Pathogenic fungi synergistically cooperate with Serratia marcescens to increase cockroach mortality.

The abuse of chemical insecticides has led to strong resistance in cockroaches, and biopesticides with active ingredients based on insect pathogens have good development prospects; however, their slow effect has limited their practical application, and improving their effectiveness has become an urgent problem. In this study, the interaction between Serratia marcescens and Metarhizium anisopliae enhanced their virulence against Blattella germanica and exhibited a synergistic effect. The combination of S. marcescens and M. anisopliae caused more severe tissue damage and accelerated the proliferation of the insect pathogen. The results of high-throughput sequencing demonstrated that the gut microbiota was dysbiotic, the abundance of the opportunistic pathogen Weissella cibaria increased, and entry into the hemocoel accelerated the death of the German cockroaches. In addition, the combination of these two agents strongly downregulated the expression of Imd and Akirin in the IMD pathway and ultimately inhibited the expression of antimicrobial peptides (AMPs). S. marcescens released prodigiosin to disrupted the gut homeostasis and structure, M. anisopliae released destruxin to damaged crucial organs, opportunistic pathogen Weissella cibaria overproliferated, broke the gut epithelium and entered the hemocoel, leading to the death of pests. These findings will allow us to optimize the use of insect pathogens for the management of pests and produce more effective biopesticides.

A new cassane diterpenoid from the seed of Caesalpinia sappan.

In this study, a previously undescribed cassane diterpenoid, named caesalpinin JF (1), along with two known cassane diterpenoids caesanine C (2) and tomocinol B (3), was isolated from 95% EtOH extract of the seeds of Caesalpinia sappan Linn. Additionally, three known compounds including pulcherrin R (4), syringaresinol-4'-O-ß-D-glucopyranoside (5) and kaempferol (6) were also identified. The structures of the isolated compounds were elucidated by comprehensive 1D and 2D NMR spectroscopic analyses. Additionally, electronic circular dichroism (ECD) calculation was used to identify the absolute structure of compound 1. Among the isolated compounds, compound 1 displayed a potent anti-neuroinflammation with an IC50 value of 9.87 ± 1.71 µM.

Rethinking therapeutic strategies of dual-target drugs: An update on pharmacological small-molecule compounds in cancer.

Oncogenes and tumor suppressors are well-known to orchestrate several signaling cascades, regulate extracellular and intracellular stimuli, and ultimately control the fate of cancer cells. Accumulating evidence has recently revealed that perturbation of these key modulators by mutations or abnormal protein expressions are closely associated with drug resistance in cancer therapy; however, the inherent drug resistance or compensatory mechanism remains to be clarified for targeted drug discovery. Thus, dual-target drug development has been widely reported to be a promising therapeutic strategy for improving drug efficiency or overcoming resistance mechanisms. In this review, we provide an overview of the therapeutic strategies of dual-target drugs, especially focusing on pharmacological small-molecule compounds in cancer, including small molecules targeting mutation resistance, compensatory mechanisms, synthetic lethality, synergistic effects, and other new emerging strategies. Together, these therapeutic strategies of dual-target drugs would shed light on discovering more novel candidate small-molecule drugs for the future cancer treatment.

Ethanol Extract of Limonium bicolor Improves Dextran Sulfate Sodium-Induced Ulcerative Colitis by Alleviating Inflammation and Restoring Gut Microbiota Dysbiosis in Mice.

Ulcerative colitis (UC) is a kind of inflammatory bowel condition characterized by inflammation within the mucous membrane, rectal bleeding, diarrhea, and pain experienced in the abdominal region. Existing medications for UC have limited treatment efficacy and primarily focus on symptom relief. Limonium bicolor (LB), an aquatic traditional Chinese medicine (TCM), exerts multi-targeted therapeutic effects with few side effects and is used to treat anemia and hemostasis. Nevertheless, the impact of LB on UC and its mechanism of action remain unclear. Therefore, the objective of this study was to investigate the anti-inflammatory effects and mechanism of action of ethanol extract of LB (LBE) in lipopolysaccharide-induced RAW 264.7 macrophages and dextran sulfate sodium (DSS)-induced UC. The results showed that LBE suppressed the secretion of cytokines in LPS-stimulated RAW 264.7 cells in a dose-dependent manner. LBE had protective effects against DSS-induced colitis in mice, decreased the disease activity index (DAI) score, alleviated symptoms, increased colon length, and improved histological characteristics, thus having protective effects against DSS-induced colitis in mice. In addition, it reversed disturbances in the abundance of proteobacteria and probiotics such as Lactobacillus and Blautia in mice with DSS-induced UC. Based on the results of network pharmacology analysis, we identified four main compounds in LBE that are associated with five inflammatory genes (Ptgs2, Plg, Ppar-γ, F2, and Gpr35). These results improve comprehension of the biological activity and functionality of LB and may facilitate the development of LB-based compounds for the treatment of UC.

Two new cassane diterpenoids from the seed kernels of Caesalpinia sinensis.

Two new cassane diterpenoids, sucupiranin MN (1) and sucupiranin ML (2), together with two known compounds sucutinirane C (3) and deacetylsucutinirane C (4) were isolated from the seed kernels of Caesalpinia sinensis. Their structures were elucidated by means of analysis of comprehensive spectroscopic data, especially HRESIMS and 1D/2D NMR spectroscopy. Compounds 1-4 are typical furan-type cassane derivatives with an aromatized C ring. Biological evaluation revealed that compounds 1-4 at the concentration of 10 µM could inhibit the overproduction of NO in LPS-stimulated RAW 264.7 macrophages.

Discovery of potential components characteristic by conjugated enone from the branches and leaves of Croton lauioides with anti-neuroinflammatory activity via regulating the NF-κB pathway.

In this study, the chemical composition and pharmacological activity of Croton lauioides were investigated for the first time. The bioactive and HPLC-UV guided isolation led to the discovery of twenty-three conjugated enone-type components (1-23), including nine previously unknown sesquiterpenoid derivatives (1-4, 9-10, 12-14). Notably, compounds 1 and 12 are epoxides containing an endoperoxide bridge (1) or a unique dioxaspiro core (12), respectively. Compounds 2-7 are non-benzenoid aromatics featuring a tropone function, while 9-11 possess a rare rearranged scaffold with tropone shift into benzene. Extensive characterization was performed using NMR spectra, HRESIMS data, and electronic circular dichroism (ECD) calculations. Furthermore, we evaluated the bioactivities of all isolated compounds against neuroinflammation in LPS-stimulated BV-2 microglial cells. Remarkably, most sesquiterpenoid derivatives exhibited significant NO inhibit activities, and compound 5 showed the most potent effect with an IC50 value of 0.14 ± 0.04 µM. Structure-activity relationship (SAR) analysis revealed that sesquiterpenoids modified with endocyclic enone conjugation may serve as a key pharmacophore for NO inhibition, particularly involving aromatic tropone moiety. The qPCR and Western blot results demonstrated that 5 exerted an inhibitory effect on the mRNA levels of iNOS, TNF-α and COX-2 in a time-dependent manner, as well as suppressed the protein expression of iNOS, TNF-α, COX-2. In mechanism, 5 could prevented activation of NF-κB pathway by suppressing phosphorylation of p65 and IκB-α. These findings revealed C. lauioides might be a promising resource for drug candidate development targeting neuroinflammation.

A cuticular protein, BgCPLCP1, contributes to insecticide resistance by thickening the cockroach endocuticle.

Overuse of insecticides has led to severe environmental problems. Insect cuticle, which consists mainly of chitin, proteins and a thin outer lipid layer, serves multiple functions. Its prominent role is as a physical barrier that impedes the penetration of xenobiotics, including insecticides. Blattella germanica (L.) is a major worldwide indoor pest that causes allergic disease and asthma. Extensive use of pyrethroid insecticides, including ß-cypermethrin, has selected for the rapid and independent evolution of resistance in cockroach populations on a global scale. We demonstrated that BgCPLCP1, the first CPLCP (cuticular proteins of low complexity with a highly repetitive proline-rich region) family cuticular protein in order Blattodea, contributes to insecticide penetration resistance. Silencing BgCPLCP1 resulted in 85.0 %-85.7 % and 81.0 %-82.0 % thinner cuticle (and especially thinner endocuticle) in the insecticide-susceptible (S) and ß-cypermethrin-resistant (R) strains, respectively. The thinner and more permeable cuticles resulted in 14.4 % and 20.0 % lower survival of ß-cypermethrin-treated S- and R-strain cockroaches, respectively. This study advances our understanding of cuticular penetration resistance in insects and opens opportunities for the development of new efficiently and environmentally friendly insecticides targeting the CPLCP family of cuticular proteins.

Marine toxins in seafood: Recent updates on sample pretreatment and determination techniques.

Marine toxins can lead to varying degrees of human poisoning, often resulting in fatal symptoms and causing significant economic losses in seafood-producing regions. To gain a deeper comprehension of the role of marine toxins in seafood and their impact on the environment, it is imperative to develop rapid, cost-effective, environmentally friendly, and efficient methods for sample pretreatment and determination to mitigate adverse impacts of marine toxins. This review presents a comprehensive overview of advancements made in sample pretreatment and determination techniques for marine toxins since 2017. The advantages and disadvantages of various technologies were critically examined. Additionally, the current challenges and future development strategies for the analysis of marine toxins are provided.

Discovery of new triterpenoids from Leptopus clarkei and their antiproliferative activity on cancer cells.

Two new triterpenoids (1-2), along with six known analogues (3-8) were obtained from the dried whole plant of Leptopus clarkei. Compound 1 is a 3,4-seco-lupane-type triterpenoid, and compound 2 is a phenylpropanoid-conjugated pentacyclic triterpenoid possessing trans-p-coumaroyl unit attached to oleanane-type skeleton. This is the first report on chemical investigation of the L. clarkei, and the triterpenoid derivatives were found in this plant for the first time. The structures of the new compounds were unequivocally elucidated by HRESIMS and 1D/2D NMR data. Additionally, the isolated compounds were evaluated for theircytotoxicities against four cancer cell lines including HepG2, MCF-7, A549 and HeLa. Notably, compound 2 exhibited the most significant antiproliferative activity with IC50 less than 20 µM for four cancer lines.

Transcriptome analysis revealed that short-term stress in Blattella germanica to ß-cypermethrin can reshape the phenotype of resistance adaptation.

Previous studies on insect resistance have primarily focused on resistance monitoring and the molecular mechanisms involved, while overlooking the process of phenotype formation induced by insecticide stress. In this study, we compared the expression profiles of a beta-cypermethrin (ß-CYP) resistant strain (R) and a susceptible strain (S) of Blattella germanica after ß-CYP induction using transcriptome sequencing. In the short-term stress experiment, we identified a total of 792 and 622 differentially expressed genes (DEGs) in the S and R strains. Additionally, 893 DEGs were identified in the long-term adaptation experiment. To validate the RNA-Seq data, we performed qRT-PCR on eleven selected DEGs, and the results were consistent with the transcriptome sequencing data. These DEGs exhibited down-regulation in the short-term stress group and up-regulation in the long-term adaptation group. Among the validated DEGs, CUO8 and Cyp4g19 were identified and subjected to knockdown using RNA interference. Subsequent insecticide bioassays revealed that the mortality rate of cockroaches treated with ß-CYP increased by 69.3% and 66.7% after silencing the CUO8 and Cyp4g19 genes (P<0.05). Furthermore, the silencing of CUO8 resulted in a significant thinning of the cuticle by 59.3% and 53.4% (P<0.05), as observed through transmission electron microscopy and eosin staining, in the S and R strains, respectively. Overall, our findings demonstrate that the phenotypic plasticity in response to short-term stress can reshape the adaptive mechanisms of genetic variation during prolonged exposure to insecticides. And the identified resistance-related genes, CUO8 and Cyp4g19, could serve as potential targets for controlling these pest populations.

Effects of Environmental and Non-Environmental Factors on Dynamic Photosynthetic Carbon Assimilation in Leaves under Changing Light.

Major research on photosynthesis has been carried out under steady light. However, in the natural environment, steady light is rare, and light intensity is always changing. Changing light affects (usually reduces) photosynthetic carbon assimilation and causes decreases in biomass and yield. Ecologists first observed the importance of changing light for plant growth in the understory; other researchers noticed that changing light in the crop canopy also seriously affects yield. Here, we review the effects of environmental and non-environmental factors on dynamic photosynthetic carbon assimilation under changing light in higher plants. In general, dynamic photosynthesis is more sensitive to environmental and non-environmental factors than steady photosynthesis, and dynamic photosynthesis is more diverse than steady photosynthesis. Finally, we discuss the challenges of photosynthetic research under changing light.

Room-temperature synthesis of imine-linked magnetic covalent organic polymers in deep eutectic solvents for the extraction of flavonoids and their determination with HPLC-MS/MS.

A novel imine-linked magnetic covalent organic polymer, Fe3O4@TAB-TFPT, was synthesized using environmentally friendly deep eutectic solvents as the reaction medium instead of conventional organic solvents. The materials were characterized by scanning electron microscope (SEM), transmission electron microscopy (TEM), FT-IR, N2 adsorption-desorption isotherms, energy dispersive spectrometer (EDS), X-ray photoelectron spectra (XPS), and thermo gravimetric analysis (TGA). Subsequently, the materials were employed as an adsorbent for magnetic solid-phase extraction (MSPE) of flavonoids, including Kurarinone, Norkurarinone, Xanthohumol, and Isoxanthohumol, prior to their determination by HPLC-MS/MS. The validation results demonstrate good linearity within the concentration range 0.1-1000 ng∙mL-1 (R2 ≥ 0.9963), high enrichment factors ranging from 18.9 to 30.7, and low LODs (0.01-0.05 ng∙mL-1) and LOQs (0.05-0.1 ng∙mL-1). Furthermore, recoveries between 80.60% and 108.40% with relative standard deviations ≤ 8.49% were achieved. The proposed MSPE-HPLC-MS/MS method was successfully applied to the determination of flavonoids in Sophora flavescens Aition sample.

Ramulus Cinnamomi essential oil exerts an anti-inflammatory effect on RAW264.7 cells through N-acylethanolamine acid amidase inhibition.

ETHNOPHARMACOLOGICAL RELEVANCE: Ramulus Cinnamomi, the dried twig of Cinnamomum cassia (L.) J.Presl., is a traditional Chinese medicine (TCM) with anti-inflammatory effects. The medicinal functions of Ramulus Cinnamomi essential oil (RCEO) have been confirmed, although the potential mechanisms by which RCEO exerts its anti-inflammatory effects have not been fully elucidated. AIM OF THE STUDY: To investigate whether N-acylethanolamine acid amidase (NAAA) mediates the anti-inflammatory effects of RCEO. MATERIALS AND METHODS: RCEO was extracted by steam distillation of Ramulus Cinnamomi, and NAAA activity was detected using HEK293 cells overexpressing NAAA. N-Palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA), both of which are NAAA endogenous substrates, were detected by liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The anti-inflammatory effects of RCEO were analyzed in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, and the cell viability was measured with a Cell Counting Kit-8 (CCK-8) kit. The nitric oxide (NO) in the cell supernatant was measured using the Griess method. The level of tumor necrosis factor-α (TNF-α) in the RAW264.7 cell supernatant was determined using an enzyme-linked immunosorbent assay (ELISA) kit. The chemical composition of RCEO was assessed by gas chromatography-mass spectroscopy (GC-MS). The molecular docking study for (E)-cinnamaldehyde and NAAA was performed by using Discovery Studio 2019 software (DS2019). RESULTS: We established a cell model for evaluating NAAA activity, and we found that RCEO inhibited the NAAA activity with an IC50 of 5.64 ± 0.62 µg/mL. RCEO significantly elevated PEA and OEA levels in NAAA-overexpressing HEK293 cells, suggesting that RCEO might prevent the degradation of cellular PEA and OEA by inhibiting the NAAA activity in NAAA-overexpressing HEK293 cells. In addition, RCEO also decreased NO and TNF-α cytokines in lipopolysaccharide (LPS)-stimulated macrophages. Interestingly, the GC-MS assay revealed that more than 93 components were identified in RCEO, of which (E)-cinnamaldehyde accounted for 64.88%. Further experiments showed that (E)-cinnamaldehyde and O-methoxycinnamaldehyde inhibited NAAA activity with an IC50 of 3.21 ± 0.03 and 9.62 ± 0.30 µg/mL, respectively, which may represent key components of RCEO that inhibit NAAA activity. Meanwhile, docking assays revealed that (E)-cinnamaldehyde occupies the catalytic cavity of NAAA and engages in a hydrogen bond interaction with the TRP181 and hydrophobic-related interactions with LEU152 of human NAAA. CONCLUSIONS: RCEO showed anti-inflammatory effects by inhibiting NAAA activity and elevating cellular PEA and OEA levels in NAAA-overexpressing HEK293 cells. (E)-cinnamaldehyde and O-methoxycinnamaldehyde, two components in RCEO, were identified as the main contributors of the anti-inflammatory effects of RCEO by modulating cellular PEA levels through NAAA inhibition.

Identification of Daphne genkwa and Its Vinegar-Processed Products by Ultraperformance Liquid Chromatography-Quadrupole Time-of-Flight Mass Spectrometry and Chemometrics.

Crude herbs of Daphne genkwa (CHDG) are often used in traditional Chinese medicine to treat scabies baldness, carbuncles, and chilblain owing to their significant purgation and curative effects. The most common technique for processing DG involves the use of vinegar to reduce the toxicity of CHDG and enhance its clinical efficacy. Vinegar-processed DG (VPDG) is used as an internal medicine to treat chest and abdominal water accumulation, phlegm accumulation, asthma, and constipation, among other diseases. In this study, the changes in the chemical composition of CHDG after vinegar processing and the inner components of the changed curative effects were elucidated using optimized ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF-MS). Untargeted metabolomics, based on multivariate statistical analyses, was also used to profile differences between CHDG and VPDG. Eight marker compounds were identified using orthogonal partial least-squares discrimination analysis, which indicated significant differences between CHDG and VPDG. The concentrations of apigenin-7-O-ß-d-methylglucuronate and hydroxygenkwanin were considerably higher in VPDG than those in CHDG, whereas the amounts of caffeic acid, quercetin, tiliroside, naringenin, genkwanines O, and orthobenzoate 2 were significantly lower. The obtained results can indicate the transformation mechanisms of certain changed compounds. To the best of our knowledge, this study is the first to employ mass spectrometry to detect the marker components of CHDG and VPDG.

An efficient method for identifying natural common homoisoflavonoid by 1H-NMR.

Homoisoflavone contains 16 carbon atoms in the skeleton. The homoisoflavonoid skeleton from natural products can be roughly divided into 13 kinds, among which 5 kinds of common skeletons contain a large amount of compounds and 8 kinds of abnormal skeletons comprise a small amount of compounds. In this article, the structure identification experience of homoisoflavonoids found in Caesalpinia mimosoides was used as references and an efficient 1H NMR spectroscopic method for identifying homoisoflavonoid structure has been established. Using the chemical shift differences of H-2, 3, 4 and 9, the common natural homoisoflavonoids can be quickly and conveniently determined.

Guided Isolation of New Cytotoxic Cassane Diterpenoids from Caesalpinia sappan.

Guided by an MS/MS-based molecular networking, six undescribed cassane diterpenoids and three known ones were isolated and identified from the seeds of Caesalpinia sappan. Their structures were unequivocally elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. Cytotoxic evaluation showed that phanginin JA exhibited significant antiproliferative activities against human non-small cell lung cancer (A549) cells with IC50 values of 16.79±0.83 µM. Further flow cytometry analysis revealed that phanginin JA could exert apoptotic effect of A549 cells by arresting cell cycle in G0/G1 phase.

The attenuation effect of licorice on the hepatotoxicity of Euodiae Fructus by inhibiting the formation of protein conjugates and GSH depletion.

ETHNOPHARMACOLOGICAL RELEVANCE: As a traditional Chinese medicine and food, Euodiae Fructus (EF) is widely used in clinics to relieve pain and prevent vomiting and for making tea for more than a thousand years. In recent years, hepatotoxic reactions to EF have been reported. The intermediates produced by evodiamine and rutaecarpine metabolism in vitro were captured by glutathione (GSH), suggesting that the toxicity of EF may be related to metabolic activation. Whether licorice can inhibit the metabolic activation of EF has not been reported, which needed an effective strategy to clarify the correlation between protein conjugates and hepatotoxicity and the attenuation mechanism of licorice processing. AIM OF THE STUDY: This study aimed to explore the toxic components and mechanisms of EF based on metabolic activation and the detoxification of licorice. MATERIALS AND METHODS: The content and toxicity index of protein conjugates in the liver were determined by orally administering mice and rats with EF. The attenuation mechanism of licorice was examined in cell and enzymology experiments. RESULTS: The change in evodiamine-cysteinylglycine (EVO-Cys-Gly) and evodiamine-cysteine (EVO-Cys) levels was consistent with the change in hepatotoxicity. Licorice inhibited the formation of the protein conjugates of EF and increased the content of GSH in L02 cells. CONCLUSION: EF mediated by P450 enzymes produced toxic intermediates, which combined with cysteine residues in animal liver and inactivate them, leading to hepatotoxicity. Interestingly, licorice can alleviate the GSH depletion caused by EF and inhibit the production of protein conjugates by inhibiting P450 enzymes.

Sertaconazole nitrate targets IDO1 and regulates the MAPK signaling pathway to induce autophagy and apoptosis in CRC cells.

Colorectal cancer (CRC) has become the third most frequently occurring malignant tumor worldwide. It is vital to identify novel, effective targeted treatments while considering side effects and drug resistance in the clinic. Recently, the tryptophan-metabolizing enzyme indole-2, 3-dioxygenase 1 (IDO1) has been widely reported to be overexpressed in CRC, indicating that blocking IDO1 with small-molecule inhibitors may be a promising approach to CRC treatment. In this study, the antifungal drug sertaconazole nitrate (STZ) was repurposed and showed antitumor activity, and therefore, its anticancer effect was further investigated in CRC cells. The SwissTargetPrediction analysis indicated that STZ binding to IDO1 was significantly and highly probable, and STZ was found to downregulate IDO1 in CRC cells in a dose-dependent manner. STZ exhibited considerable antiproliferative activity and induced apoptosis and autophagy in HCT116 and RKO cells. Moreover, based on an RNA-seq analysis, STZ was shown to regulate signal transducer and activator of transcription 3 (STAT3) and the mitogen-activated protein kinase (MAPK) signaling pathways. We discovered that STZ suppressed tumor growth in an HCT116 nude mouse xenograft tumor model without causing evident cytotoxicity. In conclusion, our results reveal that STZ induces antitumor effects in CRC by inhibiting IDO1-modulated autophagy and apoptosis, providing a clue for repurposing STZ as a novel and potentially effective candidate medication for the future treatment of CRC.

Photosynthetic mechanism of maize yield under fluctuating light environments in the field.

The photosynthetic mechanism of crop yields in fluctuating light environments in the field remains controversial. To further elucidate this mechanism, we conducted field and simulation experiments using maize (Zea mays) plants. Increased planting density enhanced the light fluctuation frequency and reduced the duration of daily high light, as well as the light-saturated photosynthetic rate, biomass, and yield per plant. Further analysis confirmed a highly significant positive correlation between biomass and yield per plant and the duration of photosynthesis related to daily high light. The simulation experiment indicated that the light-saturated photosynthetic rate of maize leaves decreased gradually and considerably when shortening the daily duration of high light. Under an identical duration of high light exposure, increasing the fluctuation frequency decreased the light-saturated photosynthetic rate slightly. Proteomic data also demonstrated that photosynthesis was mainly affected by the duration of high light and not by the light fluctuation frequency. Consequently, the current study proposes that an appropriate duration of daily high light under fluctuating light environments is the key factor for greatly improving photosynthesis. This is a promising mechanism by which the photosynthetic productivity and yield of maize can be enhanced under complex light environments in the field.

A plant-derived glucocorticoid receptor modulator with potency to attenuate the side effects of glucocorticoid therapy.

BACKGROUND AND PURPOSE: Continuous efforts have been made to move towards maintaining the beneficial anti-inflammatory functions of glucocorticoids (GCs) while minimizing side effects. Here, we investigated the selective glucocorticoid receptor (GR) modulator-like properties of a plant-derived compound caesaldekarin e (CA-e). EXPERIMENTAL APPROACH: The therapeutic efficacy of CA-e was evaluated in several mouse models, including dextran sulfate sodium-induced colitis, ovalbumin-induced lung allergic inflammation, imiquimod-induced psoriasis-like skin inflammation and skin atrophy. The action of CA-e targeting the GR was analysed using molecular docking, cellular thermal shift assays and microscale thermophoresis. Other methods included DNA-protein pull-down assays and mass spectrometry. KEY RESULTS: CA-e selectively inhibited positive GC response element ((+) GRE)-mediated direct transactivation while maintaining and even enhancing the anti-inflammatory effects of treatment with dexamethasone. CA-e, alone and in combination with dexamethasone, efficiently alleviated inflammation in several mouse models with milder side effects compared with dexamethasone alone. Mechanistically, CA-e inhibited the formation of dimers by binding to the dimerization interface located in the ligand-binding domain of GR and facilitated embryonic ectoderm development that is involved in the regulation of transcriptional repression to compete for binding to (+) GRE, eventually leading to the repression of (+) GRE-regulated genes. In addition, CA-e repressed NF-κB-dependent genes by enhancing the interaction between GR and p65. CONCLUSIONS AND IMPLICATIONS: Our results reveal that CA-e is a novel GR modulator with strong potency to attenuate the side effects of GC therapy and can be used as a potential molecular tool for deciphering GR signalling.