Search Results (943)

This study investigated the pathological processes by which two Salmonella strains induce orchitis and impair spermatogenesis in mice, with emphasis on inflammation and blood–testis barrier (BTB) integrity. Thirty male Kunming mice were randomly assigned to the human-derived Salmonella enterica serovar Enteritidis H71 group, the sheep-derived Salmonella enterica serovar Agona W42 group, or the phosphate-buffered saline control group (n = 10 per group). An acute orchitis model was established by intrascrotal injection. Histopathological examination revealed marked testicular and epididymal lesions, disruption of the spermatogenic epithelium, and reduced sperm abundance in infected mice. Transcriptomic analysis identified 4546 differentially expressed genes shared by the two infected groups and showed enrichment of the Toll-like receptor (TLR), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) signaling pathways. Real-time quantitative PCR further showed increased expression of interleukin 6 (Il6), interleukin 1 beta (Il1b), and tumor necrosis factor (Tnf), accompanied by reduced expression of tight junction protein 1 (Tjp1), occludin (Ocln), and synaptonemal complex protein 3 (Sycp3) in infected mice (p < 0.05), except for Tjp1 in the W42 group. These findings indicate that Salmonella-induced inflammatory activation is associated with BTB disruption and impaired spermatogenesis, providing a basis for further investigation of bacterial orchitis and zoonotic reproductive risks. Full article

Background: Atopic dermatitis (AD) is a persistent and recurring skin disease characterized by epidermal barrier dysfunction, immune dysregulation, and elevated expression of proinflammatory mediators. We investigated the anti-inflammatory potential of polynucleotides (PN), highly purified DNA biopolymers isolated from salmonid gonads, in keratinocyte and macrophage activation models. Methods: RAW 264.7 macrophages were stimulated with lipopolysaccharide (LPS), whereas HaCaT keratinocytes were stimulated with tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ). The effects of PN treatment on the production or expression of inflammatory mediators, cytokines, and chemokines were evaluated. Changes in the phosphorylation of mitogen-activated protein kinases (MAPKs) and Janus kinase 1/signal transducer and activator of transcription 3 (JAK1/STAT3) and in the nuclear localization of nuclear factor-κB (NF-κB) were also assessed. Results: In LPS-activated RAW 264.7 macrophages, PN treatment significantly suppressed nitric oxide production and downregulated the expression of inducible nitric oxide synthase (iNOS), TNF-α, IL-1β, and IL-8, accompanied by reduced NF-κB nuclear translocation. In TNF-α/IFN-γ-stimulated HaCaT keratinocytes, PN treatment markedly decreased the secretion levels of IL-6, IL-1β, and thymic stromal lymphopoietin. Moreover, PN treatment markedly reduced T-cell-recruiting chemokines, including MDC/CCL22, TARC/CCL17, RANTES/CCL5, and IL-8. Signaling analyses demonstrated that PN treatment attenuated the phosphorylation of key MAPKs (ERK, JNK, and p38) and the JAK1/STAT3 axis. Furthermore, PN treatment markedly reduced NF-κB nuclear translocation. Conclusions: These in vitro findings indicate that the anti-inflammatory effects of PN are associated with reduced activation of multiple core signaling pathways governing cytokine and chemokine responses, supporting further investigation of PN in AD and other chronic inflammatory skin diseases. Full article

Di-(2-ethylhexyl) phthalate (DEHP), a ubiquitous environmental plasticizer, has been increasingly linked to the exacerbation of inflammatory skin conditions, especially psoriasis. However, the mechanisms and effective therapeutic strategies targeting DEHP-aggravated psoriasis remain elusive. We integrated network toxicology, network pharmacology, and molecular docking to explore the targets of DEHP-exacerbated psoriasis and the protective effects of shikonin (SH). These findings were validated in a DEHP/IMQ-induced mouse model using a novel shikonin nanoparticle (SH-NP) that overcomes SH’s inherent hydrophobicity. Computational analyses revealed that SH counteracts DEHP skin toxicity through a multi-target network, identifying the p38 mitogen-activated protein kinase (p38 MAPK), TNF, IL-1β, proliferating cell nuclear antigen (PCNA), and matrix metalloproteinases 2 and 9 (MMP2/9) as core therapeutic nodes. Molecular docking verified this network, revealing robust binding between SH and key targets with binding energies ranging from −6.0 to −7.8 kcal/mol, consistently outperforming DEHP. In vivo experiments demonstrated that topical application of SH-NP significantly ameliorated macroscopic skin injury and reduced PASI scores. Mechanistically, SH-NP effectively reversed the DEHP-exacerbated inflammatory microenvironment by decreasing macrophage and mast cell infiltration in the dermis, reducing pro-inflammatory cytokine levels, and inhibiting the phosphorylation of p38 MAPK. Furthermore, SH-NP treatment successfully suppressed keratinocyte hyperproliferation, as evidenced by downregulated PCNA expression and reduced epidermal thickness. SH-NPs also markedly downregulated the elevated levels of MMP2/9 in mice, thereby mitigating collagen degradation and maintaining dermal matrix integrity. This study shows that SH-NPs alleviate DEHP-aggravated psoriasis by suppressing local inflammation, keratinocyte hyperproliferation, and collagen degradation, offering a targeted nanostrategy for environmentally exacerbated skin diseases. Full article

The structural and immunomodulatory properties of arabinogalactan proteins (AGPs) from edible medicinal plants remain largely unexplored. Here, A homogenous AG-II-like arabinogalactan protein (CTSP-W2, 9862 Da) was isolated from Cynanchum thesioides via hot-water extraction, ethanol precipitation, and column chromatography. Its structure was thoroughly characterized by high-performance gel permeation chromatography (HPGPC), Fourier-transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), Congo-red, scanning electron microscopy (SEM), sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), methylation analysis. The mechanism of immune activity was examined using specific inhibitors, Western blotting, and molecular docking. It comprises galactose, arabinose, glucose, galacturonic acid, xylose, and 18 amino acids (asparagine-rich), with a backbone of →3,6)-Galp-(1→ and →6)-Galp-(1→. CTSP-W2 significantly enhanced macrophage proliferation, phagocytosis, and secretion of Nitric oxide (NO), Tumor necrosis factor-alpha (TNF-α), and Interleukin-6 (IL-6). Inhibitor assays showed that Toll-like receptor 4 (TLR4, TAK-242) and Toll-like receptor 9 (TLR9, E6446) antagonists markedly reduced CTSP-W2-induced TNF-α, IL-6, and NO in a dose-dependent manner, whereas Toll-like receptor 2 (TLR2) inhibition (C29) unexpectedly upregulated these mediators. Western blot revealed that CTSP-W2 upregulated TLR4 and TLR9 protein expression and increased phosphorylation of Inhibitor of nuclear factor kappa-B alpha (IκBα), nuclear factor kappa B (NF-κB p65), and p38, indicating activation of the TLR4/9–NF-κB–p38 mitogen-activated protein kinase (MAPK) signaling axis. Furthermore, Molecular docking analysis further indicated that CTSP-W2 forms extremely strong hydrogen-bonding and hydrophobic interactions with TLR4 through its galactose chains. This study elucidates the immunoregulatory mechanism of CTSP-W2 and establishes a molecular basis for arabinogalactan proteins as potential natural immunomodulators. Full article

This study aimed to explore the protective effects of different concentration combinations of four traditional Chinese medicine (TCM) monomers (Eleutheroside E, Anemoside B4, Forsythoside A, and Esculin) on porcine intestinal epithelial cell (IPEC-J2) damage induced by soybean 7S globulin, providing preliminary in vitro evidence for future studies on dietary-allergen-induced intestinal injury in piglets. An L₉ (3⁴) orthogonal experimental design was implemented to identify the optimized ratio of these monomers. IPEC-J2 cells were co-cultured with 5 mg/mL 7S globulin and the selected combinations for 24 h. Cell viability was determined via Cell Counting Kit-8 (CCK-8) assay, while cytokine secretion, oxidative status, and mechanical barrier markers were assessed using enzyme-linked immunosorbent assay (ELISA) and RT-qPCR. The optimal combination was determined to consist of Eleutheroside E at 50 mg/L, Anemoside B4 at 25 mg/L, Forsythoside A at 80 mg/L, and Esculin at 20 mg/L. This formulation significantly alleviated inflammatory damage, upregulated tight-junction-related mRNA expression, and reversed the decrease in cellular viability caused by 7S globulin. Furthermore, Western blot and transcript analyses suggested that this combination exerted its protective effects by modulating the nuclear factor-kappa B/mitogen-activated protein kinase (NF-κB/MAPK) pathway-related markers, reducing the expression of p38 MAPK, c-Jun N-terminal kinase (JNK), NF-κB p65, and inducible nitric oxide synthase (iNOS). In conclusion, this optimized combination of TCM monomers successfully alleviates both inflammatory injury and oxidative stress in IPEC-J2 cells in vitro and holds potential as a promising dietary additive candidate for mitigating dietary-allergen-induced enteropathy in piglets. Full article

Prostate stem cell antigen (PSCA), a pivotal member of the lymphocyte antigen-6 (Ly6) protein family, has been implicated in the tumorigenesis and neoplastic progression of diverse cancer types. In this study, we conducted a thorough investigation into the role of PSCA in the development of colorectal cancer (CRC). Survival analysis based on The Cancer Genome Atlas (TCGA) dataset demonstrated that elevated expression of PSCA was tightly correlated with unfavorable overall survival, inferior relapse-free survival, and worse post-progression survival among CRC patients. Additionally, PSCA exhibited significantly higher expression levels in colorectal cancer stem cell (CRC-SCs) relative to CRC cell lines. Loss-of-function assays using small interfering RNA (siRNA)-mediated silencing were performed to evaluate the effects of PSCA downregulation on the stemness properties of CRC-SCs, including proliferative capacity, invasive potential, and apoptotic rate, which were assessed by MTS assay, transwell invasion assay, and flow cytometry analysis, respectively. The results showed that silencing PSCA markedly suppressed the proliferation and invasion of CRC-SCs, while significantly promoting cellular apoptosis. RNA sequencing was performed to identify differentially expressed genes (DEGs) in the PSCA knockdown group compared to the negative control group. Follow-up analyses using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) indicated that these DEGs were significantly enriched in the cell-substrate adherens junction term and the mitogen-activated protein kinase 9MAPK signaling pathway. Moreover, PSCA silencing substantially reduced the phosphorylation levels of the core MAPK signaling constituents, pBRAF and pERK1/2; conversely, PSCA overexpression prominently upregulated the expression of pBRAF and pERK1/2. In nude mice with CRC-SCs cancer xenograft tumors, treatment with PSCA siRNA significantly decreased tumor volume and weight, while also notably extending the survival time of the tumor-bearing mice compared to the control group. Collectively, these findings confirm that PSCA plays a critical oncogenic role in CRC cancer growth and malignant progression, suggesting its potential as a novel and promising therapeutic target for CRC. Full article

Apoptosis signal-regulating kinase 1 (ASK1) is a mitogen-activated protein kinase kinase kinase (MAP3K) involved in stress-induced apoptosis. Increasing evidence indicates that ASK1 activation contributes to the anticancer activity of numerous compounds, particularly those that induce oxidative or endoplasmic reticulum stress. This review summarizes studies demonstrating ASK1-dependent apoptosis in models of lung, breast and gynecologic, or gastrointestinal cancers following treatment with natural products, phytochemicals, and synthetic agents, focusing on mechanistic evidence linking ASK1 to downstream activation of the JNK and p38 MAPK pathways, mitochondrial dysfunction, and caspase-dependent cell death. Studies were selected based on direct experimental validation of ASK1 activation and involvement in the observed anticancer effects. Overall, this review supports ASK1 as a promising molecular target for the development of novel cancer treatment strategies. Full article

Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders; however, available treatments majorly offer symptomatic relief without delaying disease progression and are associated with various adverse effects, highlighting the need for development of alternative therapies. Acalypha indica has previously showed neuroprotective effects in aging-related animal models, yet its mechanisms against AD were not fully understood. In this study, we employed an integrated bioinformatics approach combining network pharmacology, transcriptomic analysis, and molecular docking to investigate the anti-AD potential of this herb. A total of 282 overlapping targets between A. indica compounds and AD were identified. Network pharmacology analysis indicated chrysin, daidzein, galangin, kaempferol, and quercetin as the key bioactive components. Enrichment analyses suggested that targets of these compounds are mainly associated with phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and mitogen-activated protein kinase (MAPK) signaling pathways. Protein–protein interaction (PPI) analysis identified AKT1, epidermal growth factor receptor (EGFR), interleukin 6 (IL6), tumor necrosis factor (TNF), and p53 protein (TP53) as crucial hub targets. These targets were significantly upregulated in AD brain samples and were closely associated with pathways related to neurodegeneration, inflammation, as well as alterations in immune cell infiltration. Among the compounds, quercetin exhibited the strongest binding affinity to these target proteins. Overall, these findings provide a strong foundation for the multi-target therapeutic potential of A. indica in AD. Full article

Asthma is a heterogeneous chronic airway disease in which oxidative stress (OS) plays a central mechanistic role beyond classical immune-mediated inflammation. Reactive oxygen and nitrogen species (ROS/RNS), generated by recruited inflammatory cells and activated airway structural cells, drive epithelial injury, mucus hypersecretion, airway remodeling, and modulate key transcription factors including nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways. This review synthesizes current evidence on the multilevel redox-based determinants of asthma severity, spanning from genetic polymorphisms to circulating biomarkers. We examine serum antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), peroxiredoxins (PRDXs), and the thioredoxin (Trx) system as dynamic indicators of systemic redox status and disease severity, alongside oxidative enzymes including NADPH oxidases and dual oxidases (NOX/DUOX), xanthine oxidase (XO), and myeloperoxidase (MPO) that serve as upstream sources of airway oxidant burden. Functional genetic polymorphisms in antioxidant genes (SOD2, CAT, glutathione S-transferase mu 1/glutathione S-transferase theta 1 (GSTM1/GSTT1), heme oxygenase-1 (HO-1), NAD(P)H quinone dehydrogenase 1 (NQO1), nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1 (Nrf2/KEAP1)) and oxidative enzyme genes including nitric oxide synthase 1/2/3 (NOS1/2/3), MPO, cytochrome b-245 alpha chain (CYBA), and xanthine dehydrogenase (XDH) are reviewed as modulators of individual redox capacity and asthma susceptibility, with particular attention to gene–environment interactions. We further discuss oxidative damage biomarkers, including malondialdehyde (MDA), 8-isoprostanes, 4-hydroxynonenal, 8-oxo-7, 8-dihydro-2′-deoxyguanosine, protein carbonyls, 3-nitrotyrosine, and advanced oxidation protein products as indicators of lipid, DNA, and protein oxidation that correlate with disease activity and control. The roles of micronutrient cofactors in modulating antioxidant enzyme function and their potential as contextual biomarkers are also addressed. Additionally, emerging evidence on microRNAs (miRNAs) linked to OS biology in asthma is presented. Finally, we critically evaluate the challenges limiting clinical translation, including biomarker non-specificity, analytical variability, gene–environment complexity, and the absence of standardized reference ranges. This integrated framework supports the development of multilevel redox prognostic panels combining genetic, enzymatic, and oxidative damage readouts for improved asthma phenotyping, severity stratification, and personalized therapeutic approaches. Full article

Inflammatory bowel disease (IBD) poses a significant global health burden with rising incidence, particularly in Asia. This study employed an integrative network pharmacology approach combined with molecular docking to elucidate the therapeutic mechanism of ganoderic acid A (GAA) against IBD. Potential GAA targets were retrieved from pharmacogenomic databases, while IBD-related genes were curated from OMIM and GeneCards databases. Weighted gene co-expression network analysis of IBD transcriptomic datasets (GSE38713, GSE126124) identified disease-associated modules, with the yellow module exhibiting the strongest positive correlation. Functional enrichment analyses demonstrated significant involvement of overlapping targets in lipid metabolism, the inflammatory response, and the mitogen-activated protein kinase (MAPK) signaling cascade pathway. We identified 14 IBD-GAA-ferroptosis-related genes and 54 key module genes. Intersection analysis revealed 5 overlapping targets, including tumor necrosis factor-α(TNF-α), peroxisome proliferators-activated receptor γ (PPARγ), MAPK14, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic α (PIK3CA), and Caspase 3 (CASP3). Molecular docking confirmed high-affinity binding of GAA to these targets, with binding energies ranging from −7.3 to −10 kcal/mol. Crucially, experimental evaluation demonstrated the pivotal role of GAA in alleviating disease pathology. GAA treatment suppressed the significantly elevated levels of TNF-α and p-MAPK14 in the organoids using a cytokine/LPS-induced IBD model. These findings collectively suggest a potential involvement of GAA in pathways associated with ferroptosis regulation, although direct experimental evidence for ferroptosis markers remains to be established. The observed multi-target effects on immune regulation and cellular proliferation/differentiation provide a foundation for further mechanistic investigation. Full article

Grapevine downy mildew, caused by the oomycete pathogen Plasmopara viticola (P. viticola), is one of the most devastating diseases threatening the global grape industry. The pathogen invades host plants through stomata, triggering a series of highly coordinated physiological disorders and biochemical defense events. This review systematically summarizes the dynamic changes in morphological structures (stomatal characteristics), physiological functions (photosynthesis, membrane system integrity, and carbon metabolism), and multi-level biochemical defense systems (reactive oxygen species (ROS) scavenging enzyme system, phenylpropanoid metabolic pathway, pathogenesis-related proteins, and phenolic compounds) in grapevines following infection. It focuses on analyzing the differences in the timing, intensity, and metabolic reprogramming of defense responses between resistant and susceptible cultivars, pointing out that the essence of disease resistance lies in early pathogen recognition and rapid defense induction. The conflicting conclusions regarding indicators such as soluble sugars, peroxidase (POD), and superoxide dismutase (SOD) are discussed from the perspectives of experimental systems, cultivar genetic backgrounds, and pathogen physiological race differences. Furthermore, the known physiological and biochemical alterations are linked to upstream signaling pathways, including salicylic acid and jasmonic acid (SA/JA), calcium signaling, and mitogen-activated protein kinase (MAPK) cascades. Recent advances in revealing resistance mechanisms in the omics era are also introduced. Finally, future research directions are proposed, including constructing multi-indicator dynamic evaluation models, verifying key gene functions using gene editing, exploring the potential of epigenetic regulation, and developing integrated control strategies combined with microbiome research. This review aims to provide theoretical support for grapevine downy mildew resistance breeding and sustainable disease management. Full article

Inflammaging is defined as chronic low-grade inflammation associated with aging and is increasingly recognized as a dynamic and mechanistically driven biological process rather than a state adequately described by circulating biomarkers alone. Traditional inflammatory markers alone, including interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and C-reactive Protein (CRP), fail to capture the complexity, tissue specificity, and causal architecture of inflammaging. Recent experimental evidence has demonstrated that diverse upstream drivers, including immunosenescence, gut microbiome dysbiosis, metabolic dysfunction, and cellular senescence, converge on a limited number of central inflammatory hubs, including nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, GMP–AMP synthase–stimulator of interferon genes (cGAS–STING), Janus kinase/signal transducer and activator of transcription (JAK/STAT), and p38 mitogen-activated protein kinase (p38 MAPK) signaling. These mechanistic nodes represent promising therapeutic targets, potentially modifiable biological processes, and support the emerging concept of ‘druggable inflammaging’, whereby senotherapeutics, inflammasome inhibitors, innate immune modulators, and metabolic interventions may actively modify aging-associated inflammatory biology rather than simply monitor it through biomarkers. This review highlights a paradigm shift from biomarker-based assessment toward mechanism-based intervention, where inflammaging can be characterized as a modifiable biological process and a central target for precision pharmacological strategies in aging-related diseases. Full article

Early-life factors influence adult-brain vulnerability to sporadic Alzheimer’s disease (AD), but the underlying molecular mechanisms are unknown. In this study, we performed an integrated analysis of mitogen-activated protein kinases (MAPK) pathways’ (ERK1/2, JNK, and p38 MAPK) activity in the hippocampus and prefrontal cortex of OXYS rats (a model of sporadic AD) on postnatal days 3 and 10 (P3 and P10): critical periods of brain maturation. Wistar rats (healthy controls) showed extensive developmental transcriptional remodeling of all MAPK pathways. OXYS rats exhibited alterations, most pronounced in the prefrontal cortex at P3, with the JNK pathway showing the greatest divergence. At the protein level, OXYS rats failed to show the normal age-related increase in hippocampal ERK1/2 phosphorylation and in JNK1/2 levels in both regions, indicating developmental signaling deficits. p38 MAPK remained stable among Wistar and OXYS rats. Thus, delayed brain maturation, which contributes to accelerated brain aging and neurodegeneration in OXYS rats, occurs simultaneously with alterations in MAPK signaling. These aberrations potentially are able to increase brain susceptibility to age-related pathologies later in life. Full article

Background: Progesterone (P4) is used as an antiseizure medication (ASM) to treat catamenial epilepsy, refractory to first-line drugs. P4 and other neurosteroids (NSs) are important regulators of multiple nervous system functions, including neuronal excitability and synaptic plasticity. In addition to their antiseizure properties, P4 and other NSs are also anti-inflammatory agents. Neuroinflammation is an important pathophysiological mechanism of epilepsy refractory to ASMs. Accordingly, we evaluated the ability of P4 to modulate neuroinflammation, using human microglia activated by lipopolysaccharide (LPS). Methods: Human microglia (HMC3) were stimulated for 3 h with LPS in the absence or presence of various concentrations of P4. Thereafter, levels of (i) toll-like receptor 4 (TLR4), (ii) the NLRP3 inflammasome, and (iii) pro-inflammatory cytokines were quantitated by real-time PCR and Western blot analyses. Phagocytic activity was also assessed using a phagocytosis assay employing fluorescent beads. Results: P4 treatment significantly reduced the microglial inflammatory state induced by LPS, which was mediated by upregulation of the TLR4- and NLRP3-axes. The protective effects of P4 were mediated by inhibition of Nuclear Factor kappa-light-chain-enhancer of activated B cells (NFκB) phosphorylation and reduced activation of Mitogen-Activated Protein Kinases (MAPK). The effects of P4 included a significant reduction in mRNA levels of the main pro-inflammatory cytokines and a reduction in phagocytic activity of HMC3. Conclusions: P4 is endowed with significant anti-inflammatory properties, which may be involved in the beneficial effects reported for drug-resistant catamenial epilepsy. Further research is required to clarify P4 post-receptor mechanisms of action and to explore the roles of other P4-derived NSs. Full article

Protein kinases have key roles in cells as they regulate diverse signal transduction pathways. Mitogen-activated protein kinase (MAPK) signaling route modulates several processes, such as cell proliferation, cell programming, metabolic changes and stress responses. Within the group of proteins participating in this pathway, the MAPK kinase (MEK1) is a dimeric, 393-residue-long, dual-specificity protein kinase that phosphorylates both tyrosine and threonine residues. In this study, we explored the conformational changes occurring during the unfolding of MEK1, by using orthogonal biophysical techniques. Intrinsic fluorescence, extrinsic 8-anilinonapthalene-1-sulfonic acid (ANS) fluorescence, dynamic light scattering (DLS), and far-ultraviolet (UV) circular dichroism (CD) showed that the protein acquired a native-like conformation within a narrow pH range (8.0 to 9.0). Urea and guanidinium hydrochloride (GdmCl) denaturations followed by intrinsic and ANS fluorescence and far-UV CD, at pH 8.1, where the protein acquired a native-like conformation, showed that: (i) the apparent conformational stability of isolated MEK1 was low; and (ii) the unfolding occurred through the presence of intermediates. The presence of several unfolding intermediates was also evidenced through: (i) differential scanning calorimetry (DSC) in the absence of the ligand ATP; and (ii) unfolding simulations with the help of computational techniques based on constraint network analysis (CNA). We propose that the apparent low stability of this protein was related to its flexibility and modulates its ability to interact with diverse molecular partners. Full article