TetR family regulator AbrT controls lincomycin production and morphological development in Streptomyces lincolnensis.

BACKGROUND: The TetR family of transcriptional regulators (TFRs), serving as crucial regulators of diverse cellular processes, undergo conformational changes induced by small-molecule ligands, which either inhibit or activate them to modulate target gene expression. Some ligands of TFRs in actinomycetes and their regulatory effects have been identified and studied; however, regulatory mechanisms of the TetR family in the lincomycin-producing Streptomyces lincolnensis remain poorly understood. RESULTS: In this study, we found that AbrT (SLCG_1979), a TetR family regulator, plays a pivotal role in regulating lincomycin production and morphological development in S. lincolnensis. Deletion of abrT gene resulted in increased lincomycin A (Lin-A) production, but delayed mycelium formation and sporulation on solid media. AbrT directly or indirectly repressed the expression of lincomycin biosynthetic (lin) cluster genes and activated that of the morphological developmental genes amfC, whiB, and ftsZ. We demonstrated that AbrT bound to two motifs (5'-CGCGTACTCGTA-3' and 5'-CGTACGATAGCT-3') present in the bidirectional promoter between abrT and SLCG_1980 genes. This consequently repressed abrT itself and its adjacent gene SLCG_1980 that encodes an arabinose efflux permease. D-arabinose, not naturally occurring as L-arabinose, was identified as the effector molecule of AbrT, reducing its binding affinity to abrT-SLCG_1980 intergenic region. Furthermore, based on functional analysis of the AbrT homologue in Saccharopolyspora erythraea, we inferred that the TetR family regulator AbrT may play an important role in regulating secondary metabolism in actinomycetes. CONCLUSIONS: AbrT functions as a regulator for governing lincomycin production and morphological development of S. lincolnensis. Our findings demonstrated that D-arabinose acts as a ligand of AbrT to mediate the regulation of lincomycin biosynthesis in S. lincolnensis. Our findings provide novel insights into ligand-mediated regulation in antibiotic biosynthesis.

Lewis Acid-Base Pairs: The Bonding Rule of Closed-Shell M···M' Interactions (M = HgII/PdII; M' = AgI/AuI).

Metallophilic interactions are the widespread interactions in multimetal clusters to orientate closed-shell metal self-assembly form linear, facet, or block clusters. The closed-shell metal cation does not have empty valence orbitals, but is able to attract each other. It is still a conundrum to understand the resource in balancing the strong Coulomb repulsion between two cations. Most traditional descriptions attribute the counterintuitive attractions to London dispersion, Pauli repulsions, and ambiguous orbital interactions. However, neither the dispersion nor the unsourced donor-acceptor interaction can be applied to explain the saturability and directionality in multimetal clusters, where the M···M' structure is the basic molecular unit. Here, we clarify the origination of the covalency in closed-shell metallophilic interactions based on the study of heterobimetallic compounds composed of d10-d8 species (AgI/AuI-PdII) and d10-d10 species (AgI/AuI-HgII) obtained from experiments. The inner d electrons not only participate in the metallophilic interactions but also show different Lewis acidity and basicity in the formation of M···M' structures. The present work not only provides us a novel covalent perspective to visualize the closed-shell M···M' interactions but also unveils the truth of metallophilic interactions.

Inhibitory effect of liriopesides B in combination with gemcitabine on human pancreatic cancer cells.

Gemcitabine (GEM) is a standard chemotherapeutic agent for patients with pancreatic cancer; however, GEM-based chemotherapy has a high rate of toxicity. A combination of GEM and active constituents from natural products may enhance its therapeutic efficacy and reduce its toxicity. This study investigated the synergistic effects of the combination of liriopesides B (LirB) from Liriope spicata var. prolifera and GEM on human pancreatic cancer cells. The results of our study showed that the combination of LirB and GEM synergistically decreased the viability of pancreatic cancer cells. The combination also caused a strong increase in apoptosis and a strong decrease in cell migration and invasion. Furthermore, LirB combined with GEM had potent inhibitory effects on pancreatic cancer stem cells (CSCs). Studies on the mechanisms of action showed that the combination more potently inhibited protein kinase B (Akt) and nuclear factor kappa B (NF-κB), as well as the downstream antiapoptotic molecules B-cell lymphoma 2 (Bcl-2) and survivin than either agent used alone. The results of this study suggest that the combination of LirB with GEM may improve the efficacy of GEM for the treatment of pancreatic cancer.

Identification and Analysis of lncRNA and circRNA Related to Wheat Grain Development.

The role of lncRNA and circRNA in wheat grain development is still unclear. The objectives of this study were to characterize the lncRNA and circRNA in the wheat grain development and to construct the interaction network among lncRNA, circRNA, and their target miRNA to propose a lncRNA-circRNA-miRNA module related to wheat grain development. Full transcriptome sequencing on two wheat varieties (Annong 0942 and Anke 2005) with significant differences in 1000-grain weight at 10 d (days after pollination), 20 d, and 30 d of grain development were conducted. We detected 650, 736, and 609 differentially expressed lncRNA genes, and 769, 1054, and 1062 differentially expressed circRNA genes in the grains of 10 days, 20 days and 30 days after pollination between Annong 0942 and Anke 2005, respectively. An analysis of the lncRNA-miRNA and circRNA-miRNA targeting networks reveals that circRNAs exhibit a more complex and extensive interaction network in the development of cereal grains and the formation of grain shape. Central to these interactions are tae-miR1177, tae-miR1128, and tae-miR1130b-3p. In contrast, lncRNA genes only form a singular network centered around tae-miR1133 and tae-miR5175-5p when comparing between varieties. Further analysis is conducted on the underlying genes of all target miRNAs, we identified TaNF-YB1 targeted by tae-miR1122a and TaTGW-7B targeted by miR1130a as two pivotal regulatory genes in the development of wheat grains. The quantitative real-time PCR (qRT-PCR) and dual-luciferase reporter assays confirmed the target regulatory relationships between miR1130a-TaTGW-7B and miR1122a-TaNF-YB1. We propose a network of circRNA and miRNA-mediated gene regulation in the development of wheat grains.

An adaptive weighted ensemble learning network for diabetic retinopathy classification.

Diabetic retinopathy (DR) is one of the leading causes of blindness. However, because the data distribution of classes is not always balanced, it is challenging for automated early DR detection using deep learning techniques. In this paper, we propose an adaptive weighted ensemble learning method for DR detection based on optical coherence tomography (OCT) images. Specifically, we develop an ensemble learning model based on three advanced deep learning models for higher performance. To better utilize the cues implied in these base models, a novel decision fusion scheme is proposed based on the Bayesian theory in terms of the key evaluation indicators, to dynamically adjust the weighting distribution of base models to alleviate the negative effects potentially caused by the problem of unbalanced data size. Extensive experiments are performed on two public datasets to verify the effectiveness of the proposed method. A quadratic weighted kappa of 0.8487 and an accuracy of 0.9343 on the DRAC2022 dataset, and a quadratic weighted kappa of 0.9007 and an accuracy of 0.8956 on the APTOS2019 dataset are obtained, respectively. The results demonstrate that our method has the ability to enhance the ovearall performance of DR detection on OCT images.

Pancreatic Cancer and its Attributable Risk Factors in East Asia, Now and Future.

BACKGROUND: The disease burden of pancreatic cancer in East Asia is at a high level, but the epidemiological characteristics of pancreatic cancer in the region have not been systematically studied. METHOD: Joinpoint analysis was used to identify average annual percentage change (AAPC) and annual percentage change (APC) in mortality. Age-period-cohort models were used to analyze age-period cohort effects across countries. Bayesian age-period-cohort (BAPC) analysis was used to project the burden of disease for 2020-2030. RESULTS: Pancreatic cancer mortality in males in Japan (2012-2019, APC = -0.97) and Korea (2012-2019, APC = -0.91) has shown a decreasing trend since 2012 (P < .05). However, China (2016-2019, APC = 3.21), Mongolia (2015-2.019, APC = 2.37), and North Korea (2012-2019, APC = 0.47) showed a significant increase in pancreatic cancer in both genders (P < .05). Risk factors for pancreatic cancer in East Asia remained largely stable between 2010 and 2019. Mortality of pancreatic cancer due to smoking began to decline in areas with high socio-demographic index (SDI), and mortality of pancreatic cancer due to high body mass index and high fasting plasma glucose increased with SDI. The age-standardized mortality for pancreatic cancer in Chinese males is expected to exceed that of Japan and South Korea by 2030, but the disease burden of pancreatic cancer in Japan and South Korea remains at extremely high levels. CONCLUSION: Economically developed countries are beginning to show a decreasing trend in the burden of pancreatic cancer disease, and developing countries are experiencing a rapid increase in the age-standardized death rate (ASDR) of pancreatic cancer.

The allocation of anatomical traits determines the trade-off between fine root resource acquisition-transport function.

Cortex radius (CR) and stele radius (SR) are important functional traits associated with the nutrient acquisition and transport functions of fine roots, respectively. However, for developmental and anatomical reasons, the resource acquisition-transport relationship of fine roots is expected to be different for different root orders. To address this issue, critical fine root anatomical traits were examined for the first three orders of roots of 59 subtropical woody plants. Designating the most distal fine roots as order one, SR scaled isometrically with respect to root radius (RR) (i.e., SR ∝ RR1.0) in the three root orders, whereas CR scaled allometrically with respect to RR (i.e., CR ∝ RR>1.0) with the numerical values of scaling exponents increasing significantly with increasing root orders thereby indicating a disproportional increase in CR with increasing root orders. There were also differences between normalized root tissue (CR/RR and SR/RR) and RR in different root orders. A negative isometric relationship (i.e., SR/RR ∝ RR-1.0) existed between SR/RR and RR in three order roots, whereas the allometric exponent between CR/RR and RR increased with root order (from 0.88 to 1.55). Collectively, the data indicate that root anatomical and functional traits change as a function of RR and that these changes need to be considered when modeling fine root resource acquisition-transport functions.

Unraveling the Aromatic Rule of Cyclic Superatomic Molecules in π-Conjugated Compounds.

The aromaticity of π-conjugated compounds has long been a confusing issue. Based on a recently emerged two-dimensional (2D) superatomic-molecule theory, a unified rule was built to decipher the aromaticity of cyclic superatomic molecules of π-conjugated compounds from the chemical bonding perspective. Herein, a series of planar [n]helicenes and [n]circulenes, composed of benzene, thiophene, or furfuran, are systemically studied and seen as superatomic molecules ◊On-2◊F2 or ◊On, where superatoms ◊F and ◊O denote π-conjugated units with 5 and 4 π electrons, respectively. The ascertained superatomic Lewis structures intuitively display aromaticity with each basic unit meeting the superatomic sextet rule of benzene, similar to classical valence bond theory, which is favored by the synthesized complex π-conjugated compounds comprising different numbers and kinds of subrings. The evolutionary trend of ring currents and chemical bonding suggests a local ribbon-like aromaticity in these π-conjugated compounds. Moreover, nonplanar helical π-conjugated compounds have the potential to evolve into spring-like periodic materials with excellent physical properties.

Discovery of novel cannabidiol derivatives with augmented antibacterial agents against methicillin-resistant Staphylococcus aureus.

Drug-resistant bacterium infections are a severe threat to public health and novel antimicrobial agents combating drug-resistant bacteria are an unmet medical need. Although cannabidiol (CBD) has been reported to show antibacterial effects, whether its antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) can be improved remains unclear. Herein, a series of novel CBD derivatives were designed and synthesized using various chemical approaches including amidation, Friedel-Crafts alkylation, and Negishi cross-coupling reaction for the modifications at the C-7, C-2', C-4', and C-6' positions of CBD skeleton. Derivative 21f showed augmented antibacterial activity against MRSA with a minimum inhibitory concentration of 4 µM without cytotoxic effect in microglia BV2 cells. Further mechanistic studies suggested that 21f inhibited the formation of biofilms, induced excess reactive oxygen species, and reduced bacterial metabolism, which collectively led to the acceleration of bacterial death. Findings from this study expand the understanding of CBD derivatives as promising antibacterial agents, which provides useful information for the development of cannabinoid-based antibacterial agents.

High-efficiency genetic engineering toolkit for virus based on lambda red-mediated recombination.

PURPOSE: Viruses, such as Ebola virus (EBOV), evolve rapidly and threaten the human health. There is a great demand to exploit efficient gene-editing techniques for the identification of virus to probe virulence mechanism for drug development. METHODS: Based on lambda Red recombination in Escherichia coli (E. coli), counter-selection, and in vitro annealing, a high-efficiency genetic method was utilized here for precisely engineering viruses. EBOV trVLPs assay and dual luciferase reporter assay were used to further test the effect of mutations on virus replication. RESULTS: Considering the significance of matrix protein VP24 in EBOV replication, the types of mutations within vp24, including several single-base substitutions, one double-base substitution, two seamless deletions, and one targeted insertion, were generated on the multi-copy plasmid of E. coli. Further, the length of the homology arms for recombination and in vitro annealing, and the amount of DNA cassettes and linear plasmids were optimized to create a more elaborate and cost-efficient protocol than original approach. The effects of VP24 mutations on the expression of a reporter gene (luciferase) from the EBOV minigenome were determined, and results indicated that mutations of key sites within VP24 have significant impacts on EBOV replication. CONCLUSION: This precise mutagenesis method will facilitate effective and simple editing of viral genes in E. coli.

Novel Matrine Derivatives as Potential Larvicidal Agents against Aedes albopictus: Synthesis, Biological Evaluation, and Mechanistic Analysis.

A large number of studies have shown that matrine (MA) possesses various pharmacological activities and is one of the few natural, plant-derived pesticides with the highest prospects for promotion and application. Fifty-eight MA derivatives were prepared, including 10 intermediates and 48 target compounds in 3 series, to develop novel mosquitocidal agents. Compounds 4b, 4e, 4f, 4m, 4n, 6e, 6k, 6m, and 6o showed good larvicidal activity against Aedes albopictus, which is both a highly aggressive mosquito and an important viral vector that can transmit a wide range of pathogens. Dipping methods and a bottle bioassay were used for insecticidal activity evaluation. The LC50 values of 4e, 4m, and 6m reached 147.65, 140.08, and 205.79 µg/mL, respectively, whereas the LC50 value of MA was 659.34 µg/mL. Structure-activity relationship analysis demonstrated that larvicidal activity could be improved by the unsaturated heterocyclic groups introduced into the carboxyl group after opening the D ring. The MA derivatives with oxidized N-1 lost their mosquitocidal activities, indicating that the bareness of N-1 is crucial to maintain their anti-mosquito activity. However, the activity was not greatly influenced by introducing a cyan group at C-6 or a benzene sulfonyl group at N-16. Additionally, compounds 4e and 4m exhibited good inhibitory activities against acetylcholinesterase with inhibitory rates of 59.12% and 54.30%, respectively, at a concentration of 250 µg/mL, whereas the inhibitory rate of MA was 9.88%. Therefore, the structural modification and mosquitocidal activity of MA and its derivatives obtained here pave the way for those seeking strong mosquitocidal agents of plant origin.

Naproxen-Derived New Compound Inhibits the NF-κB, MAPK and PI3K/Akt Signaling Pathways Synergistically with Resveratrol in RAW264.7 Cells.

Naproxen is widely used for anti-inflammatory treatment but it can lead to serious side effects. To improve the anti-inflammatory activity and safety, a novel naproxen derivative containing cinnamic acid (NDC) was synthesized and used in combination with resveratrol. The results showed that the combination of NDC and resveratrol at different ratios have a synergistic anti-inflammatory efficacy in RAW264.7 macrophage cells. It was indicated that the combination of NDC and resveratrol at a ratio of 2:1 significantly inhibited the expression of carbon monoxide (NO), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), induced nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2) and reactive oxygen species (ROS) without detectable side effects on cell viability. Further studies revealed that these anti-inflammatory effects were mediated by the activation of nuclear factor kappa-B (NF-κB), mitogen-activated protein kinase (MAPK) and phosphoinositide-3 kinase (PI3K)/protein kinase B (Akt) signaling pathways, respectively. Taken together, these results highlighted the synergistic NDC and resveratrol anti-inflammatory activity that could be further explored as a strategy for the treatment of inflammatory disease with an improved safety profile.

The fern economics spectrum is unaffected by the environment.

The plant economics spectrum describes the trade-off between plant resource acquisition and storage, and sheds light on plant responses to environmental changes. However, the data used to construct the plant economics spectrum comes mainly from seed plants, thereby neglecting vascular non-seed plant lineages such as the ferns. To address this omission, we evaluated whether a fern economics spectrum exists using leaf and root traits of 23 fern species living under three subtropical forest conditions differing in light intensity and nutrient gradients. The fern leaf and root traits were found to be highly correlated and formed a plant economics spectrum. Specific leaf mass and root tissue density were found to be on one side of the spectrum (conservative strategy), whereas photosynthesis rate, specific root area, and specific root length were on the other side of the spectrum (acquisitive strategy). Ferns had higher photosynthesis and respiration rates, and photosynthetic nitrogen-use efficiency under high light conditions and higher specific root area and lower root tissue density in high nutrient environments. However, environmental changes did not significantly affect their resource acquisition strategies. Thus, the plant economics spectrum can be broadened to include ferns, which expands its phylogenetic and ecological implications and utility.

The phase stability of predicted pentazole derivate compounds under high pressure.

Pentazole as one typical extreme explosive has been applied in the synthesis of a metal pentazole complex under extremely-high pressure and low temperature. In order to evaluate the stabilities and detonation performances of pentazole complexes in possible applications, we predict four pentazole derivate molecules and crystals (dipentazole, octaazapentalene, azidopentazole and tripentazolamine) based on DFT and Monte-Carlo methods, wherein both crystalline octaazapentalene and tripentazolamine display remarkable dynamic stabilities and excellent denotation properties. To understand the relationship between the structures and gradually increased pressure, all the predicted crystal structures are studied under gradually increased pressure from ambient pressure to 200 Gpa. In response to extremely high pressures, the stability of the energetic crystals is dominated by molecular compressibility under limit states, where the bond cleavage results in structural dissociation under high pressure. However, low molecular planarization energy generally corresponds to a pressure-induced phase transition of pentazolate crystals.

New insight into the electronic structure of SiF4: synergistic back-donation and the eighteen-electron rule.

SiF4 demonstrated high thermal stability in dry air or vacuum, and a Si-F bond length of 1.554 Å is close to the second period element C-C bond length (1.54 Å) of C2H6. To determine which factors confer this property of SiF4, here we conduct a comparative study of a series of molecules SiHnF4-n (n = 0, 1, 2, 3), SiX4 (X = Cl, Br, I), CF4 and TiF4 in terms of bond length and energy, molecular orbitals, and adaptive natural density partitioning (AdNDP) analysis. The AdNDP analysis shows that there are five 5c-2c bonds in SiF4, here named synergistic back-donation (SBD) bonds. These SBD bonds together with the Si-F σ bonds and the eighteen-electron rule are demonstrated as the main factors contributing to the short Si-F bond length and the high thermal stability of SiF4 in dry air or vacuum. Moreover, the SBD bonds exist widely in other isoelectronic species of SiF4 such as ClO4-, SO42-, PO43- and XeO4.

Exoergic pathways triggered by O/H radicals in different metallic carbohydrazide perchlorates (M2+ = Mn2+, Fe2+, Co2+, Ni2+, Zn2+ and Cd2+).

Metallic carbohydrazide perchlorates (M[(N2H3)2C = O](ClO4)2, M2+ = Mn2+, Fe2+, Co2+, Ni2+, Zn2+ and Cd2+, simplified as MCPs) are a series of energetic primary explosives, among which ZnCP and CdCP are already applied in civilian/military fields. The six MCPs possess similar structures but demonstrate different energetic performances in their decomposition, which are obviously determined by their different central metals. Here, we apply DFT and Car-Parrinello molecular dynamics (CPMD) to understand the electronic structures and decomposition pathways of the MCPs. Based on the results, the crystal MCPs with larger electronic band gaps show lower impact sensitivity. However, the friction sensitivity of MCPs is dominated by the strength of their intermolecular O⋯H interactions. In the CPMD simulations, we obtained a different conclusion from the traditional viewpoint, where the decomposition is spontaneous from the cleavage of M-N bonds. Indeed, there are two stages in the decomposition of the MCPs, based on our calculations: (I) nonspontaneous 3-step departure of the CHZ groups and (II) spontaneous exoergic decomposition pathways of the CHZ groups triggered by the transfer of O/H radicals. Our study provides a systematic study of the MCP family, which also affords a new route for understanding the relationship between the energetic properties and electronic structures of energetic metal complexes.

Novel 18ß-glycyrrhetinic acid derivatives as a Two-in-One agent with potent antimicrobial and anti-inflammatory activity.

18ß-glycyrrhetinic acid (GA) is a well-known natural compound of oleanane-type triterpene and is found possessing antimicrobial and anti-inflammatory properties. Nonetheless, its relatively low bioactivity restricts its potential in pharmaceutical applications. To maximize the potential use of this natural herbal compound as antimicrobial and anti-inflammatory agents, the rational modification of GA to enhance its pharmacological activity with low toxicity and to understand the mechanism of action is critically essential. We reported herein the design and synthesis of a series of new GA derivatives. The antimicrobial activities of these new compounds were evaluated by inhibition zone test and minimum inhibitory concentration (MIC) assay. In addition, the anti-inflammatory activity was evaluated by LPS induced BV2 cells inflammation model and 12-O-tetradecanoyl phorbol-13-acetate (TPA) induced ear inflammation mice model. It was found that the derivatives functionalized with a di-substituted phenyl group at the 2-position of GA generally displayed high antimicrobial activity against Gram-positive bacteria (MIC down to 2.5 µM) and potent anti-inflammatory effects (inhibition of NO production up to 55%, comparable to dexamethasone). The in vitro and in vivo results also showed that GA-O-02 and GA-O-06 exert their anti-inflammatory activities through downregulation of NO, pro-inflammatory cytokines and chemokines (IL-1ß, IL-6, IL-12, TNF-α, MCP-1 and MIP-1α) and upregulation of anti-inflammatory cytokines (IL-10). The anti-inflammatory mechanism may involve the inhibition of NF-κB, MAPKs and PI3K/Akt related inflammatory signaling pathways and activation of Nrf2/HO-1 signaling pathway. The results demonstrated that GA-O-02 and GA-O-06 possess great application potential as potent antimicrobial and anti-inflammatory agents.

Crosstalk of TetR-like regulator SACE_4839 and a nitrogen regulator for erythromycin biosynthesis.

TetR family transcriptional regulators (TFRs) are widespread in actinomycetes, which exhibit diverse regulatory modes in antibiotic biosynthesis. Nitrogen regulators play vital roles in modulation of primary and secondary metabolism. However, crosstalk between TFR and nitrogen regulator has rarely been reported in actinomycetes. Herein, we demonstrated that a novel TFR, SACE_4839, was negatively correlated with erythromycin yield in Saccharopolyspora erythraea A226. SACE_4839 indirectly suppressed erythromycin synthetic gene eryAI and resistance gene ermE and directly inhibited its adjacent gene SACE_4838 encoding a homologue of nitrogen metabolite repression (NMR) regulator NmrA (herein named NmrR). The SACE_4839-binding sites within SACE_4839-nmrR intergenic region were identified. NmrR positively controlled erythromycin biosynthesis by indirectly stimulating eryAI and ermE and directly repressing SACE_4839. NmrR was found to affect growth viability under the nitrogen source supply. Furthermore, NmrR directly repressed glutamine and glutamate utilization-related genes SACE_1623, SACE_5070 and SACE_5979 but activated nitrate utilization-associated genes SACE_1163, SACE_4070 and SACE_4912 as well as nitrite utilization-associated genes SACE_1476 and SACE_4514. This is the first reported NmrA homolog for modulating antibiotic biosynthesis and nitrogen metabolism in actinomycetes. Moreover, combinatorial engineering of SACE_4839 and nmrR in the high-yield S. erythraea WB resulted in a 68.8% increase in erythromycin A production. This investigation deepens the understanding of complicated regulatory network for erythromycin biosynthesis. KEY POINTS: • SACE_4839 and NmrR had opposite contributions to erythromycin biosynthesis. • NmrR was first identified as a homolog of another nitrogen regulator NmrA. • Cross regulation between SACE_4839 and NmrR was revealed.

Synthesis and bioactivities evaluation of oleanolic acid oxime ester derivatives as α-glucosidase and α-amylase inhibitors.

Different oleanolic acid (OA) oxime ester derivatives (3a-3t) were designed and synthesised to develop inhibitors against α-glucosidase and α-amylase. All the synthesised OA derivatives were evaluated against α-glucosidase and α-amylase in vitro. Among them, compound 3a showed the highest α-glucosidase inhibition with an IC50 of 0.35 µM, which was ∼1900 times stronger than that of acarbose, meanwhile compound 3f exhibited the highest α-amylase inhibitory with an IC50 of 3.80 µM that was ∼26 times higher than that of acarbose. The inhibition kinetic studies showed that the inhibitory mechanism of compounds 3a and 3f were reversible and mixed types towards α-glucosidase and α-amylase, respectively. Molecular docking studies analysed the interaction between compound and two enzymes, respectively. Furthermore, cytotoxicity evaluation assay demonstrated a high level of safety profile of compounds 3a and 3f against 3T3-L1 and HepG2 cells.HighlightsOleanolic acid oxime ester derivatives (3a-3t) were synthesised and screened against α-glucosidase and α-amylase.Compound 3a showed the highest α-glucosidase inhibitory with IC50 of 0.35 µM.Compound 3f presented the highest α-amylase inhibitory with IC50 of 3.80 µM.Kinetic studies and in silico studies analysed the binding between compounds and α-glucosidase or α-amylase.

Inhibitory effect of roburic acid in combination with docetaxel on human prostate cancer cells.

Roburic acid (ROB) is a naturally occurred tetracyclic triterpenoid, and the anticancer activity of this compound has not been reported. Docetaxel (DOC) is the first-line chemotherapeutic agent for advanced stage prostate cancer but toxic side effects and drug resistance limit its clinical success. In this study, the potential synergistic anticancer effect and the underlying mechanisms of ROB in combination with DOC on prostate cancer were investigated. The results showed that ROB and DOC in combination synergistically inhibited the growth of prostate cancer cells. The combination also strongly induced apoptosis, and suppressed cell migration, invasion and sphere formation. Mechanistic study showed that the combined effects of ROB and DOC on prostate cancer cells were associated with inhibition of NF-κB activation, down regulation of Bcl-2 and up regulation of Bax. Knockdown of NF-κB by small interfering RNA (siRNA) significantly decreased the combined effect of ROB and DOC. Moreover, we found that esomeprazole (ESOM), a proton pump inhibitor (PPI), strongly enhanced the effectiveness of ROB and DOC on prostate cancer cells in acidic culture medium. Since acidic micro environment is known to impair the efficacy of current anticancer therapies, ESOM combined with ROB and DOC may be an effective approach for improving the treatment of prostate cancer patients.