Predictive modeling for postoperative delirium in elderly patients with abdominal malignancies using synthetic minority oversampling technique

BACKGROUND Postoperative delirium,particularly prevalent in elderly patients after abdominal cancer surgery,presents significant challenges in clinical management.AIM To develop a synthetic minority oversampling technique(SMOTE)-based model for predicting postoperative delirium in elderly abdominal cancer patients.METHODS In this retrospective cohort study,we analyzed data from 611 elderly patients who underwent abdominal malignant tumor surgery at our hospital between September 2020 and October 2022.The incidence of postoperative delirium was recorded for 7 d post-surgery.Patients were divided into delirium and non-delirium groups based on the occurrence of postoperative delirium or not.A multivariate logistic regression model was used to identify risk factors and develop a predictive model for postoperative delirium.The SMOTE technique was applied to enhance the model by oversampling the delirium cases.The model’s predictive accuracy was then validated.RESULTS In our study involving 611 elderly patients with abdominal malignant tumors,multivariate logistic regression analysis identified significant risk factors for postoperative delirium.These included the Charlson comorbidity index,American Society of Anesthesiologists classification,history of cerebrovascular disease,surgical duration,perioperative blood transfusion,and postoperative pain score.The incidence rate of postoperative delirium in our study was 22.91%.The original predictive model(P1)exhibited an area under the receiver operating characteristic curve of 0.862.In comparison,the SMOTE-based logistic early warning model(P2),which utilized the SMOTE oversampling algorithm,showed a slightly lower but comparable area under the curve of 0.856,suggesting no significant difference in performance between the two predictive approaches.CONCLUSION This study confirms that the SMOTE-enhanced predictive model for postoperative delirium in elderly abdominal tumor patients shows performance equivalent to that of traditional methods,effectively addressing data imbalance.

Targeting CXCR4 and EDN1 for the treatment of recurrent miscarriage using stearic acid from traditional Chinese medicine

Background:Recurrent miscarriage(RM)affects an estimated 1-3%of couples attempting to conceive,and its molecular components stay ineffectively caught on.This study aims to explore potential therapeutic targets for RM by examining gene expression patterns and biological pathways in both mouse and human RM models.Meanwhile,explore relevant traditional Chinese medicine(TCM)components targeting potential therapeutic targets.Methods:We utilized the GSE211251 mouse and the GSE26787 human datasets,employing gene set enrichment analysis and gene metaphysics analysis to examine differentially expressed genes and enriched pathways.Single-cell RNA analysis uncovered cellular heterogeneity and arranged pharmacology-mapped potential drug-target intelligence.We employed molecular docking strategies to assess the affinity of TCM components for key proteins.Results:In the mouse model,genes such as Ly6f1 and Gpr26 were upregulated,while Stc5a and Galca exhibited downregulation.Gene set enrichment analysis identified key pathways,including the tumor necrosis factor-mediated signaling pathway.In human samples,Gene Ontology analysis highlighted processes such as apoptosis and cell adhesion.Single-cell RNA analysis revealed distinct cellular populations between normal and RM samples.Systems pharmacology identified C-X-C motif chemokine receptor 4(CXCR4)and endothelin 1(EDN1)as potential key targets,and molecular docking confirmed that stearic acid from TCM appears to regulate these proteins.Conclusion:This study presents a comprehensive analysis of the genetic and cellular underpinnings of RM,identifying CXCR4 and EDN1 as promising therapeutic targets.Stearic acid from TCM could provide targeted treatment by modulating these key proteins,paving the way for new RM treatment strategies.

微创青光眼手术的新进展

微创青光眼手术(micro invasive glaucoma surgery,MIGS)是新兴的一类青光眼手术,与传统小梁切除术相比,手术并发症相对少。MIGS按降眼压原理分为三类:减少房水生成术(如内窥镜下激光睫状体光凝术,高强度聚焦超声睫状体成形术),外引流手术(如EX-PRESS微型引流钉植入术,Schlemm管成形术),内引流手术(如小梁网微分流支架iStent植入术,内路小梁消融术)。本文将对近年MIGS的优缺点及适应证进行简单综述。

体外受精-胚胎移植超促排卵周期中金属蛋白酶3、肿瘤坏死因子、血管内皮生长因子的表达与卵巢反应性的研究

目的分析在体外受精-胚胎移植(IVF-ET)超促排卵周期中不孕妇女血清及卵泡液中的金属蛋白酶3(MMP-3)、肿瘤坏死因子(TNF)、血管内皮生长因子(VEGF)的表达,了解MMP-3、VEGF及TNF在其中的分布特点,分析其与卵巢反应的相关性。方法收集2013年3月-2015年10月行IVF-ET治疗的413例超促排卵周期的患者,不孕原因均为输卵管因素,年龄22~38岁,依据患者获卵数分为高反应组(获卵数≥20个)、正常反应组(获卵数6~19个)及低反应组(获卵数≤5个),分别用酶联免疫方法测定各组在促性腺激素(Gn)起始注射日、绒毛膜促性腺激素(h CG)注射日血清及卵泡液中VEGF、TNF及MMP-3的水平,分析组间的差异。结果在3组患者的基本情况差异无统计学意义的情况下:(1)3组患者h CG日血清MMP-3和VEGF的表达均高于Gn启动日(P<0.05);(2)3组患者h CG日血清中TNF的表达低于Gn启动日(P<0.05);(3)高反应组患者卵泡液中MMP-3的表达均高于正常反应组和低反应组(P<0.05);(4)高反应组患者卵泡液中VEGF和TNF的表达均低于正常反应组和低反应组。(P<0.05)。结论 (1)随着促排卵过程中卵泡的发育,血清中VEGF和MMP-3的表达增多,TNF则随着卵泡的发育逐渐减少;(2)经超排卵后患者卵泡液中MMP-3表达与卵巢反应呈正相关,而VEGF和TNF与卵巢反应呈负相关。

c.822＋126T〉G/C：a novel triallelic polymorphism of the TSSK6 gene associated with spermatogenic impairment in a Chinese population

TSSK6 is a member of the testis-specific serine/threonine kinase family. Male Tssk6 knockout mice are infertile owing to sperrnatogenic impairment,including sperm count reduction,a decrease in motile sperm number and motility rates,and an increase in the number of sperms with abnormal morphology. We investigated the possible association between variations oftbe TSSK6 gene and spermatogenic impairment in humans. Mutation screening of TSSK6 was carried out in 519 patients with azoospermia （n = 273） or severe oligozoospermia （n = 246） and in 359 controls with normozoospermia by denaturing high-performance liquid chromatography and DNA sequencing. The frequencies of alleles and genotypes of gene polymorphism were compared between patients and controls. A novel triallelic polymorphism in TSSK6,c.822＋126T〉G/C,was identified. The frequencies of genotype TT and allele T were increased dramatically in infertile patients compared with controls,whereas genotype TG,allele G and allele C frequencies were significantly higher in controls than in patients. Further study revealed that the allele C frequency of controls was remarkably higher than that of patients with oligospermia. Our findings,for the first time,suggested an association of c.822＋I26T〉G/C in TSSK6 with spermatogenic impairment in humans in which allele T may be a risk factor for male infertility,while alleles C and G may decrease susceptibility to male infertility.

On-line near-infrared spectroscopy optimizing and monitoring biotransformation process of γ-aminobutyric acid

Near-infrared spectroscopy （NIRS） with its fast and nondestructive advantages can be qualified for the real-time quantitative analysis. This paper demonstrates that NIRS combined with partial least squares （PLS） regression can be used as a rapid analytical method to simultaneously quantify L-glutamic acid （L- GIu） and γ-aminobutyric acid （GABA） in a biotransformation process and to guide the optimization of production conditions when the merits of NIRS are combined with response surface methodology. The high performance liquid chromatography （HPLC） reference analysis was performed by the o-phthaldialdehyde pre-column derivatization. NIRS measurements of two batches of 141 samples were firstly analyzed by PLS with several spectral pre-processing methods. Compared with those of the HPLC reference analysis, the resulting determination coefficients （R2）, root mean square error of prediction （RMSEP） and residual predictive deviation （RPD） of the external validation for the L-GIu concentration were 99.5%, 1.62 g/L, and 11.3, respectively. For the GABA concentration, R2, RMSEP, and RPD were 99.8%, 4.00 g/L, and 16.4, respectively. This NIRS model was then used to optimize the biotransformation process through a Box- Behnken experimental design. Under the optimal conditions without pH adjustment, 200 gjL L-GIu could be catalyzed by 7148 U/L glutamate decarboxylase （GAD） to GABA, reaching 99% conversion at the fifth hour. NIRS analysis provided timely information on the conversion from L-GIu to GABA. The results suggest that the NIRS model can not only be used for the routine profiling of enzymatic conversion, providing a simple and effective method of monitoring the biotransformation process of GABA, but also be considered to be an optimal tool to guide the optimization of production conditions.

Crystallographic and magnetic properties of van der Waals layered FePS_3 crystal

The crystallographic and magnetic properties are presented for van der Waals antiferromagnetic FePS_3. High-quality single crystals of millimeter size have been successfully synthesized through the chemical vapor transport method. The layered structure and cleavability of the compound are apparent, which are beneficial for a potential exploration of the interesting low dimensional magnetism, as well as for incorporation of FePS_3 into van der Waals heterostructures. For the sake of completeness, we have measured both direct current(dc) and alternating current(ac) magnetic susceptibility.The paramagnetic to antiferromagnetic transition occurs at approximately T_N 115 K. The effective moment is larger than the spin-only effective moment, suggesting that an orbital contribution to the total angular momentum of the Fe^(2+) could be present. The ac susceptibility is independent of frequency, which means that the spin freezing effect is excluded.Strong anisotropy of out-of-plane and in-plane susceptibility has been shown, demonstrating the Ising-type magnetic order in FePS_3 system.

Sensitivity enhancement of WS2-coated SPR-based optical fiber biosensor for detecting glucose concentration

In this paper,we propose a theoretical model of the surface plasmon resonance-based optical fiber biosensor for detecting glucose concentration.The Au/ZnO/WS2 multilayer film is coated around optical fiber.Compared with the conventional surface plasmon resonance sensor,WS2 material can increase the sensitivity of the biosensor.The absorption capacity of WS2 is used to load glucose oxidase by forming a sensitive area to recognize glucose.Refractive index of the solution is calculated and then the concentration of the glucose can be obtained by the correspondence between refractive index and glucose concentration.The highest sensitivity of the SPR biosensor with a structure of 40-nm Au/5-nm ZnO/14 layers of WS2 is 4310 nm/RIU.The proposed WS2-based SPR fiber biosensor has a unique effect on the detection of glucose concentration.It is expected to have potential applications in future medical blood glucose concentration detection.

Research Status of Preemptive Analgesia and its Application in Clinical Anesthesia

The most effective treatment for postoperative pain is to reduce it by preventing or reducing the sensitivity and sensory disturbance on the central nervous system during the operation,prolonging the pain-relief time and reducing the use of analgesics.Preemptive analgesia refers to the intervention of central neuraxis sensitization and peripheral sensitization to prevent the expansion and spread of pain,so as to achieve postoperative pain-relief.In postoperative patient-controlled analgesia,preemptive analgesia has become a common treatment method for anesthesiologists.However,the clinical specifications for advanced analgesia are still lacking.Based on this,this paper reviews the use of advanced analgesia drugs and their clinical applications.

Effects of Surgical Anesthesia on Postoperative Cognitive Function of Elderly Patients

Postoperative cognitive dysfunction in elderly patients is a common complication after surgical anesthesia.The occurrence of complications is also related to many other factors,and the cause is still unclear.This paper reviews the influencing factors and corresponding measures for postoperative cognitive function of elderly patients caused by anesthesia.

Ethnopharmacology,phytochemistry,pharmacology and product application of Platycodon grandiflorum:A review

Platycodonis Radix(Jiegeng in Chinese)is a well-known traditional Chinese medicine used for both medicinal and culinary purposes.Its historical use as an antitussive and expectorant has been extensively documented.Researchers,to date,have identified 219 chemical constituents in Platycodon grandiflorum(Jacq.)A.DC,encompassing 89 saponins,11 flavonoids,21 polysaccharides,14 phenolic acids,six polyacetylenes,five sterols,34 fatty acids,17 amino acids,and 22 trace elements.Jiegeng exhibits diverse pharmacological effects,including antitussive and anti-phlegm properties,anti-cancer activity,anti-inflammatory effects,immune regulation,antioxidant properties,anti-obesity,and antidiabetic effects.Additionally,Jiegeng shows potential in protecting the heart and liver.Beyond its medicinal benefits,Jiegeng is highly esteemed in culinary applications,and its global demand is on the rise.Its utilization has expanded beyond medicine and food to encompass daily necessities,cosmetics,agricultural supplies,and other fields.Currently,there are 18272 patents related to P.grandiflorum.This comprehensive review summarizes the latest research published over the past 20 years,providing a robust foundation for further exploration of the medicinal and health benefits of P.grandiflorum.

Förster resonance energy transfer reveals phillygenin and swertiamarin concurrently target AKT on different binding domains to increase the anti-inflammatory effect

The clinical benefit of combination therapy is significant,but it is not easy to define the mechanism of complexity and diversity.Previous studies illustrate that phillygenin(Phi)binds in the allosteric inhibit pocket of protein kinase B(AKT),and swertiamarin(Swe)acts on the pleckstrin homology(PH)domain of AKT.However,the combined synergistic effect of relieving the inflammatory response has yet to be elucidated.Based on high sensitivity,specificity and fast-responsibility fluorescent sensors,the Förster resonance energy transfer(FRET)technique offers a route to provide clear insights into physiological and pathological processes.In the study,molecular docking,the fluorescent probes of Phi and Swe for FRET were designed and synthesized.FRET analysis shown that Swe and Phi concurrently acted on the PH domain and allosterically inhibited pocket of AKT,respectively.The combination of Swe and Phi significantly increased the heat stability of AKT and decreased protease-induced degeneration.In lipopolysaccharides(LPS)-induced mice and cells,the combination arrested AKT activation,nuclear factor kappa-B(NF-κB)phosphorylation,and the expression of tumor necrosis factor-α(TNF-α),interleukin(IL)-6 and IL-8.In conclusion,FRET revealed Phi and Swe concurrently targeted AKT on different domains and the combination of Phi and Swe enhanced the anti-inflammatory effect.

Branched-chain amino acid transaminase 1 confers EGFRTKI resistance through epigenetic glycolytic activation

Third-generation EGFR tyrosine kinase inhibitors(TKIs),exemplified by osimertinib,have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer(NSCLC).Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application(NDA)submission in China.Despite substantial progress,acquired resistance to EGFR-TKIs remains a significant challenge,impeding the long-term effectiveness of therapeutic approaches.In this study,we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models,and found a notable upregulation of branched-chain amino acid transaminase 1(BCAT1)expression in both osimertinib-and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors.Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs.Mechanistically,upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid(BCAA)metabolism and promoted alpha ketoglutarate(α-KG)-dependent demethylation of lysine 27 on histone H3(H3K27)and subsequent transcriptional derepression of glycolysis-related genes,thereby enhancing glycolysis and promoting tumor progression.Moreover,we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression.In summary,our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC,thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Male reproductive system and simulated high-altitude environment:preliminary results in rats

This study assessed the effects of a simulated high-altitude environment on the reproductive system of prepubertal male rats and the reversibility of these effects upon return to a normal environment.Three-week-old male Wistar rats were randomly allocated to 4 groups that were exposed to different conditions:a normal environment for 6 weeks and 12 weeks,respectively,hypobaric hypoxia for 6 weeks,and hypobaric hypoxia for 6 weeks followed by a normal environment for 6 weeks.Multiple pathophysiological parameters were evaluated at the histological,endocrine,and molecular levels.Hypobaric hypoxia exposure for 6 weeks during the prepubertal phase significantly altered physiological parameters,body functions,blood indices,and reproductive potential.Six weeks after returning to a normal environment,the damaged reproductive functions partially recovered due to compensatory mechanisms.However,several changes were not reversed after returning to a normal environment for 6 weeks,including disorders of body development and metabolism,increased red blood cells,increased fasting blood glucose,abnormal blood lipid metabolism,decreased testicular and epididymis weights,abnormal reproductive hormone levels,excessive apoptosis of reproductive cells,and decreased sperm concentration.In summary,a hypobaric hypoxic environment significantly impaired the reproductive function of prepubertal male rats,and a return to normal conditions during the postpubertal phase did not fully recover these impairments.

Chemical proteomics combined with metabonomics reveals berberine targets NDUFV1 of complex Ⅰ in the respiratory chain to regulate energy metabolism

Berberine(BBR) is the primary alkaloid compound of the heat-clearing traditional Chinese medicine Huanglian(Coptis chinensis) and exerts regulatory effects on energy metabolism. However, the specific targets and molecular mechanisms are not clear. In this paper, the BBR-affected energy metabolism pathway was screened by nontargeted metabolomics, and a BBR-derived photoaffinity labeled(PAL) probe was designed to identify potential targets via a chemical proteomics approach. NDUFV1, a subunit of complex Ⅰ on mitochondria, was identified as a potential target of BBR. In the respiratory chain, BBR suppressed the activity of complex Ⅰ, reduced the electrochemical potential in the mitochondrial intermembrane and inhibited the generation of ATP and heat via competitive binding with NDUFV1. The results illustrated the underlying mechanism of BBR in the downregulation of energy metabolism.

Glucuronic acid metabolites of phenolic acids target AKT-PH domain to improve glucose metabolism

Objective:Phenolic acids widely exist in the human diet and exert beneficial effects such as improving glucose metabolism.It is not clear whether phenolic acids or their metabolites play a major role in vivo.In this study,caffeic acid(CA)and ferulic acid(FA),the two most ingested phenolic acids,and their glucuronic acid metabolites,caffeic-4’-O-glucuronide(CA4G)and ferulic-4’-O-glucuronide(FA4G),were investigated.Methods:Three insulin resistance models in vitro were established by using TNF-a,insulin and palmitic acid(PA)in HepG2 cells,respectively.We compared the effects of FA,FA4G,CA and CA4G on glucose metabolism in these models by measuring the glucose consumption levels.The potential targets and related pathways were predicted by network pharmacology.Fluorescence quenching measurement was used to analyze the binding between the compounds and the predicted target.To investigate the binding mode,molecular docking was performed.Then,we performed membrane recruitment assays of the AKT pleckstrin homology(PH)domain with the help of the PH-GFP plasmid.AKT enzymatic activity was determined to compare the effects between the metabolites with their parent compounds.Finally,the downstream signaling pathway of AKT was investigated by Western blot analysis.Results:The results showed that CA4G and FA4G were more potent than their parent compounds in increasing glucose consumption.AKT was predicted to be the key target of CA4G and FA4G by network pharmacology analysis.The fluorescence quenching test confirmed the more potent binding to AKT of the two metabolites compared to their parent compounds.The molecular docking results indicated that the carbonyl group in the glucuronic acid structure of CA4G and FA4G might bind to the PH domain of AKT at the key Arg-25 site.CA4G and FA4G inhibited the translocation of the AKT PH domain to the membrane,while increasing the activity of AKT.Western blot analysis demonstrated that the metabolites could increase the phosphorylation of AKT and downstream glycogen synthase kinase 3βin the AKT signaling pathway to increase glucose consumption.Conclusion:In conclusion,our results suggested that the metabolites of phenolic acids,which contain glucuronic acid,are the key active substances and that they activate AKT by targeting the PH domain,thus improving glucose metabolism.

A temperature-regulated bioorthogonal reaction to target lysine:Hemiacetal pharmacophore in genipin irreversibly binds with UCP2,inhibiting mitochondrial thermogenesis

Mitochondria are essential for eukaryotic life as powerhouses for energy metabolism. Excessive mitochondrial hyperthermia and reactive oxygen species(ROS) production have been associated with aging, cancer,neurodegenerative diseases, and other disorders. Uncoupling protein 2(UCP2) is the effector responsible for regulating cellular thermogenesis and ROS production via dissipating protons in an electrochemical gradient. A UCP2 inhibitor named genipin(GNP) is being researched for its effect on mitochondrial temperature, but little is known about its mechanisms. This study developed several molecular probes to explore the interactions between GNP and UCP2. The result indicated that the hemiacetal structure in GNP could selectively react with the ?-amine of lysine on the UCP2 proton leakage channel through ringopening condensation at the mitochondrial, cellular, and animal levels. A notable feature of the reaction is its temperature sensitivity and ability to conjugate with UCP2 at high fever as lysine-specific covalent inhibitors that prevent mitochondrial thermogenesis. The result not only clarifies the existence of an antipyretic properties of GNP via its irreversible coupling to UCP2, but also reveals a bioorthogonal reaction of hemiacetal iridoid aglycone for selectively binding with the ?-amine of lysine on proteins.

Effect of damage zone around borehole on carbon dioxide injection promoted gas extraction in soft and low-permeability coal seam

Injecting external CO_(2) into soft and low-permeability coal seams can improve CH4 extacctinn efficiency, and also benefit in CO_(2) sequestration. However, the distribution law of damage zone around borehole in soft coal seam and its effect on the efficiency of CO_(2) injection promoted CH4 extraction are not clear. In this paper, a multi-physics coupling mathematical model considering damage effect is established for simulating the process of CO_(2) injection promoted CH4 extraction in soft and low-permeability coal seam. The distribution of damage zone and permeability around boreholes under different diameters and coal strengths are analyzed. The gas pressure and gas content in coal seam during CO_(2) injection promoted CH4 extraction when the model considered damage effect are compared with that of ignored. The results show that small borehole diameter corresponds to narrow damage zone around the borehole in coal seam. The damage zone expands with the increase of the borehole diameter. The damage zone increases exponentially with the borehole diameter, while decreases exponentially with the compressive strength of coal seam. The highest permeability in the damage zone has increased by nearly 300 times under the condition of simulated case. CH4 pressure around the extraction borehole reduces, and the reduction area expands with the increase of time. Compared with the result of considering the damage effect, the reduction area of ignoring it is smaller, and the reducing speed is slower. The integrated effect of CO_(2) injection and CH4 extraction leads to rapid decrease of CH4 content in coal seam near the boreholes. The CO_(2) pressure and content increase around the injection borehole, and the increasing area gradually extends to the whole coal seam. In soft coal seams, failure to consider the damage effect will underestimate the efficiency of CH4 extraction and CO_(2) sequestration, resulting conservative layout of boreholes.

Qingfei Xiaoyan Wan,a traditional Chinese medicine formula, ameliorates Pseudomonas aeruginosa–induced acute lung inflammation by regulation of PI3K/AKT and Ras/MAPK pathways

Gram-negative pathogen–induced nosocomial infections and resistance are a most serious menace to global public health. Qingfei Xiaoyan Wan(QF), a traditional Chinese medicine(TCM)formula, has been used clinically in China for the treatment of upper respiratory tract infections, acute or chronic bronchitis and pulmonary infection. In this study, the effects of QF on Pseudomonas aeruginosa–induced acute pneumonia in mice were evaluated. The mechanisms by which four typical antiinflammatory ingredients from QF, arctigenin(ATG), cholic acid(CLA), chlorogenic acid(CGA) and sinapic acid(SPA), regulate anti-inflammatory signaling pathways and related targets were investigated using molecular biology and molecular docking techniques. The results showed that pretreatment with QF significantly inhibits the release of cytokines(TNF-α and IL-6) and chemokines(IL-8 and RANTES),reduces leukocytes recruitment into inflamed tissues and ameliorates pulmonary edema and necrosis. In addition, ATG was identified as the primary anti-inflammatory agent with action on the PI3K/AKT and Ras/MAPK pathways. CLA and CGA enhanced the actions of ATG and exhibited synergistic NF-κB inactivation effects possibly via the Ras/MAPK signaling pathway. Moreover, CLA is speculated to target FGFR and MEK firstly. Overall, QF regulated the PI3K/AKT and Ras/MAPK pathways to inhibit pathogenic bacterial infections effectively.

Glycyrrhetinic acid binds to the conserved P-loop region and interferes with the interaction of RAS-effector proteins

Members of the RAS proto-oncogene superfamily are indispensable molecular switches that play critical roles in cell proliferation, differentiation, and cell survival. Recent studies have attempted to prevent the interaction of RAS/GTP with RAS guanine nucleotide exchange factors(GEFs), impair RASeffector interactions, and suppress RAS localization to prevent oncogenic signalling. The present study aimed to investigate the effect of the natural triterpenoic acid inhibitor glycyrrhetinic acid, which is isolated from the roots of Glycyrrhiza plant species, on RAS stability. We found that glycyrrhetinic acid may bind to the P-loop of RAS and alter its stability. Based on our biochemical tests and structural analysis results, glycyrrhetinic acid induced a conformational change in RAS. Meanwhile, glycyrrhetinic acid abolishes the function of RAS by interfering with the effector protein RAF kinase activation and RAS/MAPK signalling.