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Background: Investigating the underlying molecular mechanisms responsible for endometrial dysfunction in women with PCOS is essential, particularly focusing on the role of hyperinsulinemia. Methods: We explored the role of insulin in the decidualization process using a synthetic decidualization assay. To dissect the effects of PI3K/AKT-NR4A signaling, we employed small interfering RNAs (siRNAs) targeting the NR4A genes and inhibitors of the PI3K/AKT pathway. We also investigated the disruption of AKT-NR4A1 signaling in the endometrium of PCOS female rats induced with dehydroepiandrosterone (DHEA). Quantitative real-time PCR (qRT-PCR) and Western blot (WB) analyses were utilized to evaluate gene expression regulation. Results: Insulin was found to suppress the expression of decidualization markers in human endometrial stromal cells (hESC) in a dose-dependent manner, concurrently triggering an inappropriate activation of the PI3K/AKT pathway. Members of the NR4A family, as downstream effectors in the PI3K/AKT pathway, were implicated in the insulin-induced disruptions during the decidualization process. Moreover, the endometrium of PCOS models showed significantly elevated levels of phosphorylated (Ser473) AKT, with a corresponding reduction in Nr4a1 protein. Conclusions: Our research demonstrates that insulin negatively regulates decidualization in hESC via the PI3K/AKT-NR4A pathway. In vivo analysis revealed a significant dysregulation of the AKT-NR4A1 pathway in the endometrium of PCOS rats. These findings offer novel insights into the pathogenesis of infertility and endometrial disorders associated with hyperinsulinemia in PCOS. [ABSTRACT FROM AUTHOR]

Endogenous signals, namely nitric oxide (NO) and electrons, play a crucial role in regulating cell fate as well as the vascular and neuronal systems. Unfortunately, utilizing NO and electrical stimulation in clinical settings can be challenging due to NO's short half‐life and the invasive electrodes required for electrical stimulation. Additionally, there is a lack of tools to spatiotemporally control gas release and electrical stimulation. To address these issues, an "electromagnetic messenger" approach that employs on‐demand high‐frequency magnetic field (HFMF) to trigger NO release and electrical stimulation for restoring brain function in cases of traumatic brain injury is introduced. The system comprises a NO donor (poly(S‐nitrosoglutathione), pGSNO)‐conjugated on a gold yarn‐dynamos (GY) and embedded in an implantable silk in a microneedle. When subjected to HFMF, conductive GY induces eddy currents that stimulate the release of NO from pGSNO. This process significantly enhances neural stem cell (NSC) synapses' differentiation and growth. The combined strategy of using NO and electrical stimulation to inhibit inflammation, angiogenesis, and neuronal interrogation in traumatic brain injury is demonstrated in vivo. [ABSTRACT FROM AUTHOR]

Abstract β/γ-Crystallins are predominant structural proteins in vertebrate lens with unique properties of extremely high solubility, long-term stability and resistance to UV damage. Four conserved Trp residues in β/γ-crystallins account for UV absorbance and thereafter fluorescence quenching to avoid photodamage. Herein we found that βB2-crystallin Trp fluorescence was greatly enhanced by the introduction of an extra unquenched Trp fluorophore by cataract-associated mutations S31W and R145W. Both mutations impaired oligomerization, decreased stability and promote thermal aggregation, while S31W was more deleterious. S31W accelerated βB2-crystallin aggregation under UV damaging conditions, whereas R145W delayed. These observations suggested that the introduction of an extra Trp fluorophore had complicated effects on βB2-crystallin stability and aggregation against various stresses. Our findings highlight that the number of Trp fluorophores in β/γ-crystallin is evolutionarily optimized to exquisitely perform their structural roles in the lens. Graphical abstract Image 1 Highlights • S31W and R145W introduce an extra fluorophore in βB2-crystallin. • S31W and R145W destabilize βB2-crystallin and promote thermal aggregation. • S31W accelerates but R145W retards UV-induced aggregation of βB2-crystallin. • The number of Trp fluorophores in β/γ-crystallin is evolutionarily optimized. [ABSTRACT FROM AUTHOR]

Cataract, a crystallin protein aggregation disease, is the leading cause of human blindness worldwide. Congenital cataract may be induced by many factors and genetic disorders accounts for about half of the cases. Inherited mutations can promote cataract formation by affecting crystallin structure, solubility, stability, protein interactions and aggregatory propensity. In this research, we investigated the potential role of oxidative damage in congenital cataracts caused by six mutations in γC- and γD-crystallins, the predominant structural proteins in the lens. H 2 O 2 treatment induced structural changes for both the wild type and mutated proteins. Oxidization by H 2 O 2 or UV light facilitated protein oligomerization and thermal aggregation. H 2 O 2 treatment promoted thermal aggregation of all proteins. By increasing the susceptibility, cataract-causing mutations amplified the deleterious effects of oxidative damage. Our results suggested that oxidative damage might play an important role in the onset and/or progression of congenital cataract caused by both Cys and non-Cys substitutions. [ABSTRACT FROM AUTHOR]

Restorations of 98 implant-supported single crowns in anterior maxillary area were divided into 5 groups: zirconia abutment, titanium abutment, and gold/gold hue abutment with zirconia coping, respectively, and titanium abutment with metal coping as well as gold/gold hue abutment with metal coping. A reflectance spectrophotometer was used to evaluate the color difference between the implant crowns and contralateral/neighboring teeth, as well as the color difference between the peri-implant soft tissue and the natural marginal mucosa. The mucosal discoloration score was used for subjective evaluation of the esthetic outcome of soft tissue around implant-supported single crowns in the anterior zone, and the crown color match score was used for subjective evaluation of the esthetic outcome of implant-supported restoration. ANOVA analysis was used to compare the differences among groups and Spearman correlation was used to test the relationships. A gold/gold hue abutment with zirconia coping was the best choice for an esthetic crown and the all-ceramic combination was the best for peri-implant soft tissue. Significant correlation was found between the spectrophotometric color difference of peri-implant soft tissue and mucosal discoloration score, while no significant correlation was found between the total spectrophotometric color difference of implant crown and crown color match score. [ABSTRACT FROM AUTHOR]

β/γ-Crystallins, the predominant structural proteins in vertebrate lens with lifelong stability to maintain lens transparency, share a high similarity in their primary sequences and tertiary structures. Four conserved Trp residues have been shown to be important to γ-crystallin structure, stability and protection against UV irradiation, whereas their roles in β-crystallins remain elusive. Herein we found that two congenital cataract-causing mutations, W59C and W151C, dramatically decreased βB2-crystallin solubility and stability against thermal and guanidine hydrochloride-induced denaturation. The two mutated proteins were prone to form aggregates when irradiated by UV light in the tubes or exogenously expressed in the cells. Although W59 and W151 are structurally identical in β/γ-crystallin domains, substituting them by Cys led to dissimilar influences on βB2-crystallin stability. Our results suggested that the conserved Trp residues might play a more crucial role in the correct folding and structural integrity of β-crystallin domains than in γ-crystallins. [ABSTRACT FROM AUTHOR]

Based on the concept of performance-price ratio, we propose a quantitative method to solve multi-objective optimization problems. A new hypothesis is established in this paper: market rules that seek a higher-performing product with a lower price are used to compare and select Pareto non-inferior solutions. After carefully observing the distribution of the Pareto front, we find that the distribution is monotonically increasing or decreasing. This means that different variability exists in the Pareto front and that new inherent disciplines can be found. Based on this discovery, we use the performance-price ratio as a reference to construct the average variability that adjacent non-inferior solutions correspond to the objective function values. Then, the sensitivity ratio that is similar to the performance-price ratio is obtained, and a quantitative method is developed to evaluate Pareto non-inferior solutions. Two important achievements are derived: (1) based on the sensitivity ratio, a new subset of the Pareto non-inferior solution set is formed in accordance with the dominance relationship. The number of Pareto non-inferior solutions is reduced, and the bias degree corresponding to every Pareto non-inferior solution is obtained for different objectives. Thus, it is convenient for decision makers to select Pareto non-inferior solutions based on their preferences. (2) In the new subset of Pareto non-inferior solutions, the solution that corresponds to the minimal absolute value difference of the sensitivity ratio for different optimization objectives is defined as an unbiased and good solution. Accordingly, we obtain the optimal solution that is acceptable for every objective. Finally, the method is illustrated with a numerical example. [ABSTRACT FROM AUTHOR]

Disease-causing mutations can be stabilizing or destabilizing. Missense mutations of structural residues are generally destabilizing, while stabilizing mutations are usually linked to alterations in protein functions. Stabilizing mutations are rarely identified in mutations linked to congenital cataract, a disease caused by the opacification of the lens. In this research, we found that R233H mutation had little impact on βB1-crystallin structure, solubility and thermal stability under neutral solution pH conditions. The mutation increased βB1 stability against guanidine hydrochloride-induced denaturation, suggesting that Arg233 might be a functional residue. Further analysis indicated that the R233H mutation did not affect the formation of βA3/βB1 heteromer, but significantly reduced heteromer stability against heat- and guanidine hydrochloride-induced denaturation. The R233H mutation negatively affected the thermal stabilities and aggregatory propensities of βB1 and βA3/βB1 with different pH-dependence, implying that the protonation of His side chains during acidification played a regulatory role in crystallin stability and aggregation. Molecular dynamic simulations indicated that Arg233 is one of the residues forming an inter-subunit ion-pairing network with intrinsically dynamic nature. Based on these observations, we proposed that the highly dynamic ion-pairing network contributed to the tradeoff among βB1 solubility, stability, aggregatory propensity and function of protecting βA3. [ABSTRACT FROM AUTHOR]

Abstract: Congenital cataract is the leading cause of childhood blindness worldwide. Investigations of the effects of inherited mutations on protein structure and function not only help us to understand the molecular mechanisms underlying congenital hereditary cataract, but also facilitate the study of complicated cataract and non-lens abnormities caused by lens-specific genes. In this research, we studied the effects of the V187M, V187E and R188H mutations on βB2-crystallin structure and stability using a combination of biophysical, cellular and molecular dynamic simulation analysis. Both V187 and R188 are located at the last strand of βB2-crystallin Greek-key motif 4. All of the three mutations promoted βB2-crystallin aggregation in vitro and at the cellular level. These three mutations affected βB2-crystallin quite differentially: V187M influenced the hydrophobic core of the C-terminal domain, V187E was a Greek-key motif breaker with the disruption of the backbone H-bonding network, while R188H perturbed the dynamic oligomeric equilibrium by dissociating the dimer and stabilizing the tetramer. Our results highlighted the importance of the last strand in the structural integrity, folding, assembly and stability of β-crystallins. More importantly, we proposed that the perturbation of the dynamic equilibrium between β-crystallin oligomers was an important mechanism of congenital hereditary cataract. The selective stabilization of one specific high-order oligomer by mutations might also be deleterious to the stability and folding of the β-crystalllin homomers and heteromers. The long-term structural stability and functional maintenance of β-crystallins are achieved by the precisely regulated oligomeric equilibrium. [Copyright &y& Elsevier]

• Summarized the experiment of desalination by graphene-based nanomaterials. • Focus on computer simulation on the desalination by graphene-based nanomaterials. • The gap between the results of experiment and simulation were discussed in detail. Reverse Osmosis (RO) for the desalination of saline water is associated with tremendous energy costs and low efficiency. Biomimetic membranes incorporate biological elements or borrow concepts, ideas or inspiration from biological systems. Such membranes can take advantage of the strategies evolved by nature over billions of years for improving transport efficiency and specificity. Biomimetic membrane based on graphene has achieved great progress on the desalination performance. With the development of nanotechnology and computational science, the computational simulation has been a powerful tool to uncover the atomic details in desalination by graphene based biomimetic nanomaterials. In this mini review, we will summarize the experiment of desalination by graphene-based nanomaterials and focus on computational simulation on the desalination by graphene-based nanomaterials. Especially, the gap between the results of experiment and simulation will be discussed in detail. [ABSTRACT FROM AUTHOR]

Abstract: Congenital hereditary cataract, which is mainly caused by the deposition of crystallins in light-scattering particles, is one of the leading causes of newborn blindness in human beings. Recently, an autosomal dominant congenital cataract-microcornea syndrome in a Chinese family has been associated with the S129R mutation in βB1-crystallin. To investigate the underlying molecular mechanism, we examined the effect of the mutation on βB1-crystallin structure and thermal stability. Biophysical experiments indicated that the mutation impaired the oligomerization of βB1-crystallin and shifted the dimer–monomer equilibrium to monomer. Molecular dynamic simulations revealed that the mutation altered the hydrogen-bonding network and hydrophobic interactions in the subunit interface of the dimeric protein, which resulted in the opening of the tightly associated interacting sites to allow the infiltration of the solvent molecules into the interface. Despite the disruption of βB1-crystallin assembly, the thermal stability of βB1-crystallin was increased by the mutation accompanied by the reduction of thermal aggregation at high temperatures. Further analysis indicated that the mutation significantly increased the sensitivity of βB1-crystallin to trypsin hydrolysis. The digested fragments of the mutant were prone to aggregate and unable to protect βA3-crystallin against aggregation. These results indicated that the thermal stability-beneficial mutation S129R in βB1-crystallin provided an excellent model for discovering molecular mechanisms apart from solubility and stability. Our results also highlighted that the increased sensitivity of mutated crystallins towards proteases might play a crucial role in the pathogenesis of congenital hereditary cataract and associated syndrome. [Copyright &y& Elsevier]

Abstract: The reaction of aryldiazoacetates with enamines catalyzed by copper and rhodium complexes provided γ-keto esters in good yields. A full investigation of the effects of solvents, catalysts, enamines and aryldiazoacetates on the reaction was carried out. Careful analysis of the crude reaction mixture revealed a substituted enamine as the primary product, which was hydrolyzed over silica gel to give a γ-keto ester as the final product. A reaction mechanism involving nucleophilic addition of an enamine to a metal carbene and subsequent hydrogen transfer was proposed. Chiral dirhodium and copper catalysts were examined and found to provide γ-keto esters with no enantioselectivity. The result could be rationalized based on the proposed reaction mechanism. Attempts to trap the enamine intermediate with several electrophilic reagents were not successful. [Copyright &y& Elsevier]

This is a discussion on the paper titled “Assessing feed-in tariffs on wind power installation and industry development in Taiwan” published by Hsu et al. In the discussed paper, there were several missing variables in the historical test of the system dynamics (SD) model, and thus the test was not integrated and valid. Additionally, the simulated results of the missing variables were used as important indexes to observe the behavior of the SD model. Therefore, it was highly likely that the solution and related policy analysis based on the simulated results were incorrect. Accordingly, the present study illustrated the structure characteristics of the SD model with respect to the fore-mentioned problems, discussed the reason for missing variables and proposed a method to assess whether or not the historical test was integrated. Finally, after a careful analysis, this study offered suggestions to perfect the historical test proposed in the discussed paper. [ABSTRACT FROM AUTHOR]

Advanced exfoliation techniques are crucial for exploring the intrinsic properties and applications of 2D materials. Though the recently discovered Au‐enhanced exfoliation technique provides an effective strategy for the preparation of large‐scale 2D crystals, the high cost of gold hinders this method from being widely adopted in industrial applications. In addition, direct Au contact could significantly quench photoluminescence (PL) emission in 2D semiconductors. It is therefore crucial to find alternative metals that can replace gold to achieve efficient exfoliation of 2D materials. Here, the authors present a one‐step Ag‐assisted method that can efficiently exfoliate many large‐area 2D monolayers, where the yield ratio is comparable to Au‐enhanced exfoliation method. Differing from Au film, however, the surface roughness of as‐prepared Ag films on SiO2/Si substrate is much higher, which facilitates the generation of surface plasmons resulting from the nanostructures formed on the rough Ag surface. More interestingly, the strong coupling between 2D semiconductor crystals (e.g., MoS2, MoSe2) and Ag film leads to a unique PL enhancement that has not been observed in other mechanical exfoliation techniques, which can be mainly attributed to enhanced light‐matter interaction as a result of extended propagation of surface plasmonic polariton (SPP). This work provides a lower‐cost and universal Ag‐assisted exfoliation method, while at the same time offering enhanced SPP‐matter interactions. [ABSTRACT FROM AUTHOR]

Cataract is a lens opacification disease prevalent worldwide. Cataract-causing mutations in crystallins generally lead to the formation of light-scattering particles in the lens. However, it remains unclear for the detailed structural and pathological mechanisms of most mutations. In this study, we showed that the G129C mutation in γC-crystallin, which is associated with autosomal dominant congenital nuclear cataract, perturbed the unfolding process by promoting the accumulation of two distinct aggregation-prone intermediates under mild denaturing conditions. The abnormally accumulated intermediates escaped from the chaperone-like function of αA-crystallin during refolding. Molecular dynamics simulations indicated that the mutation altered domain pairing geometry and allowed the penetration of extra solvent molecules into the domain binding interface, thereby weakening domain binding energy. Under mild denaturation conditions, the increased domain movements may facilitate the formation of non-native oligomers via domain swapping, which further assembled into amyloid-like fibrils. The intermediate that appeared at 1.6 M guanidine hydrochloride was more compact and less aggregatory than the one populated at 0.9 M guanidine hydrochloride, which was caused by the increased solvation of acidic residues in the ion-pairing network via the competitive binding of guanidinium ions. More importantly, both the amyloid-like fibrils preformed in vitro and intracellular aggresomes formed by exogenously overexpressed mutant proteins significantly inhibited cell proliferation and induced cell death. The combined data from spectroscopic, structural and cellular studies strongly suggest that both the formation of light-scattering aggregates and the toxic effects of the aggregates may contribute to the onset and development of cataract. [ABSTRACT FROM AUTHOR]

Abstract: The electropolishing behaviour of 73 brass in a 70% H3PO4 solution was studied using a rotating disc electrode (RDE). Based on the results of an anodic polarisation test, a transition peak from kinetic-controlled to diffusion-controlled dissolution was detected when a blue Cu2+-rich layer was developed on the RDE. The blue Cu2+-rich layer impedes the anodic dissolution rate of the brass-RDE and is essential for levelling during electropolishing. Potentiostatic polishing at different locations on the limiting-current plateau was studied. By polishing at the transition-peak potential, grain boundaries were preferentially etched. In contrast, a well-polished surface with a nanosized surface roughness (R a) was achieved after electropolishing in the middle of the limiting-current plateau. By polishing at the end of the limiting-current plateau at a relatively low rotational speed, nipple-like and flow-streak features were observed. The formation of these features is attributed to the evolution of oxygen bubbles on the RDE surface. Mechanisms for the formation of the above-mentioned features were proposed. [Copyright &y& Elsevier]

Abstract: Stilbene derivatives have wide range of activities. In an effort to find other potential activities of this kind of compounds, 17 derivatives, including resveratrol, were synthesized. Twelve of them were evaluated for their antiviral potential against severe acute respiratory syndrome (SARS)-CoV-induced cytopathicity in Vero E6 cell culture. The result showed that SARS virus was totally inhibited by compounds 17 and 19 (≤0.5 mg ml–1) and no significant cytotoxic effects were observed in vitro. [Copyright &y& Elsevier]

The reaction of enamines with ethyl diazoacetate (EDA) catalyzed by dirhodium and copper complexes provided ϒ-keto esters in good yields. The influences of catalyst, reaction solvent, temperature, and structure of enamines on this transformation were investigated. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The mechanism of rearrangement of curcumol to form orobanone analogues is studied. • Curcumol and four orobanone analogues inhibited HIF-1 transcription under hypoxia. • Compound 6 inhibited hypoxia-induced HIF-1 activity in HeLa cells with the IC 50 = 2.4 μM. Abstract In this paper, the mechanism of orobanone analogues formation via aromatization rearrangement of curcumol was minutely explored. Aromatization of curcumol with acetone under acidic condition was selected as the model reaction. The formation of a stable aromatic system was the driving force for this reaction. Based on the model reaction, other four new orobanone analogues were prepared through curcumol reacting with different carbonyl compounds. The results showed that the stability of carbocation, which was generated from the carbonyl compounds, and the steric hindrance were main factors affecting the aromatization. We also synthesized the analogue of aromaticane B using compound 2. In vitro anti-proliferative activity of some derivatives were tested by MTT assay. Two derivatives showed weak anti-tumor effect on two cancer cell lines (HepG2 and MCF7) under normoxia. Four orobanone analogue 2 , 5 , 6 and 9 significantly inhibited hypoxia-induced HIF-1 luciferase reporter activity in HeLa cells with the IC 50 values of 13.6, 6.6, 2.4 and 18.2 μM, respectively. [ABSTRACT FROM AUTHOR]

Objective: To investigate the potential inhibitory effects of structurally novel steroidal dimer by001 in esophageal cancer in vitro.Methods: The cytotoxicity of by001 on esophageal, gastric, neuroblastoma and prostate cancer cells was examined MTT assay and colony formation assay. By001 induced apoptosis and production of intracellular reactive oxygen species on esophageal cancer cells Ec109, TE-1 and human normal gastric epithelial cells GES-1 was detected by flow cytometry. The effect of by001 on mitochondrial membrane potential was detected by fluorescence microscope through JC-1 staining. The level of intracellular reactive oxygen species was measured by fluorescence microscope and flow cytometry via DCFH-DA staining. The effect of by001 on members of Bcl-2 family, Fas, LC3, PARP and caspases was determined by Western blot. The effect of by001 on migration was measured by transwell assay.Results: By001 effectively inhibited proliferation of esophageal, gastric, neuroblastoma and prostate cancer cells in a time- and concentration-dependent manner in vitro. By001 reduced the number and the size of colonies at low micromolar concentrations, elevated cellular ROS levels and caused mitochondrial dysfunction in esophageal cancer cells. Molecular mechanistic studies showed that by001 triggered apoptosis through regulating members of Bcl-2 family and Fas.Conclusions: These findings suggested that by001 may inhibited proliferation of esophageal cancer cells through mitochondria and death receptor-mediated apoptotic pathways, autophagy induction, as well as suppressed migration of esophageal cancer cells. [ABSTRACT FROM AUTHOR]

This paper points out an important factor that was neglected by “Case studies of shipping along Arctic routes. Analysis and profitability perspectives for the container sector,” when analysing the operating economy of Arctic routes. Further, this paper explains the idea that cargo has a time value. Arctic routes are likely to bring greater commercial value than the Suez, if cargo time value were to be considered. [ABSTRACT FROM AUTHOR]

A series of flavone-7-phosphoramidate derivatives were synthesized and tested for their antiproliferative activity in vitro against human hepatoma cell line HepG2 and human normal hepatic cell line L-O2. Compound 8d , 16d and 17d , incorporating the amino acid alanine, exhibited high inhibitory activity on HepG2 cell line with IC 50 values of 9.0 μmol/L, 5.5 μmol/L and 6.6 μmol/L. The introduction of acyl groups played a pivotal role in the selective inhibition toward human hepatoma HepG2 cells, except for compound 8a , 9a and 16b . Compound 8d , 16d and 17d could significantly induce G2/M arrest in HepG2 cells. Specially, Compound 16d could lead early apoptosis in HepG2 cells. [ABSTRACT FROM AUTHOR]

Abstract: With the application of near-infrared spectroscopy (NIRS), a convenient and rapid method for determination of alkaloids in Corydalis Tuber extract and classification for samples from different locations have been developed. Five different samples were collected according to their geographical origin, 2-Der with smoothing point of 17 was applied as the spectral pre-treatment, and the 1st to scaling range algorithm was adjusted to be optimal approach, classification model was constructed over the wavelength range of 4582–4270cm−1, 5562–4976cm−1 and 7000–7467cm−1 with a great recognition rate. For prediction model, partial least squares (PLS) algorithm was utilized referring to HPLC-UV reference method, the optimum models were obtained after adjustment. Pre-processing methods of calibration models were COE for protopine and min–max normalization for palmatine and MSC for tetrahydropalmatine, respectively. The root mean square errors of cross-validation (RMSECV) for protopine, palmatine, tetrahydropalmatine were 0.884, 1.83, 3.23mg/g. The correlation coefficients (R 2) were 99.75, 98.41 and 97.34%. T test was applied, in the model of tetrahydropalmatine; there is no significant difference between NIR prediction and HPLC reference method at 95% confidence interval with t =0.746< t (0.05,20) =2.086, therefore NIRS is a reliable analytical tool in establishing prediction models. [Copyright &y& Elsevier]

• 21 oleanolic acid derivatives containing α,β-unsaturated carbonyl were synthesized. • Most synthesized compounds exhibited potent in vitro antiproliferative activities. • Compound 3d displayed the most potent inhibitory activity in MCF-7 cells. • Compound 3d inhibited the cells migration and arrested cell cycle at S phase. • Compound 3d inhibited PI3K/AKT/mTOR signaling pathway in MCF-7 cells. Oleanolic acid (OA) and its semi-synthetic derivatives have been reported to have a wide range of biological activities. The introduction of electrophilic Michael acceptor group can increase the reactivity of OA to cellular targets and thus improve the anti-tumor activity. In this work, a series of novel α,β-unsaturated carbonyl derivatives of OA were designed and synthesized. Their in vitro cytotoxic activity against MCF-7, HepG2 and HeLa cells were tested. Most derivatives exhibited improved cell growth inhibitory activity, especially for 3d with an IC 50 of 0.77 μM in MCF-7 cells. Moreover, 3d inhibited the migration of MCF-7 and HeLa cells at the concentration of 4 μM. Flow cytometric analysis revealed that 3d induced cell apoptosis and S phase arrest in a concentration-dependent manner. Western blotting experiment demonstrated that 3d inhibited the phosphorylation of AKT and mTOR. These results suggest that this series of OA derivatives bearing exocyclic methylene ketone pharmacophore are promising anticancer agents as potential PI3K/AKT/mTOR pathway inhibitors. [ABSTRACT FROM AUTHOR]