibitor H89 (Figure 6A). Relative to the DSS + Sal group, the DSS + Sal + H89 group demonstrated pronounced weight loss (Figure 6B) and substantially elevated DAI scores (Figure 6C). The DSS + Sal + H89 group exhibited marked colon length reduction (Figure 6D). HE and AB-PAS histological evaluations revealed exacerbated tissue damage, encompassing mucosal injury, crypt architectural destruction, substantial submucosal inflammation featuring dense inflammatory cell accumulation (Figure 6E and F), increased HI scores, and marked goblet cell depletion (Figure 6G and H).
Immunofluorescent histochemical analysis demonstrated pronounced EGCs activation throughout the colonic MP and SP in mice receiving combined Sal and H89 treatment. The morphological changes paralleled those in untreated colitic mice, featuring hypertrophic EGCs process terminals in the MP and augmented branching with elongation in the SP (Figure 7A-L). GFAP protein levels showed substantial elevation (P < 0.05), with concurrent increases in IL-1β, IL-6, TNF-α, and NF-κB concentrations (P < 0.05, Figure 7M-P). These findings demonstrate that Sal’s anti-inflammatory action in DSS-induced colitis operates predominantly through cAMP/PKA/CREB signaling pathway activation, which inhibits EGCs activation and restricts proinflammatory cytokine secretion.
The DSS + Sal + H89 group manifested increased serum FITC-dextran levels relative to the DSS + Sal group (P < 0.05, Figure 6I). TEM analysis revealed colonic microvilli with heterogeneous length, irregular distribution, and poorly defined intercellular tight junctions, characteristics reflecting mucosal barrier compromise (Figure 8A). Western blot examination showed that DSS exposure diminished protein levels of phosphorylated PKA (p-PKA), phosphorylated CREB (p-CREB), and GDNF, while elevating GFAP expression. Sal intervention counteracted these modifications by promoting p-PKA, p-CREB, and GDNF expression while inhibiting GFAP expression (Figure 8B-J). Conversely, combined Sal and H89 administration substantially reduced p-PKA, p-CREB, and GDNF expression, with concomitant significant GFAP level elevation (Figure 8B-J). These observations indicate that Sal engages the cAMP/PKA/CREB pathway, resulting in EGCs activation inhibition, intestinal inflammatory response attenuation, mucosal barrier integrity preservation, and DSS-induced colitis amelioration in mice.
UC represents a complex IBD of multifactorial origin, predominantly manifested through compromised intestinal mucosal barrier function and chronic persistent inflammation. Our investigation revealed that Sal suppressed EGCs activation, attenuated intestinal inflammatory responses, and maintained mucosal barrier functional integrity. Integrative network pharmacology coupled with transcriptomic profiling further revealed that Sal’s protective efficacy in DSS-induced experimental colitis correlated strongly with regulatory effects on the cAMP/PKA/CREB signaling axis. Our experimental findings demonstrated that Sal-mediated activation of this signaling cascade significantly suppressed EGCs activation patterns and reduced pro-inflammatory cytokine secretion. Such modulation of immune responses contributed to maintaining both architectural and functional aspects of the mucosal barrier system. Collectively, these protective mechanisms culminated in ameliorating colitis disease progression.
Prior investigations have documented Sal’s protective capacity in UC pathology, primarily ascribing these protective mechanisms to Sal’s modulatory influence on immune cellular populations and intestinal microbiota composition. Prior studies have solidly demonstrated that Sal exerts potent anti-colitis effects by targeting macrophage pyroptosis and the T helper 17 (Th17)/regulatory T (Treg) immune balance[16,17]. Sal has been shown to inhibit the assembly of the NOD-like receptor thermal protein domain associated protein 3 inflammasome, thereby reducing the release of pro-inflammatory cytokines (IL-1β and IL-18) and alleviating pyroptotic process to the intestinal barrier[16]. Meanwhile, Sal exerts a regulatory effect on the Th17/Treg ratio in the colonic lamina propria. Specifically, it downregulates the expression of retinoic acid receptor-related orphan receptor γt, the key transcription factor of Th17 cells, and upregulates forkhead box protein p3, the marker of Treg cells. This modulation consequently suppresses the pathogenic immune response mediated by Th17 cells and enhances the immunosuppressive function of Treg cells[17]. Our preceding work identified dysregulated EGCs activation patterns throughout the MP and SP of colonic tissues in colitis mouse models, wherein suppression of EGCs activity within the ENS demonstrated inflammatory reduction alongside restoration of microbial equilibrium[18,19]. These collective observations focused investigative attention toward EGCs’ potential mediatory functions in Sal’s colitis-protective actions.
Our present findings have demonstrated that Sal-mediated suppression of EGCs activation complement these previous reports showing Sal’s effects on immune cell function. The EGCs pathway identified in our study may interact with these immune mechanisms, as activated EGCs release factors such as macrophage colony-stimulating factor that directly influence macrophage polarization and function. Furthermore, EGCs-derived cytokines can modulate T cell differentiation in the lamina propria. Thus, Sal’s therapeutic effects likely result from coordinated regulation of both neuroglial and immune components, warranting future investigations into these interconnected pathways.
EGCs originate developmentally from ectodermal neural crest precursors. These cells display widespread anatomical distribution throughout MP and SP ganglionic structures, establishing intercellular communication networks via cy
Intestinal mucosal architectural destruction accompanied by resultant barrier functional compromise constitutes a cardinal pathological hallmark of UC. Mucosal layer attenuation or ablation signifies structural barrier impairment. Gob
The cAMP/PKA/CREB signaling cascade occupies a pivotal regulatory position in immune system homeostasis. Cyclic AMP functions as an intracellular second messenger molecule that suppresses T lymphocyte activation processes[28]. PKA and CREB serve as principal mediators orchestrating anti-inflammatory and immunomodulatory responses[29]. PKA constitutes the primary downstream effector of cAMP signaling, whereas CREB operates as its subsequent transcriptional regulatory factor. Cyclic AMP binds to PKA’s regulatory subunit domain, triggering conformational structural alterations that liberate the catalytic subunit component. This catalytic subunit subsequently undergoes nuclear translocation and initiates CREB activation[30]. Such activation culminates in suppression of nuclear transcriptional regulatory factors and inflammatory mediator production, thereby manifesting anti-inflammatory bioactivity under inflammatory pathological conditions. Relevant studies have confirmed that ADCY6 and ADCY9, the genes encoding adenylate cyclases and key upstream regulators of cAMP synthesis, are significantly dysregulated in patients with UC[29,30]. Meanwhile, the expression of PKA subunits PRKACA and PRKAR1A has also been shown to be significantly correlated with UC severity[29,30]. Downstream of this pathway, the CREB transcription factor target genes ATF3 and NR4A1 can participate in maintaining epithelial barrier function by influencing the transcriptional regulation of the tight junction-related gene TJP1 in epithelial cells. These results suggest that abnormalities in the cAMP/PKA/CREB signaling pathway play an important role in the progression of UC. Our present research findings similarly demonstrate that activation of the cAMP/PKA/CREB signaling pathway can restore tight junctions between colonic epithelial cells and alleviate colonic inflammation.
Within our present investigation, p-PKA/PKA and p-CREB/CREB expression levels in colonic tissues from DSS-induced colitis mice demonstrated marked reduction, signifying cAMP/PKA/CREB signaling pathway inhibition. This signaling suppression facilitated enhanced EGCs activation, augmented pro-inflammatory cytokine secretion, and compromised intestinal mucosal barrier structural and functional integrity. Sal therapeutic administration markedly restored p-PKA/PKA and p-CREB/CREB expression profiles, reactivating the signaling cascade, thereby suppressing EGCs activation patterns, diminishing mucosal inflammatory responses, preserving barrier functional integrity, and ameliorating DSS-induced colitis pathology. Critically, pharmacological pathway blockade using H89 inhibitor abrogated Sal’s protective therapeutic effects in colitis mice. As illustrated in the mechanistic schematic (Figure 9), Sal exerts therapeutic benefit through cAMP/PKA/CREB signaling pathway activation to modulate EGCs functional behavior.
Sal possesses the capacity to activate the cAMP/PKA/CREB signaling cascade, culminating in EGCs activation sup
This study demonstrates for the first time that Sal alleviates DSS-induced colitis by targeting EGCs. Within the ENS, EGCs respond to the intestinal inflammatory microenvironment through alterations in activation state and morphology. Sal inhibits EGCs overactivation by selectively activating the cAMP/PKA/CREB pathway. This inhibition diminishes the secretion of proinflammatory cytokines IL-1β, IL-6, and TNF-α while enhancing GDNF production. This dual regulatory effect mitigates intestinal inflammation, restores mucosal integrity, preserves barrier function, and ultimately slows the progression of colitis (Figure 9). This study offers a theoretical foundation that supports the clinical application of Sal in UC therapy.
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