Inhibitory Activity Research Articles

Mechanistic Investigation of the Pyrolysis Temperature of Reed Wood Vinegar for Maximising the Antibacterial Activity of Escherichia coli and Its Inhibitory Activity

To solve the problem of large-scale growth of wetland reeds, wood vinegar, a by-product of pyrolysed reed wood vinegar, can be used as a natural antimicrobial agent. In this study, we compare the changes in growth and bacterial morphology of Escherichia coli (E. coli) treated with reed wood vinegar at different pyrolysis temperatures (300 °C, 500 °C and 700 °C) and reveal the bacterial inhibition mechanism of reed wood vinegar by RNA-Seq. The results of bacteria inhibitory activity showed that 1/2MIC 500 °C wood vinegar had the most prominent bacteria inhibitory activity. qPCR results showed that reed wood vinegar was able to significantly inhibit the expression of E. coli biofilm and genes related to the cell membrane transporter proteins. Electron microscopy observed that the wood vinegar disrupted the cellular morphology of E. coli, resulting in the crumpling of E. coli cell membranes. RNA-Seq showed the multifaceted antimicrobial effects of wood vinegar and demonstrated that the inhibitory effect of wood vinegar on E. coli was mainly realized through the inhibition of the expression of malE, which is an ATP-binding cassette (ABC) transporter complex of E. coli. In conclusion, our study provides an effective method and a theoretical basis for the mechanism of reed wood vinegar as a natural antimicrobial agent and its pathway of bacterial inhibition.

Aromatic polyketides isolated from the marine-derived fungus Didymella aeria and their neuroprotective activity.

Two novel aromatic polyketides, penicanesins J and K (1, 2), were isolated from the marine-derived fungus Didymella aeria, along with the known compound integrastatin B (3). The structures of the new compounds were determined by NMR spectroscopy and synthetic methods. The isolated compounds were tested for monoamine oxidase (MAO) B inhibition, anti-amyloid beta (Aβ) aggregation, and protective activity against H2O2-induced cell death in human neuroblastoma SH-SY5Y cells. Integrastatin B (3) showed potential activity for inhibition of Aβ aggregation and protection against H2O2-induced cell death.

The effect of unilateral hand muscle contraction on frontal alpha asymmetry and inhibitory control in intrinsic reward contexts, a randomized controlled trial

Challenged inhibitory control has been implicated in various disorders, including addiction. Previous research suggests that asymmetry of frontal brain activity, indexed by frontal alpha asymmetry (FAA), is associated with inhibitory control and could be a target for neuromodulatory intervention. Some evidence suggests that unilateral muscle contraction (UMC) can modulate FAA; however, experimental evidence is scarce. We conducted a randomized controlled trial, with 65 participants (Mage = 26.6; SD = 7.4), 37 of whom were females. We collected EEG data to calculate FAA and assessed inhibitory performance using the Stop Signal Task (SST) in neutral and intrinsic reward (palatable food) conditions, both before and after a unilateral left-hand muscle contraction task aimed at enhancing right relative to left frontal activity. We found a significant main effect of group on FAA. Specifically, UMC group was associated with higher right relative to left frontal activity, associated with resting state inhibitory activity. Event-related potential analyses revealed a significant dissociation between the stop N2 and stop P3 components as a function of time. More specifically, as time progressed, the stop N2 was enhanced, while the stop P3 was reduced. These results did not lead to observable changes in the behavioral index of stopping. In conclusion, UMC did not affect any behavioral and brain activity indices. There is some indication of a potential effect on FAA. However, this effect could reflect coincidental differences in trait FAA. Our findings provide new insights into the temporal dynamics of brain activity indices of inhibitory control.

Structure-based design and synthesis of novel FXIa inhibitors targeting the S2' subsite for enhanced antithrombotic efficacy.

Factor XIa (FXIa), a key component of the intrinsic coagulation pathway, has recently been recognized as a safe and effective target for antithrombotic therapy. Research indicates that FXIa inhibitors can lower bleeding risk compared to novel oral anticoagulants. In this study, we designed and synthesized a series of novel FXIa inhibitors based on the structure of Asundexian, with a particular focus on optimizing the P2' region to enhance binding to the S2' subsite of FXIa. This strategy led to the discovery of compound F47, which demonstrated significantly greater FXIa inhibition (IC50 = 2.0nM) compared to Asundexian (IC50 = 5.0nM). F47 also showed excellent anticoagulant activity in the aPTT assay (EC2x = 0.4μM), with strong efficacy and minimal impact on the extrinsic coagulation pathway. Additionally, F47 exhibited inhibitory activity against plasma kallikrein (PKal), with selectivity comparable to that of Asundexian. The compound also displayed acceptable stability in human liver microsomal stability assays. Molecular modeling revealed that F47 binds tightly to the S1, S1', and S2' pockets of FXIa while maintaining key interactions; notably, its P2' moiety forms two additional π-π stacking interactions with the crucial amino acid TYR143. Further studies demonstrated that F47 exhibits dose-dependent antithrombotic efficacy in a rat FeCl3-induced thrombosis model. Ongoing research aims to further elucidate the potential of compound F47 as a promising lead in antithrombotic therapy.

Cervicovaginal lavages uncover growth factors as key biomarkers for early diagnosis and prognosis of endometrial cancer

Endometrial cancer (EC) rates are continuing to rise and it remains the most common gynecologic cancer in the US. Existing diagnostic methods are invasive and can cause pain and anxiety. Hence, there is a need for less invasive diagnostics for early EC detection. The study objective was to evaluate the utility of growth factors collected through minimally invasive cervicovaginal lavage (CVL) sampling as diagnostic and prognostic biomarkers for EC. CVL samples from 192 individuals undergoing hysterectomy for benign or malignant conditions were collected and used to quantify the concentrations of 19 growth and angiogenic factors using multiplex immunoassays. Patients were categorized based on disease groups: benign conditions (n = 108), endometrial hyperplasia (n = 18), and EC (n = 66). EC group was stratified into grade 1/2 endometrial endometrioid cancer (n = 53) and other EC subtypes (n = 13). Statistical associations were assessed using receiver operating characteristics, Spearman correlations and hierarchical clustering. Growth and angiogenic factors: angiopoietin-2, endoglin, fibroblast activation protein (FAP), melanoma inhibitory activity, and vascular endothelial growth factor-A (VEGF-A) were significantly (p < 0.0001) elevated in EC patients. A multivariate model combining 11 proteins with patient age and body mass index exhibited excellent discriminatory potential (area under curve = 0.918) for EC, with a specificity of 90.7% and a sensitivity of 87.8%. Moreover, angiopoietin-2, FAP and VEGF-A significantly (p < 0.05–0.001) associated with tumor grade, size, myometrial invasion, and mismatch repair status. Our results highlight the innovative use of growth and angiogenic factors collected through CVL sampling for the detecting endometrial cancer, showcasing not only their diagnostic potential but also their prognostic value.

Antioxidant activity and whitening effect of vitamin C and superoxide dismutase from Rosa roxburghii Tratt

Abstract With growing concerns about the negative impact of environmental pollution on skin health, there is an increased demand for natural active ingredients to combat free radicals and excessive melanin production. We focus on the Rosa roxburghii Tratt (RR) as a potential source of skin-lightening compounds. Vitamin C (Vc) and superoxide dismutase (SOD)-rich extracts (RRVC and RRSOD) were extracted from RR using macroporous resin column chromatography and graded ammonium sulfate precipitation. The antioxidant and skin-lightening effects of these extracts were evaluated. RRVC and RRSOD showed strong inhibitory activity against various radicals and tyrosinase. When formulated together, their antioxidant and skin-lightening abilities were significantly enhanced, with an optimal ratio of 5:32 (RRVS). In vivo studies on C57BL/6J mice revealed that these two extracts and their formulations effectively lowered oxidative stress levels in a model of D-galactose-induced aging in mice. Furthermore, they inhibited melanogenesis, and tyrosinase activity in B16 cells and reduced UV (ultraviolet radiation)-induced melanin deposition in mouse ears. The combination of RRVC and RRSOD had a more potent melanin-scavenging effect compared with the individual extracts. These findings suggest that RRVC and RRSOD extracts, especially when combined in the optimal ratio, can whiten skin, both enhancing the value of RR products and offering natural alternatives for skin lightening.

Synthesis and evaluation of fluorinated piperazine‐hydroxyethylamine analogues as potential antiplasmodial candidates

In this manuscript, twenty‐one novel fluorinated piperazine‐hydroxyethylamine analogues were synthesized and tested against Plasmodium falciparum (Pf). Among tested compounds, two 13g and 14g exhibited promising inhibitory activity on Pf3D7 with IC50 values of 0.28 and 0.09 µM, respectively. Neither of the hits exhibited cytotoxicity on HepG2 cells up to 150 µM and Vero cells up to 20 µM. Compounds 13g and 14g were also evaluated against chloroquine‐resistant PfDd2 and displayed IC50 values of 0.11 and 0.10 µM, respectively. Next, 13g and 14g were administered to the Plasmodium berghei mice model at 30mg/kg intraperitoneally for four consecutive doses, which showed 25% and 50% reduction in the parasitemia load, respectively. The efficacy of hits 13g and 14g was improved along with mean survival time when administered in combination with artesunate. On liver‐stage parasites, compounds 13g and 14g showed &gt;90% inhibition at 1µM. Compound 14g was also tested for toxicity in mice at 100 mg/kg dose, which revealed no abnormality in mice organs. Preliminary pharmacokinetic studies of compound 14g exhibited absorption and maintained a presence in the body for more than six hours.

Phytosterols as inhibitors of New Delhi metallo-β-lactamase (NDM-1): an in silico study.

The global emergence of New Delhi metallo-β-lactamase-1 (NDM-1) poses a formidable challenge to antibiotic therapy, as it confers resistance to a wide range of β-lactam antibiotics. This study aims to identify potential inhibitors of NDM-1 and thereby restore the effectiveness of the current antibiotics. Employing a comprehensive computational approach integrating molecular docking and molecular dynamics (MD) simulations, a library of phytosterols was screened to identify promising candidates for inhibiting NDM-1 activity. Using the binding energy of meropenem, a frontline carbapenem antibiotic, as a reference, avenasterol, brassicasterol, and stigmasterol emerged as top phytosterol candidates for further investigation. Subsequent MD simulations confirmed the stability of NDM-1 complexes with avenasterol and stigmasterol over the simulation period, indicating their potential efficacy. These findings suggest that avenasterol and stigmasterol may effectively inhibit NDM-1 activity, warranting validation through in vitro and in vivo studies. Furthermore, these phytosterols hold promise as lead compounds for developing novel NDM-1 inhibitors. Their natural origin and potential inhibitory activity against NDM-1 offer compelling avenues for developing alternative antibacterial therapies to combat multidrug-resistant infections. This study underscores the utility of computational methods in drug discovery and highlights the potential of phytosterols as valuable candidates for addressing antibiotic resistance.

Red Yeast Rice or Lovastatin? A Comparative Evaluation of Safety and Efficacy Through a Multifaceted Approach.

The increasing use of red yeast rice (RYR) as a natural supplement to manage blood cholesterol levels is driven by its active compound, monacolin K (MK), which is chemically identical to the statin drug lovastatin (LOV). Despite its growing popularity, concerns persists regarding the safety and efficacy of RYR compared to pure statins. This study aimed to evaluate the phytochemical composition, pharmacological effects, and safety profile of various RYR samples in comparison with LOV. RYR samples with different MK content were analyzed using HPLC-DAD to quantify monacolins and other bioactive compounds. The inhibitory activity on HMG-CoA reductase was assessed through an enzymatic assay, while pharmacokinetic properties were predicted using invitro simulated digestion and in silico models. Invitro cytotoxicity was evaluated in intestinal, hepatic, renal, and skeletal muscle cell models. Additionally, the transcriptional levels of muscle damage-related target genes were evaluated by qRT-PCR in skeletal muscle cells treated with a selection of RYR samples. Significant variability in the phytochemical composition of RYR sampleswas observed, particularly in the content of secondary monacolins, triterpenes, and polyphenols. The RYR phytocomplex exhibited superior inhibition of HMG-CoA reductase activity compared to isolated LOV, suggesting synergistic effects between secondary monacolins and other compounds. Molecular insights revealed that RYR samples had a lower impact on muscle cells than LOV, as reflected also by cell viability. These findings suggest that RYR could serve as a safe alternative to purified statins. However, further research is needed to fully elucidate the mechanisms behind the synergistic activity of the phytocomplex and to firmly establish the clinical efficacy of this natural product.

Development of Mussaenda frondosa sepal infused functional tea with enhanced antioxidant and alpha-amylase inhibitory activities

Mussaenda frondosa (MF) is an edible species of the genus Mussaenda (Rubiaceae) that contains a wide array of medicinal compounds. The present study was conducted to evaluate the physicochemical and functional properties of the MF sepals and to develop a novel herbal tea with improved functional properties. Remarkably high antioxidant and α-amylase inhibitory activities were exhibited by water and ethanol extracts of MF, attributed to their high phenolic and flavonoid contents. None of the extracts showed toxicity, as evaluated by the brine shrimp lethality assay. A tea was formulated by blending different proportions (30, 40 and 50%) of dry sepals of MF with black tea. The sensory analysis showed a significantly high level of acceptance for the formula containing 40% MF (MFT-40) with augmented phenolic contents (138.82 ± 0.21 mg GAE/g), antioxidant (DPPH scavenging activity with IC50 of 12.23 ± 0.45 µg/mL), and hypoglycemic activities (α-amylase inhibition with IC50 of 104.80 ± 0.59 µg/mL) compared to the black tea control (with the values of 128.47 ± 0.13 mg GAE/g, 18.70 ± 0.68 µg/mL and 153.07 ± 0.61 µg/mL respectively). This study revealed the potential use of MF as a source of antioxidants for the development of new functional teas with enhanced health benefits.

Beyond expectations: the development and biological activity of cytokinin oxidase/dehydrogenase inhibitors.

Cytokinins are one of the main groups of plant hormones that regulate growth and development of plants. Cytokinin oxidase/dehydrogenase (CKX) is an enzyme that rapidly and irreversibly degrades cytokinins and thus directly affects their concentration and physiological effect. Genetically modified plants with reduced CKX activity in the shoot, i.e. with a higher concentration of cytokinins, showed e.g. increased tolerance to drought stress, formed larger inflorescences and had higher grain yield. For these reasons, chemical compounds capable of inhibiting the CKX activity (CKX inhibitors) were sought. First, they were identified among strong synthetic cytokinins, but their inhibitory activity was low. The trend has been to develop potent CKX inhibitors with minimal intrinsic cytokinin activity in the hope of avoiding the negative effect of cytokinins on root growth. Cloning CKX, production of key recombinant enzymes from Arabidopsis (AtCKX2) and maize (ZmCKX1 and ZmCKX4a), development of screening bioassays and progress in X-ray crystallography and synthetic organic chemistry led to extensive progress in the development of these compounds. Currently, the most suitable CKX inhibitors are seeking their application in research and the commercial sphere in two main areas - plant tissue cultures and agriculture. The key milestones that preceded it are summarized in this review.

Phytochemical profiling, antioxidant, enzymatic inhibitory, and antibacterial activities of Wigandia ecuadorensis

Phytochemical profiling, antioxidant, enzymatic inhibitory, and antibacterial activities of Wigandia ecuadorensis

DESIGN, SYNTHESIS, AND BIO PROFILING OF 2, 3-DIHYDROQUINAZOLIN-4(1H)-ONE DERIVATIVE AS TYPE II DIABETES AGENTS: A COMPREHENSIVE IN SILICO, IN VITRO, AND IN VIVO STUDY

Objective: Diabetes mellitus is a significant global health challenge, with Type 2 Diabetes Mellitus (T2DM) being a leading cause of mortality worldwide, demanding the need for effective interventions by developing innovative therapeutic strategies or novel antidiabetic agents. This study explores in silico, in vitro, and in vivo approaches to identify the most potent 2,3-Dihydroquinazolin-4(1H)-One derivative molecule with antidiabetic activity. Methods: Eleven new derivatives were designed, studied in silico to identify the most promising compounds, synthesized, studied spectrally to describe them, and evaluated for both in vitro and in vivo investigations. Alpha amylase and alpha-glucosidase inhibitory activities were investigated in vitro. The endogenous suppression of glucose synthesis in Hepatoblastoma cell line 2(HepG2) cells and the in vitro glucose absorption assay on cultivated L6 cell lines were conducted. To assess the ability of the newly synthesized compounds to prevent diabetes, in vivo investigations were conducted on Streptozotocin (STZ)-induced diabetic rats and the effects on various biochemical parameters were identified.Results: Leveraging computational methods, the QZ9 molecule was identified with stable interactions with key biomolecules associated with T2DM. Subsequent in vitro assays confirmed the inhibitory effects of QZ2, QZ8, and QZ9 on alpha-amylase and alpha-glucosidase activities, suggesting their potential as enzyme inhibitors. Additionally, QZ8 and QZ9 demonstrated enhanced glucose uptake and production inhibition in HepG2 cells, indicating their role in improving glucose homeostasis. In vitro, the top-ranked molecules QZ2, QZ8, and QZ9 were analyzed to validate the in silico findings and assess their potential as therapeutic agents for T2DM. The inhibition of α-amylase activity by QZ2, QZ8, and QZ9 was dose-dependent, with maximum inhibition observed at 1000 µg/ml: 57.33% for QZ2, 52.21% for QZ8, and 87.16% for QZ9. Similarly, α-glucosidase inhibition at 1000 µg/ml was 59.96% for QZ2, 53.50% for QZ8, and 81.51% for QZ9. Both QZ8 and QZ9 significantly increased glucose uptake and inhibited glucose production in HepG2 cells, with maximum glucose production inhibition at 100 µg/ml: 62.22% for QZ8 and 62.35% for QZ9. These findings suggest that QZ8 and QZ9 contribute to glucose homeostasis. QZ9 demonstrated superior enzyme inhibition compared to QZ2 and QZ8, with α-amylase and α-glucosidase inhibition up to 87.16% and 81.51%, respectively, at 1000 µg/ml. In vivo investigations in Diabetic rat models further confirmed the efficacy of these compounds by showing significant reductions in blood glucose levels. These results suggests the potentiality of QZ9 as a promising novel Antidiabetic agent.Conclusion: Combining computational predictions with experimental validations, this integrated approach highlights the promise of 2,3-Dihydroquinazolin-4(1H)-One derivative QZ9 as a novel antidiabetic agent, warranting further investigation for clinical translation.

Discovery of novel fused-heterocycle-bearing diarypyrimidine derivatives as HIV-1 potent NNRTIs targeting tolerant region I for enhanced antiviral activity and resistance profile

As an important part of anti-AIDS therapy, HIV-1 non-nucleoside reverse transcriptase inhibitors are plagued by resistance and toxicity issues. Taking our reported XJ-18b1 as lead compound, we designed a series of novel diarypyrimidine derivatives by employing a scaffold hopping strategy to discover potent NNRTIs with improved anti-resistance properties and drug-like profiles. The most active compound 3k exhibited prominent inhibitory activity against wild-type HIV-1 (EC50 = 0.0019 μM) and common mutant strains including K103 N (EC50 = 0.0019 μM), L100I (EC50 = 0.0087 μM), E138K (EC50 = 0.011 μM), along with low cytotoxicity and high selectivity index (CC50 = 21.95 μM, SI = 11478). Additionally, compound 3k demonstrated antiviral activity against HIV-2 with EC50 value of 6.14 μM. The enzyme-linked immunosorbent assay validated that 3k could significantly inhibit the activity of HIV-1 reverse transcriptase (IC50 = 0.025 μM). Furthermore, molecular dynamics simulation studies were performed to illustrate the potential binding mode and binding free energy of the RT-3k complex, and in silico prediction revealed that 3k possessed favorable drug-like profiles. Collectively, 3k proved to be a promising lead compound for further optimization to obtain anti-HIV drug candidates.

In Silico Investigation Targeting the IL-6/JAK-1/TNF-α Pathway in Rheumatoid arthritis: Matricaria chamomilla L. Compounds

Chamomile, emphasized as an herbal remedy with healing potential for human health, is used in traditional medicine. In this study, the potential of compounds derived from Matricaria chamomilla L. against IL-6, JAK-1 and TNF-[Formula: see text] target proteins associated with rheumatoid arthritis (RA) was compared with known inhibitors. The drug-likeness and ADME/T properties of these compounds were investigated using online tools, and molecular docking and molecular dynamics simulations of the selected structures were examined. IL-6, JAK-1 and TNF-[Formula: see text] formed stable complexes with apigenin, quercetin and galaxolide, respectively, demonstrating that these compounds exhibit potential inhibitory activity against RA.

Whole Genome Sequencing and Biocontrol Potential of Streptomyces luteireticuli ASG80 Against Phytophthora Diseases

Phytophthora-induced crop diseases, commonly known as “plant plagues”, pose a significant threat to global food security. In this study, strain ASG80 was isolated from sisal roots and demonstrated a broad-spectrum antagonistic activity against several Phytophthora species and fungal pathogens. Strain ASG80 was identified as Streptomyces luteireticuli via phylogenetic analysis, digital DNA–DNA hybridization (dDDH), and average nucleotide identity (ANI). Whole-genome sequencing identified 40 biosynthetic gene clusters (BGCs) related to secondary metabolite production, including antimicrobial compounds. Strain ASG80 extract exhibited broad-spectrum inhibitory activity against Phytophthora nicotianae, P. vignae, P. cinnamomi, and P. sojae. Pot experiments showed that strain ASG80 extract significantly reduced sisal zebra disease incidence, with an efficacy comparable to the fungicide metalaxyl. These findings suggest that strain ASG80 is a promising biocontrol agent with substantial potential for managing Phytophthora-related diseases in agriculture.

Discovery of novel thiosemicarbazone-acridine targeting butyrylcholinesterase with antioxidant, metal complexing and neuroprotector abilities as potential treatment of Alzheimer's disease: In vitro, in vivo, and in silico studies

Inhibition of cholinesterases, combined with antioxidant activity, metal-chelating capacity, and neuroprotection, is recognized as an effective multitarget therapy for the treatment of Alzheimer's disease (AD). Based on our in-house thiosemicarbazone-acridine compounds, this study recognized these derivatives as possible multi-target-directed ligand (MTDL). Initial screening against cholinesterases identified CL-01, which exhibited a promising IC50 value of 0.71 μM against butyrylcholinesterase (BChE). Twelve new derivatives were designed based on CL-01 aiming to retain the BChE inhibitory activity while incorporating a MTDL profile, including antioxidant properties and metal-complexing abilities. Among the new derivatives, CL-13 maintained a good BChE inhibition (IC50 = 1.15 μM) with improved selective index against acetylcholinesterase (SI = 9.2). The acridine nucleus was important for the activity, as its saturated tetrahydroacridine analogue (TA-01) showed a decrease in cholinesterases inhibition potencies and altered the mode of inhibition, revealing for the first time distinct functional roles for the two nuclei. Moreover, CL-13 emerged as a promising lead compound, demonstrating interesting antioxidant activity (DPPH EC50 = 47.01 μM), chelating capacity of biometals involved in Aβ aggregation and/or oxidative stress, and a lack of neurotoxicity at 50 μM in SH-SY5Y cells. It also exhibited neuroprotective effects in an in vitro oxidative stress model induced by H2O2. Finally, in vivo experiments confirmed that CL-13 effectively reversed scopolamine-induced cognitive impairment, without affecting locomotor activity in the mice.

Anthrax lethal toxin exerts potent metabolic inhibition of the cardiovascular system.

Bacillus anthracis causes anthrax through a combination of bacterial infection and toxemia. As a major virulence factor of B. anthracis, anthrax lethal toxin (LT) is a zinc-dependent metalloproteinase, exerting its cytotoxicity through proteolytic cleavage of the mitogen-activated protein kinase kinases, thereby shutting down the MAPK pathways. Anthrax lethal toxin induces host lethality mostly by targeting the cardiovascular system. Although the enzymatic activity and the molecular targets of LT have long been known, the detailed mechanisms underlying cellular/tissue/organ toxicity are still poorly understood. In this work, we sought to investigate the mechanism of LT-induced cellular damage in the cardiovascular system. We demonstrate for the first time that anthrax lethal toxin has potent inhibitory effects on the central metabolism of cardiomyocytes and endothelial cells. This is likely due to the observed downregulating of c-Myc expression through the toxin-induced inhibition of the ERK pathway. Since c-Myc is a master transcription factor controlling the expression of many rate-limiting metabolic enzymes in glycolysis and the tricarboxylic acid cycle, LT's downregulation of c-Myc may lead to the observed bioenergetic collapse, particularly, in cardiomyocytes. Since cardiac cell contraction requires continuous production of large amounts of ATP, potent inhibition of the bioenergetics of cardiomyocytes would be incompatible with life. Thus, LT-induced lethality through targeting cardiomyocytes and endothelial cells appears to be a consequence of a bioenergetic collapse, likely due to the toxin's potent inhibitory activity on the MEK-ERK-c-Myc-metabolic/bioenergetic axis within these target cells of cardiovascular system.IMPORTANCEAnthrax lethal toxin (LT) is a major virulence factor of Bacillus anthracis, the causative pathogen of anthrax disease. Anthrax lethal toxin is a metalloproteinase that cleaves and inactivates MEKs, thereby shutting down MAPK pathways, leading to host mortality primarily through targeting of the cardiovascular system. However, the detailed mechanisms underlying the toxin's cellular and tissue toxicity are still poorly understood. Here, we found that anthrax lethal toxin has potent inhibitory activity on glycolysis and oxidative phosphorylation of cardiomyocytes and endothelial cells. These effects appear to be the consequence of downregulation of c-Myc, a master transcription factor that controls many rate-limiting enzymes of glycolysis and the tricarboxylic acid cycle. With the high demand on energy for cardiac contraction, the potent inhibition of cardiomyocyte metabolism by LT would be incompatible with life. This work provides critical insights into why the cardiovascular system is the major in vivo target of LT-induced lethality.

Chemical Constituents and AChE Inhibitory Activities of Four Soil-Derived Streptomyces

Chemical Constituents and AChE Inhibitory Activities of Four Soil-Derived Streptomyces

Studies on the synthesis, crystal structures, biological activities and molecular docking of novel natural methylxanthine derivatives containing piperazine moiety.

A series of novel methylxanthine Mannich base derivatives containing substituted piperazine groups were synthesized through Mannich reaction. The structures of these new compounds were confirmed by NMR, HRMS or elemental analyses, and X-ray single crystal diffraction. Bioassay results showed that some of the compounds exhibit favorable fungicidal and insecticidal potentials. Particularly, compounds IIk, IIq, IIs and compounds If, IIk against Physalospora piricola and Rhizoctonia cerealis, respectively, were comparable with Azoxystrobin and Chlorothalonil; compound Ik exhibited higher potency than Triflumuron against Plutella xylostella L., suggesting its potential as a lead compound for further development in insecticidal applications. Despite possessing weak herbicidal activities, the target compounds, especially the methylxanthine S-Mannich base derivatives I displayed remarkable inhibitory activities toward ketol-acid reductoisomerase (KARI); compounds Ib, If, and Ik which had Ki values of 2.41-8.08 µmol/L can be novel potent KARI inhibitors for deeper exploration. The SARs were analyzed in detail. The molecular docking studies on the highly active inhibitors with KARI provided possible binding modes between inhibitor and the target enzyme. The physicochemical parameter predictions indicated that compounds Ik, IIk, IIq and IIs have "druglike structure" features. The research results in this article may bring a new inspiration to the extensive explorations on new methylxanthine derivatives in pesticide area.