Search

Unstable tetra(methoxycarbonyl)cyclopentadienone was investigated in the synthesis of electron-deficient cycloheptatrienes via [4+2]-cycloaddition/cycloelimination reaction with cyclopropenes. The use of its stable dimer did not afford the product although similar reactions with alkynes have been reported. Quantum chemical calculation revealed that cyclopentadienone is not generated from the dimer and the reaction with alkynes proceeds via a more complicated cycloelimination/cycloaddition/cycloelimination cascade. However, the formation of cycloheptatrienes was found favorable over the formation of the dimer. Therefore, the trapping of tetra(methoxycarbonyl)cyclopentadienone upon formation was successful to give cycloheptatrienes with five ester groups. The use of methyl coumalate as a four-electron component was successful with cyclopropenes containing only one ester group to afford only two ester groups in the product. [ABSTRACT FROM AUTHOR]

This article explores the total synthesis of lucidumone, a compound found in Ganoderma lucidum mushrooms that has potential therapeutic applications for inflammation treatment. The authors detail their approach to synthesizing lucidumone, with a focus on the formation of a specific molecular structure. They discuss the challenges they encountered during the synthesis process, including the selection of protecting groups and the introduction of a methyl ketone. Despite these challenges, the researchers were ultimately successful in synthesizing lucidumone in an efficient manner, with a high yield and scalability. The article also provides experimental results and procedures for key steps in the synthesis. [Extracted from the article]

Type III polyketide synthases (type III PKSs) are single homodimeric enzymes that produce diverse products such as phloroglucinol, pyrones, resorcinols and chalcones which are biotechnologically important molecules. In an attempt to identify new type III PKS from extreme environments, the deep-sea sediment metagenome from Bay of Bengal was screened for type III PKS genes. BLASTX analyses of Nanopore sequence derived metagenome with the in-house created PKS database revealed a full length type III PKS from a 5 kb fragment. The annotated full length type III PKS, S9PKS showed 25–30 % sequence identity towards previously characterized enzymes. To functionally characterize the gene, it was synthesized, cloned into pET28a and pColdI vectors under T7 and csp promoters, respectively, and expressed in Escherichia coli Rosetta(DE3) pLysS. The optimized PKS (OptiPKS) was expressed as inclusion bodies under both promoters. The inclusion bodies were successfully solubilised using low concentration of urea, refolded and purified using Ni-NTA Agarose resin. The purified OptiPKS was tested for functionality using fatty acyl-CoA substrates at various temperatures. High performance liquid chromatography (HPLC) analyses revealed that OptiPKS produced tri and tetraketide pyrones using C 4 to C 10 acyl-CoA starter substrates. Further characterization and mutation of the enzyme would reveal its functional significance. Thus, the study could be a lead for the annotation and functional characterization of putative type III PKS from environmental metagenome data. [Display omitted] [ABSTRACT FROM AUTHOR]

Plants and microbes share common metabolic pathways for producing a range of bioproducts that are potentially foundational to the future bioeconomy. However, in planta accumulation and microbial production of bioproducts have never been systematically compared on an economic basis to identify optimal routes of production. A detailed technoeconomic analysis of four exemplar compounds (4-hydroxybenzoic acid [4-HBA], catechol, muconic acid, and 2-pyrone-4,6-dicarboxylic acid [PDC]) is conducted with the highest reported yields and accumulation rates to identify economically advantaged platforms and breakeven targets for plants and microbes. The results indicate that in planta mass accumulation ranging from 0.1 to 0.3 dry weight % (dwt%) can achieve costs comparable to microbial routes operating at 40 to 55% of maximum theoretical yields. These yields and accumulation rates are sufficient to be cost competitive if the products are sold at market prices consistent with specialty chemicals ($20 to $50/kg). Prices consistent with commodity chemicals will require an order-of-magnitude-greater accumulation rate for plants and/or yields nearing theoretical maxima for microbial production platforms. This comparative analysis revealed that the demonstrated accumulation rates of 4-HBA (3.2 dwt%) and PDC (3.0 dwt%) in engineered plants vastly outperform microbial routes, even if microbial platforms were to reach theoretical maximum yields. Their recovery and sale as part of a lignocellulosic biorefinery could enable biofuel prices to be competitive with petroleum. Muconic acid and catechol, in contrast, are currently more attractive when produced microbially using a sugar feedstock. Ultimately, both platforms can play an important role in replacing fossil-derived products.

The mechanism and dynamics for the formation of the delitschiapyrone family of natural products are studied by density functional theory (DFT) calculations and quasiclassical molecular dynamics simulations with DFT and xTB. In the uncatalyzed reaction, delitschiapyrones A and B are formed by Diels-Alder reactions through a single transition state and a post-transition state bifurcation that favors formation of delitschiapyrone B. In water and most likely in the enzyme, the acidic hydroxyquinone ionizes, and the resulting conjugate base undergoes cycloaddition preferentially to delitschiapyrone A. We demonstrate a new type of biosynthetic transformation and variable selectivity from a (4 + 2)/(4 + 3) ambimodal transition state.

Intron selection during the formation of prespliceosomes is a critical event in pre-mRNA splicing. Chemical modulation of intron selection has emerged as a route for cancer therapy. Splicing modulators alter the splicing patterns in cells by binding to the U2 snRNP (small nuclear ribonucleoprotein)-a complex chaperoning the selection of branch and 3' splice sites. Here we report crystal structures of the SF3B module of the U2 snRNP in complex with spliceostatin and sudemycin FR901464 analogs, and the cryo-electron microscopy structure of a cross-exon prespliceosome-like complex arrested with spliceostatin A. The structures reveal how modulators inactivate the branch site in a sequence-dependent manner and stall an E-to-A prespliceosome intermediate by covalent coupling to a nucleophilic zinc finger belonging to the SF3B subunit PHF5A. These findings support a mechanism of intron recognition by the U2 snRNP as a toehold-mediated strand invasion and advance an unanticipated drug targeting concept.

Fungi produce secondary metabolites that are not directly involved in their growth, but often contribute to their adaptation to extreme environmental stimuli and enable their survival. Conidial pigment or melanin is one of the secondary metabolites produced naturally by a polyketide synthesis (PKS) gene cluster in several filamentous fungi and is known to protect these fungi from extreme radiation conditions. Several pigmented or melanized fungi have been shown to grow under extreme radiation conditions at the Chernobyl nuclear accident site. Some of these fungi, including Paecilomyces variotii, were observed to grow towards the source of radiation. Therefore, in this study, we wanted to identify if the pigment produced by P. variotii, contributes to providing protection against radiation condition. We first identified the PKS gene responsible for synthesis of pigment in P. variotii and confirmed its role in providing protection against UV irradiation through CRISPR-Cas9 mediated gene deletion. This is the first report that describes the use of CRISPR methodology to create gene deletions in P. variotii. Further, we showed that the pigment produced by this fungus, was not inhibited by DHN-melanin pathway inhibitors, indicating that the fungus does not produce melanin. We then identified the pigment synthesized by the PKS gene of P. variotii, as a naptho-pyrone Ywa1, by heterologously expressing the gene in Aspergillus nidulans. The results obtained will further aid in understanding the mechanistic basis of radiation resistance.

2-Pyrone-4,6-dicarboxylic acid (PDC), a chemically stable intermediate that naturally occurs during microbial degradation of lignin by bacteria, represents a promising building block for diverse biomaterials and polyesters such as biodegradable plastics. The lack of a chemical synthesis method has hindered large-scale utilization of PDC and metabolic engineering approaches for its biosynthesis have recently emerged. In this study, we demonstrate a strategy for the production of PDC via manipulation of the shikimate pathway using plants as green factories. In tobacco leaves, we first showed that transient expression of bacterial feedback-resistant 3-deoxy-D-arabinoheptulosonate 7-phosphate synthase (AroG) and 3-dehydroshikimate dehydratase (QsuB) produced high titers of protocatechuate (PCA), which was in turn efficiently converted into PDC upon co-expression of PCA 4,5-dioxygenase (PmdAB) and 4-carboxy-2-hydroxymuconate-6-semialdehyde dehydrogenase (PmdC) derived from Comamonas testosteroni. We validated that stable expression of AroG in Arabidopsis in a genetic background containing the QsuB gene enhanced PCA content in plant biomass, presumably via an increase of the carbon flux through the shikimate pathway. Further, introducing AroG and the PDC biosynthetic genes (PmdA, PmdB, and PmdC) into the Arabidopsis QsuB background, or introducing the five genes (AroG, QsuB, PmdA, PmdB, and PmdC) stacked on a single construct into wild-type plants, resulted in PDC titers of ~1% and ~3% dry weight in plant biomass, respectively. Consistent with previous studies of plants expressing QsuB, all PDC producing lines showed strong reduction in lignin content in stems. This low lignin trait was accompanied with improvements of biomass saccharification efficiency due to reduced cell wall recalcitrance to enzymatic degradation. Importantly, most transgenic lines showed no reduction in biomass yields. Therefore, we conclude that engineering plants with the proposed de-novo PDC pathway provides an avenue to enrich biomass with a value-added co-product while simultaneously improving biomass quality for the supply of fermentable sugars. Implementing this strategy into bioenergy crops has the potential to support existing microbial fermentation approaches that exploit lignocellulosic biomass feedstocks for PDC production.

Anaerobic bacteria are a promising new source for natural product discovery. Examination of extracts from the obligate anaerobe Clostridium roseum led to the discovery of a new family of natural products, the clostyrylpyrones. The polyketide synthase-based biosynthetic mechanism of clostyrylpyrones is further proposed on the basis of bioinformatic, gene knockout, biochemical analysis, and heterologous expression studies.

We report an asymmetric inverse-electron-demand Diels–Alder reaction of electron-deficient 2-pyrones with various phenyl vinyl selenides catalyzed by a chiral bis(oxazoline)/Cu(OTf)2 complex. By using a side-arm-modified chiral bis(oxazoline)ligand, a variety of [2,2,2]-bicyclic lactones with phenyl selenide substituents were obtained in good to excellent yields (up to 99%) and enantioselectivities (up to 98% ee) under mild conditions. Based on this strategy, a highly concise enantioselective synthesis of the Corey lactone was accomplished. [ABSTRACT FROM AUTHOR]

Melanin is a dark color pigment biosynthesized naturally in most living organisms. Fungal melanin is a major putative virulence factor of Mucorales fungi that allows intracellular persistence by inducing phagosome maturation arrest. Recently, it has been shown that the black pigments of Rhizopus delemar is of eumelanin type, that requires the involvement of tyrosinase (a copper-dependent enzyme) in its biosynthesis. Herein, we have developed a series of compounds (UOSC-1-14) to selectively target Rhizopus melanin and explored this mechanism therapeutically. The compounds were designed based on the scaffold of the natural product, cuminaldehyde, identified from plant sources and has been shown to develop non-selective inhibition of melanin production. While all synthesized compounds showed significant inhibition of Rhizopus melanin production and limited toxicity to mammalian cells, only four compounds (UOSC-1, 2, 13, and 14) were selected as promising candidates based on their selective inhibition to fungal melanin. The activity of compound UOSC-2 was comparable to the positive control kojic acid. The selected candidates showed significant inhibition of Rhizopus melanin but not human melanin by targeting the fungal tyrosinase, and with an IC50 that are 9 times lower than the reference standard, kojic acid. Furthermore, the produced white spores were phagocytized easily and cleared faster from the lungs of infected immunocompetent mice and from the human macrophages when compared with wild-type spores. Collectively, the results suggested that the newly designed derivatives, particularly UOSC-2 can serve as promising candidate to overcome persistence mechanisms of fungal melanin production and hence make them accessible to host defenses.

A nonribosomal peptide synthetase (NRPS)-nonreducing polyketide synthase (NRPKS) hybrid enzyme (AnATPKS) from Aspergillus niger was shown to produce amino acid derived α-pyrone natural products (pyrophen and campyrone B). Biochemical characterization of the NRPS module in vitro reveals that the adenylation domain is promiscuous toward a variety of substituted phenylalanine analogues. Using precursor feeding and heterologous expression of AnATPKS and an associated O-methyltransferase (AnOMT), we were able to access a library of substituted pyrophen analogues. Our study paves the way for future combinatorial biosynthesis of diverse α-pyrone natural products using NRPS-NRPKS hybrids.

Microbial-based production of natural products provides a promising alternative to synthetic production and isolation from the native producer. The recently discovered NEPS1 cyclase/oxidase completes the biosynthetic pathway to nepetalactone, a biologically relevant iridoid known as both an insect repellent and cat attractant. In this work, we employ yeast-based whole-cell biocatalysis to produce semi-biosynthetic nepetalactone from a low-cost precursor via a four-step enzymatic process. The dependence of product yield on bioprocess parameters ranging from induction of gene expression to substrate loading was investigated. Subsequent factorial design and response surface methodology optimization approach enabled a 5.8-fold increase in nepetalactone titer to 153 mg/L. Our study provides insights into strategies for operating plasmid-based bioconversion of a fed substrate and sets the stage for scalable, microbial synthesis of nepetalactone.

Nigerapyrone A, aloenin aglycone, 4′-methyl klavuzon, and allantopyrone C were synthesized from commercially available aldehydes. [ABSTRACT FROM AUTHOR]

In conclusion, a nucleophilic intramolecular ring transformation of 2-pyrone derivatives into 2-pyridone derivatives with a 1,5-diketo motif through a translocative rearrangement has been developed. Keywords: ring transformation; rearrangement; pyrones; pyridones; diketones; medicinal chemistry EN ring transformation rearrangement pyrones pyridones diketones medicinal chemistry 1631 1633 3 07/31/23 20230815 NES 230815 Graph 2-Pyridone derivatives are abundant in natural products, several of which have important pharmaceutical properties such as antimicrobial, antimalarial, antitumor, or cardiotonic activities. Ring transformation, rearrangement, pyrones, pyridones, diketones, medicinal chemistry. [Extracted from the article]

NK cell exhaustion (NCE) due to sustained proliferation results in impaired NK cell function with loss of cytokine production and lytic activity. Using murine models of chronic NK cell stimulation, we have identified a phenotypic signature of NCE characterized by up-regulation of the terminal differentiation marker KLRG1 and by down-regulation of eomesodermin and the activating receptor NKG2D. Chronic stimulation of mice lacking NKG2D resulted in minimized NCE compared to control mice, thus identifying NKG2D as a crucial mediator of NCE. NKG2D internalization and downregulations on NK cells has been previously observed in the presence of tumor cells with high expression of NKG2D ligands (NKG2DL) due to the activation of the DNA damage repair pathways. Interestingly, our study revealed that during NK cell activation there is an increase of MULT1, and NKG2DL, that correlates with an induction of DNA damage. Treatment with the ATM DNA damage repair pathway inhibitor KU55933 (KU) during activation reduced NCE by improving expression of activation markers and genes involved in cell survival, by sustaining NKG2D expression and by preserving cell functionality. Importantly, NK cells expanded ex vivo in the presence of KU displayed increased anti-tumor efficacy in both NKG2D-dependent and -independent mouse models. Collectively, these data demonstrate that NCE is caused by DNA damage and regulated, at least in part, by NKG2D. Further, the prevention of NCE is a promising strategy to improve NK cell-based immunotherapy.

We characterized the flavor chemicals in a broad sample of commercially available electronic cigarette (EC) refill fluids that were purchased in four different countries. Flavor chemicals in 277 refill fluids were identified and quantified by gas chromatography-mass spectrometry, and two commonly used flavor chemicals were tested for cytotoxicity with the MTT assay using human lung fibroblasts and epithelial cells. About 85% of the refill fluids had total flavor concentrations >1 mg/ml, and 37% were >10 mg/ml (1% by weight). Of the 155 flavor chemicals identified in the 277 refill fluids, 50 were present at ≥1 mg/ml in at least one sample and 11 were ≥10 mg/ml in 54 of the refill fluids. Sixty-one% (170 out of 277) of the samples contained nicotine, and of these, 56% had a total flavor chemical/nicotine ratio >2. Four chemicals were present in 50% (menthol, triacetin, and cinnamaldehyde) to 80% (ethyl maltol) of the samples. Some products had concentrations of menthol ("Menthol Arctic") and ethyl maltol ("No. 64") that were 30 times (menthol) and 100 times (ethyl maltol) their cytotoxic concentration. One refill fluid contained cinnamaldehyde at ~34% (343 mg/ml), more than 100,000 times its cytotoxic level. High concentrations of some flavor chemicals in EC refill fluids are potentially harmful to users, and continued absence of any regulations regarding flavor chemicals in EC fluids will likely be detrimental to human health.

There is an increased need for improved and affordable insect repellents to reduce transmission of rapidly spreading diseases with high mortality rates. Natural products are often used when DEET cannot be afforded or accessed and when consumers choose not to use a synthetic repellent. The essential oils from two newly bred Nepeta cataria (catnip) plants representing two different chemotypes and their respective isolated nepetalactone isomers were evaluated as mosquito repellents against Aedes aegypti mosquitoes that transmit the Zika and Dengue virus in a one choice landing rate inhibition assay. A dose response curve was generated for each treatment and a time course analysis of repellency was performed over 24 hours with a N. cataria essential oil sample. The results indicate that all essential oil samples and their respective purified nepetalactone isomers were able to achieve greater than 95% repellency. Between two and four hours, the ability to repel more than 95% of the mosquitoes diminished. At the lowest concentrations tested, the nepetalactones and crude essential oil samples were more effective than DEET at reducing the number of mosquito landings.

Yarrowia lipolytica is an oleaginous yeast that is recognized for its ability to accumulate high levels of lipids, which can serve as precursors to biobased fuels and chemicals. Polyketides, such as triacetic acid lactone (TAL), can also serve as a precursor for diverse commodity chemicals. This study used Y. lipolytica as a host organism for the production of TAL via expression of the 2-pyrone synthase gene from Gerbera hybrida. Induction of lipid biosynthesis by nitrogen-limited growth conditions increased TAL titers. We also manipulated basal levels of TAL production using a DNA cut-and-paste transposon to mobilize and integrate multiple copies of the 2-pyrone synthase gene. Strain modifications and batch fermentation in nitrogen-limited medium yielded TAL titers of 2.6 g/L. Furthermore, we show that minimal medium allows TAL to be readily concentrated at >94% purity and converted at 96% yield to pogostone, a valuable antibiotic. Modifications of this reaction scheme yielded diverse related compounds. Thus, oleaginous organisms have the potential to be flexible microbial biofactories capable of economical synthesis of platform chemicals and the generation of industrially relevant molecules.

Polyketides are attractive compounds for uses ranging from biorenewable chemical precursors to high-value therapeutics. In many cases, synthesis in a heterologous host is required to produce these compounds in industrially relevant quantities. The type III polyketide synthase 2-pyrone synthase (2-PS) from Gerbera hybrida was used for the production of triacetic acid lactone (TAL) in Saccharomyces cerevisiae. Initial in vitro characterization of 2-PS led to the identification of active site variants with improved kinetic properties relative to wildtype. Further in vivo evaluation in S. cerevisiae suggested certain 2-PS mutations altered enzyme stability during fermentation. In vivo experiments also revealed beneficial cysteine to serine mutations that were not initially explored due to their distance from the active site of 2-PS, leading to the design of additional 2-PS enzymes. While these variants showed varying catalytic efficiencies in vitro, they exhibited up to 2.5-fold increases in TAL production when expressed in S. cerevisiae. Coupling of the 2-PS variant [C35S,C372S] to an engineered S. cerevisiae strain led to over 10 g/L TAL at 38% of theoretical yield following fed-batch fermentation, the highest reported to date. Our studies demonstrate the success of a coupled in vitro/in vivo approach to engineering enzymes and provide insight on cysteine-rich enzymes and design principles toward their use in non-native microbial hosts.

Background: As a significant biomarker of melanocytic lesions, tyrosinase (TYR) plays an essential role in the clinical diagnosis and treatment of melanin-related diseases. Thus, it is important to develop robust methods for assessing TYR activity. Covalent organic frameworks (COFs) have garnered considerable attention owing to their unique properties, including high chemical stability, good biocompatibility, and large surface area compared with organic dyes, noble metal nanoclusters, and semiconductor quantum dots. However, most COFs are insoluble in water and exhibit weak or no fluorescence emission. Therefore, the development of a water-soluble fluorescent COF for detecting TYR activity in biological samples remains highly desired., Results: In this work, a sensitive and facile fluorometric method based on fluorescent COF was constructed for the detection of TYR activity in human serum samples. The water-soluble COF was fabricated through the condensation polymerization of 4',4‴,4''''',4'''''''-(1,2-ethene-diylidene) tetrakis [1,1'-biphenyl]-4-carboxaldehyde and 2,4,6-tris-(4-aminophenyl)-triazine. The resulting COF displayed yellow-green fluorescence with a maximum emission peak at 560 nm. Tyrosine was catalyzed by TYR to produce melanin-like polymers which formed a coating on the surface of COF and effectively quenched its fluorescence due to fluorescence resonance energy transfer. The proposed approach demonstrated a strong linear correlation in the range of 0.5-80 U/L with a low detection limit of 0.09 U/L. Additionally, the limit of detection for kojic acid, serving as a representative TYR inhibitor, was determined to be 0.0004 μg/mL., Significance: Our proposed fluorometric sensing platform exhibited exceptional selectivity, sensitivity, and satisfactory recoveries in human serum samples, which is of paramount importance for the clinical diagnostics of melanin-related diseases. Furthermore, the proposed approach was further employed for the screening of TYR inhibitors, suggesting the potential applications in clinical treatment and pharmaceutical research., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

A new total synthesis of the natural δ-lactone cleistenolide (1) and its (6S)-stereoisomer 2 was achieved starting from d-glucose. Key steps in the synthesis of 1 involved: oxidative cleavage of the C 1 -C 2 bond in partially protected d-glucose derivative (20), and chain extension of resulting aldehyde 20a with a single C 2 fragment using (Z)-selective Wittig olefination. Synthesis of 2 involves the following key steps: periodate cleavage of the C 5 -C 6 bond in the commercially available monoacetone d-glucose (24), followed by C 2 chain elongation by using the (Z)-selective Wittig olefination. This new approach is also applied to prepare a few new 4-substituted cleistenolide analogues (3 - 18). Compounds 3 - 7 were designed using molecular hybridization, while the remaining eleven analogues were designed using the bioisosterism method. MTT assay showed that most analogues were more active than lead 1 against several malignant cells, but were completely inactive in the culture of normal foetal lung fibroblasts (MRC-5). The K562 cells appeared to be the most sensitive to the synthesized analogues. The strongest antiproliferative activity against this cell line was shown by 4-O-cinnamoyl derivative 3 and 4,6-di-O-benzyl derivative 17, with submicromolar IC 50 values (0.76 and 0.67 μM, respectively). Structural features important for the activity of this class of compounds were identified by SAR analysis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

This work investigated interactions ascribed to the administration of phytomedicines containing Valeriana officinalis and Piper methysticum with conventional drugs. The phytomedicines were characterized by HPLC and administered per os to male Wistar rats, either concomitantly or not with the CYP3A substrate midazolam. To distinguish between the presystemic or systemic effect, midazolam was given orally and intravenously. The effects on the P-gp substrate fexofenadine uptake by Caco-2 cells were examined. The valerenic acid content was 1.6 ± 0.1 mg per tablet, whereas kavain was 13.7 ± 0.3 mg/capsule. Valerian and kava-kava extracts increased the maximum plasma concentration (C max ) of midazolam 2- and 4-fold compared to the control, respectively. The area under the plasma concentrations versus time curve (AUC (0-∞) ) was enhanced from 994.3 ± 152.3 ng.h/mL (control) to 3041 ± 398 ng.h/mL (valerian) and 4139 ± 373 ng.h/mL (kava-kava). The half-life of midazolam was not affected. These changes were attributed to the inhibition of midazolam metabolism by the enteric CYP3A since the i. v. pharmacokinetic of midazolam remained unchanged. The kava-kava extract augmented the uptake of fexofenadine by 3.5-fold compared to the control. Although Valeriana increased the uptake of fexofenadine, it was not statistically significant to that of the control (12.5 ± 3.7 ng/mg protein vs. 5.4 ± 0.3 ng/mg protein, respectively). Therefore, phytomedicines containing V. officinalis or P. methysticum inhibited the intestinal metabolism of midazolam in rats. Conversely, the P-gp-mediated transport of fexofenadine was preferably affected by kava-kava., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Monopolar spindle 1 kinase (Mps1, also known as TTK protein kinase) inhibitors exert marked anticancer effects against triple‑negative breast cancer (TNBC) by causing genomic instability and cell death. As aneuploid cells are vulnerable to compounds that induce energy stress through adenosine monophosphate‑activated protein kinase (AMPK) activation, the synergistic effect of Mps1/TTK inhibition and AMPK activation was investigated in the present study. The combined effects of CFI‑402257, an Mps1/TTK inhibitor, and AICAR, an AMPK agonist, were evaluated in terms of cytotoxicity, cell‑cycle distribution, and in vivo xenograft models. Additional molecular mechanistic studies were conducted to elucidate the mechanisms underlying apoptosis and autophagic cell death. The combination of CFI‑402257 and AICAR showed selective cytotoxicity in a TNBC cell line. The formation of polyploid cells was attenuated, and apoptosis was increased by the combination treatment, which also induced autophagy through dual inhibition of the PI3K/Akt/mTOR and mitogen‑activated protein kinase (MAPK) signaling pathways. Additionally, the combination therapy showed strongly improved efficacy in comparison with CFI‑402257 and AICAR monotherapy in the MDA‑MB‑231 xenograft model. The present study suggested that the combination of CFI‑402257 and AICAR is a promising therapeutic strategy for TNBC.

Biodegradable food packaging films with good antimicrobial properties are highly sought after for prolonging the shelf-life of fruits and vegetables whilst minimizing waste streams originating from the food sector. In this work, a series of PBAT/PLA food packaging films containing sodium dehydroacetate-loaded diatomite (SD/D) as an antimicrobial agent were fabricated. Structural analyses showed that the sodium dehydroacetate was incorporated into the pores of the diatomite. A uniform dispersion of SD/D in the composite films effectively enhanced water and gas permeability, whilst also giving the films good mechanical properties. The slow release of SD endowed the composite films with long-acting antibacterial ability (>90 % bacteriostasis rate for E. coli and >85 % bacteriostasis rate for S. aureus). The composite films were able to effectively maintain the quality of banana fruits during storage at room temperature, encouraging their use in food applications where non-biodegradable petrochemical-derived packaging films have traditionally been used., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neocosmospora solani causes Fusarium wilt disease and root rot, which are serious problems worldwide. To determine the growth inhibition of Neocosmospora solani by Trichoderma hamatum volatile organic compounds (VOCs), the major chemical components of Trichoderma hamatum VOCs and the differences in their contents at different times were analysed, and the activity of these components was evaluated. The antifungal activity of Trichoderma hamatum was measured by a screening test, as Trichoderma hamatum exhibited strong antagonism against Neocosmospora solani in vitro. The double plate technique was used to verify the activity of Trichoderma hamatum VOCs, and the inhibition rate was 63.77%. Neocosmospora solani mycelia were uneven and expanded, the contents of the cells leaked, and the mycelia shrank and presented a diaphragm in the hyphae upon Trichoderma hamatum VOCs treatment. Trichoderma hamatum VOCs and their contents at different times were analysed by using gas chromatography-mass spectrometry. 6-Pentyl-2H-pyran-2-one clearly presented in greater amounts than the other components on day 3, 4, 5, and 6. VOCs from Trichoderma hamatum exhibited evident effects on the percentage of healthy fruit after day 3. Moreover, Trichoderma hamatum can improve the biological control of diseases caused by soilborne pathogens, and can be applied in biocontrol fields., (© The Author(s) 2024. Published by Oxford University Press on behalf of Applied Microbiology International.)

Sodium dehydroacetate (DHA-Na) is a fungicidal preservative widely used in food and animal feed. DHA-Na can induce coagulation disorders in rats and poultry by inhibiting carboxylation of vitamin K-dependent proteins; it can also impair bone development in zebrafish. However, the effects of DHA-Na on broiler chicken bones remain unknown. Here, we assessed whether DHA-Na impairs bone development in broiler chickens. We administered Suji yellow chickens with 200 to 800 mg/kg DHA-Na, 2 mg/kg vitamin K, or both for 2 mo. Bone metabolite-related serum indicators, tissue micromorphology, and relevant protein expression were monitored during the treatment period. We also assessed primary chicken osteoblast activity, differentiation, and bone metabolite-related proteins after treatment with DHA-Na, vitamin K, or both. The results demonstrated that DHA-Na reduced bone index values and serum and bone osteoblast differentiation marker levels but blocked bone vitamin K cycle. DHA-Na also increased serum osteoclast differentiation marker levels, as well as the bone ratio of receptor activator of nuclear factor kappa-Β ligand to osteoprotegerin ratio. Moreover, DHA-Na reduced bone trabecular number, thickness, and area and increased trabecular separation considerably. In general, compared with the control group, the DHA-Na group demonstrated impairments in osteoblast activity and differentiation, as well as in the vitamin K cycle. By contrast, vitamin K supplementation led to considerable attenuation of the DHA-Na-induced decrease in osteogenic marker levels, along with a considerable increase in serum bone absorption marker levels and restoration of DHA-Na-induced bone microstructure damage. Vitamin K also attenuated DHA-Na-induced impairment in osteoclasts. In conclusion, the results indicated that in broiler chickens, DHA-Na supplementation can damage bones by inhibiting osteoblast function and increasing osteoclast activity; this damage can be prevented through vitamin K supplementation., (Copyright © 2024. Published by Elsevier Inc.)

Intensive study of the organic extract of the marine-derived bacterium Saccharomonospora sp. CNQ-490 has yielded three new α-pyrones, saccharomonopyrones A-C (1-3). The chemical structures of these compounds were assigned from the interpretation of 1D, 2D NMR and mass spectrometry data. Saccharomonopyrone A (1) is the first α-pyrone microbial natural product bearing the ethyl-butyl ether chain in the molecule, while saccharomonopyrones B and C possess unusual 3-methyl and a 6-alkyl side-chain within a 3,4,5,6-tetrasubstituted α-pyrone moiety. Saccharomonopyrone A exhibited weak antioxidant activity using a cation radical scavenging activity assay with an IC50 value of 140 μM.

BACKGROUND: Olfactory stimulation is an often overlooked method of environmental enrichment for cats in captivity. The best known example of olfactory enrichment is the use of catnip, a plant that can cause an apparently euphoric reaction in domestic cats and most of the Pantherinae. It has long been known that some domestic cats and most tigers do not respond to catnip. Although many anecdotes exist of other plants with similar effects, data are lacking about the number of cats that respond to these plants, and if cats that do not respond to catnip respond to any of them. Furthermore, much is still unknown about which chemicals in these plants cause this response. METHODS: We tested catnip, silver vine, Tatarian honeysuckle and valerian root on 100 domestic cats and observed their response. Each cat was offered all four plant materials and a control, multiple times. Catnip and silver vine also were offered to nine tigers. The plant materials were analyzed by gas chromatography coupled with mass spectrometry to quantify concentrations of compounds believed to exert stimulating effects on cats. RESULTS: Nearly all domestic cats responded positively to olfactory enrichment. In agreement with previous studies, one out of every three cats did not respond to catnip. Almost 80% of the domestic cats responded to silver vine and about 50% to Tatarian honeysuckle and valerian root. Although cats predominantly responded to fruit galls of the silver vine plant, some also responded positively to its wood. Of the cats that did not respond to catnip, almost 75% did respond to silver vine and about one out of three to Tatarian honeysuckle. Unlike domestic cats, tigers were either not interested in silver vine or responded disapprovingly. The amount of nepetalactone was highest in catnip and only present at marginal levels in the other plants. Silver vine contained the highest concentrations of all other compounds tested. CONCLUSIONS: Olfactory enrichment for cats may have great potential. Silver vine powder from dried fruit galls and catnip were most popular among domestic cats. Silver vine and Tatarian honeysuckle appear to be good alternatives to catnip for domestic cats that do not respond to catnip.

Kojic acid (KA) is a naturally occurring fungal metabolite that is utilized as a skin-lightener and antibrowning agent owing to its potent tyrosinase inhibition activity. While efficacious, KA's inclination to undergo pH-mediated, thermal-, and photodegradation reduces its efficacy, necessitating stabilizing vehicles. To minimize degradation, poly(carbonate-esters) and polyesters comprised of KA and natural diacids were prepared via solution polymerization methods. In vitro hydrolytic degradation analyses revealed KA release was drastically influenced by polymer backbone composition (e.g., poly(carbonate-ester) vs polyester), linker molecule (aliphatic vs heteroatom-containing), and release conditions (physiological vs skin). Tyrosinase inhibition assays demonstrated that aliphatic KA dienols, the major degradation product under skin conditions, were more potent then KA itself. All dienols were found to be less toxic than KA at all tested concentrations. Additionally, the most lipophilic dienols were statistically more effective than KA at inhibiting melanin biosynthesis in cells. These KA-based polymer systems deliver KA analogues with improved efficacy and cytocompatible profiles, making them ideal candidates for sustained topical treatments in both medical and personal care products.

There is an urgent unmet need for new therapeutics for Alzheimer's disease (AD), the most common cause of dementia in the elderly. Therapeutic approaches targeting amyloid-β (Aβ) and its downstream toxicities have become major strategies in AD drug development. We have taken a rational design approach and synthesized a class of tricyclic pyrone (TP) compounds that show anti-Aβ and other neuroprotective actions. The in vivo efficacy of a lead TP named CP2 to ameliorate AD-like pathologies has been shown in mouse models. Here we report the selection and initial characterization of a new lead TP70, which exhibited an anti-Aβ therapeutic index even higher than CP2. Moreover, TP70 was able to reduce oxidative stress, inhibit acyl-coenzyme A:cholesterol acyltransferase (ACAT), and upregulate the expression of ATP-binding cassette subfamily A, member 1 (ABCA1), actions considered neuroprotective in AD. TP70 further showed excellent pharmacokinetic properties, including brain penetration and oral availability. When administered to 5xFAD mice via intraperitoneal or oral route, TP70 enhanced the overall solubility and decreased the level of cerebral Aβ, including both fibrillary and soluble Aβ species. Interestingly, TP70 enhanced N-methyl-D-aspartate (NMDA) receptor-mediated excitatory post-synaptic potential (EPSP) in the hippocampal CA1 area, increased the magnitude of NMDA-dependent hippocampal long-term potentiation (LTP), a cellular model of learning and memory, and prevented the Aβ oligomer-impaired LTP. Significantly, a single dose of TP70 administered to aged 5xFAD mice was effective in mitigating the impaired LTP induction, recorded at 24 h after administration. Our results support a potential of TP70 in clinical development for AD in view of its synergistic neuroprotective actions, ability to positively modulate NMDA receptor-mediated hippocampal plasticity, and favorable pharmacokinetic properties in rodents.

To study the olfactory perceptual interaction of odorants (OPIO) in binary mixtures containing maltol, a simple and efficient analysis method was developed. This method correlated three variables of the binary mixture: two rates of change in perceived odor intensities of two odorants within the binary mixtures, and the degree of overall odor synergy exhibited by the binary mixtures. By creating a three-dimensional scatter matrix with the variables, the changes in odor intensity of the binary mixture due to OPIO were visualized. The results revealed that the proportions of mutual antagonism, opposite effect, mutual independence, and mutual synergy in the binary mixtures were 64.7%, 32.9%, 1.9%, and 0.5%, respectively. The odor of maltol was mainly masked, and those of esters (68%), aldehydes and ketones (33%) in the mixture were enhanced. In terms of overall odor intensity, 67% of cases involved partial addition, followed by 22.2% overshadowing, and 19.6% stronger component effect., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Bioassay-guided fractionation of two marine cyanobacterial extracts using the H-460 human lung cancer cell line and the OVC-5 human ovarian cancer cell line led to the isolation of three related α-methoxy-β, β'-dimethyl-γ-pyrones each containing a modified alkyl chain, one of which was identified as the previously reported kalkipyrone and designated kalkipyrone A. The second compound was an analog designated kalkipyrone B. The third was identified as the recently reported yoshinone A, also isolated from a marine cyanobacterium. Kalkipyrone A and B were obtained from a field-collection of the cyanobacterium Leptolyngbya sp. from Fagasa Bay, American Samoa, while yoshinone A was isolated from a field-collection of cyanobacteria (cf. Schizothrix sp.) from Panama. One-dimensional and two-dimensional NMR experiments were used to determine the overall structures and relative configurations of the kalkipyrones, and the absolute configuration of kalkipyrone B was determined by (1)H NMR analysis of diastereomeric Mosher's esters. Kalkipyrone A showed good cytotoxicity to H-460 human lung cancer cells (EC50=0.9μM), while kalkipyrone B and yoshinone A were less active (EC50=9.0μM and >10μM, respectively). Both kalkipyrone A and B showed moderate toxicity to Saccharomyces cerevisiae ABC16-Monster strain (IC50=14.6 and 13.4μM, respectively), whereas yoshinone A was of low toxicity to this yeast strain (IC50=63.8μM).

Plants produce interesting secondary metabolites that are a valuable source of both medicines for human use, along with significant advantages for the manufacturer species. The active compounds which lead to these instrumental effects are generally secondary metabolites produced during various plant growth phases, which provide the host survival advantages while affecting human health inadvertently. Different chemical classes of secondary metabolites are biosynthesized by the plant type III polyketide synthases (PKSs). They are simple homodimeric proteins with the unique mechanistic potential to produce a broad array of secondary metabolites by utilizing simpler starter and extender units. These PKS derived products are majorly the precursors of some important secondary metabolite pathways leading to products such as flavonoids, stilbenes, benzalacetones, chromones, acridones, xanthones, cannabinoids, aliphatic waxes, alkaloids, anthrones, and pyrones. These secondary metabolites have various pharmaceutical, medicinal and industrial applications which make biosynthesizing type III PKSs an important tool for bioengineering purposes. Because of their structural simplicity and ease of manipulation, these enzymes have garnered interest in recent years due to their application in the generation of unnatural natural polyketides and modified products in the search for newer drugs for a variety of health problems. The following review covers the biosynthesis of a variety of type III PKS-derived secondary metabolites, their biological relevance, the associated enzymes, and recent research. [ABSTRACT FROM AUTHOR]

Based on the fact that substances with a β-phenyl-α,β-unsaturated carbonyl (PUSC) motif confer strong tyrosinase inhibitory activity, benzylidene-3-methyl-2-thioxothiazolidin-4-one (BMTTZD) analogs 1 - 8 were prepared as potential tyrosinase inhibitors. Four analogs ( 1 - 3 and 5 ) inhibited mushroom tyrosinase strongly. Especially, analog 3 showed an inhibitory effect that was 220 and 22 times more powerful than kojic acid in the presence of l-tyrosine and l-dopa, respectively. A kinetic study utilizing mushroom tyrosinase showed that analogs 1 and 3 competitively inhibited tyrosinase, whereas analogs 2 and 5 inhibited tyrosinase in a mixed manner. A docking simulation study indicated that analogs 2 and 5 could bind to both the tyrosinase active and allosteric sites with high binding affinities. In cell-based experiments using B16F10 cells, analogs 1 , 3 , and 5 effectively inhibited melanin production; their anti-melanogenic effects were attributed to their ability to inhibit intracellular tyrosinase activity. Moreover, analogs 1 , 3 , and 5 inhibited in situ B16F10 cellular tyrosinase activity. In three antioxidant experiments, analogs 2 and 3 exhibited strong antioxidant efficacy, similar to that of the positive controls. These results suggest that the BMTTZD analogs are promising tyrosinase inhibitors for the treatment of hyperpigmentation-related disorders.

Seen initially as wonder drugs, the widespread and often inappropriate use of antibiotics led to the development of microbial resistances. As a result, a true emergency has arisen, and a significant need has emerged to discover and develop new safe and valuable antibiotics. The captivating chemical structure of the fungal metabolite diplopyrone C has caught our attention as an excellent candidate for a circumstantial study aimed at revealing its antimicrobial and antibiofilm activities. In this work, we describe the full analytical strategy from the isolation/identification to the evaluation of the metabolomics effect on target microorganisms of this fungal metabolite. Our results show interesting antimicrobial and antibiofilm activities of diplopyrone C against two frequently isolated nosocomial pathogens (i.e., the fungus Candida albicans and the gram-negative bacterium Klebsiella pneumoniae). Moreover, a GC-MS based metabolomics footprinting approach gave an insight into the uptake and excretion of metabolites from and into the culture medium as a response to the presence of this active substance. The workflow employed in this study is suitable to exploit natural resources for the search of lead compounds for drug development., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Acute kidney injury (AKI) disrupts energy metabolism. Targeting metabolism through AMP-activated protein kinase (AMPK) may alleviate AKI. ATX-304, a pan-AMPK activator, was evaluated in C57Bl/6 mice and tubular epithelial cell (TEC) cultures. Mice received ATX-304 (1 mg/g) or control chow for 7 days before cisplatin-induced AKI (CI-AKI). Primary cultures of tubular epithelial cells (TECs) were pre-treated with ATX-304 (20 µM, 4 h) prior to exposure to cisplatin (20 µM, 23 h). ATX-304 increased acetyl-CoA carboxylase phosphorylation, indicating AMPK activation. It protected against CI-AKI measured by serum creatinine (control 0.05 + 0.03 mM vs ATX-304 0.02 + 0.01 mM, P = 0.03), western blot for neutrophil gelatinase-associated lipocalin (NGAL) (control 3.3 + 1.8-fold vs ATX-304 1.2 + 0.55-fold, P = 0.002), and histological injury (control 3.5 + 0.59 vs ATX-304 2.7 + 0.74, P = 0.03). In TECs, pre-treatment with ATX-304 protected against cisplatin-mediated injury, as measured by lactate dehydrogenase release, MTS cell viability, and cleaved caspase 3 expression. ATX-304 protection against cisplatin was lost in AMPK-null murine embryonic fibroblasts. Metabolomic analysis in TECs revealed that ATX-304 (20 µM, 4 h) altered 66/126 metabolites, including fatty acids, tricarboxylic acid cycle metabolites, and amino acids. Metabolic studies of live cells using the XFe96 Seahorse analyzer revealed that ATX-304 increased the basal TEC oxygen consumption rate by 38%, whereas maximal respiration was unchanged. Thus, ATX-304 protects against cisplatin-mediated kidney injury via AMPK-dependent metabolic reprogramming, revealing a promising therapeutic strategy for AKI., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Amplifier Therapeutics (Betagenon) provided ATX-304 used in this study, however, Amplifier Therapeutics (Betagenon) did not contribute to the study design or contribute specific funding to the study. JSO has received payment from Amplifier Therapeutics (Betagenon) to perform mechanistic studies on ATX-304., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background/aim: Chemotherapy is mainly used in the clinical treatment of prostate cancer. Different anticancer mechanisms can induce cell death in various cancers. Reactive oxygen species (ROS) play crucial roles in cell proliferation, differentiation, apoptosis, and signal transduction. It is widely accepted that ROS accumulation is closely related to chemical drug-induced cancer cell death., Materials and Methods: We utilized the MTT assay to detect changes in cell proliferation. Additionally, colony formation and wound healing assay were conducted to investigate the effect of hispidin on cell colony formation and migration ability. Fluorescence microscopy was used to detect intracellular and mitochondrial ROS levels, while western blot was used for detection of cell apoptosis., Results: Hispidin treatment significantly decreased viability of PC3 and DU145 cancer cells but exhibited no cytotoxicity in WPMY-1 cells. Furthermore, hispidin treatment inhibited cell migration and colony formation and triggered cellular and mitochondrial ROS accumulation, leading to mitochondrial dysfunction and mitochondrion-dependent apoptosis. Moreover, hispidin treatment induced ferroptosis in PC3 cells. Scavenging of ROS with N-acetyl cysteine significantly inhibited hispidin-induced apoptosis by altering the expression of apoptosis-related proteins, such as cleaved caspase-3, 9, Bax, and Bcl2. Furthermore, hispidin treatment dramatically up-regulated MAPK (involving p38, ERK, and JNK proteins) and NF-kB signaling pathways while down-regulating AKT phosphorylation. Hispidin treatment also inhibited ferroptosis signaling pathways (involving P53, Nrf-2, and HO-1 proteins) in PC3 cells. In addition, inhibiting these signaling pathways via treatment with specific inhibitors significantly reversed hispidin-induced apoptosis, cellular ROS levels, mitochondrial dysfunction, and ferroptosis., Conclusion: Hispidin may represent a potential candidate for treating prostate cancer., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Iridoids are non-canonical monoterpenoids produced by both insects and plants. An example is the cat-attracting and insect-repelling volatile iridoid nepetalactone, produced by Nepeta sp. (catmint) and aphids. Recently, both nepetalactone biosynthetic pathways were elucidated, showing a remarkable convergent evolution. The iridoid, dolichodial, produced by Teucrium marum (cat thyme) and multiple insect species, has highly similar properties to nepetalactone but its biosynthetic origin remains unknown. We set out to determine the genomic, enzymatic, and evolutionary basis of iridoid biosynthesis in T. marum. First, we generated a de novo chromosome-scale genome assembly for T. marum using Oxford Nanopore Technologies long reads and proximity-by-ligation Hi-C reads. The 610.3 Mb assembly spans 15 pseudomolecules with a 32.9 Mb N50 scaffold size. This enabled identification of iridoid biosynthetic genes, whose roles were verified via activity assays. Phylogenomic analysis revealed that the evolutionary history of T. marum iridoid synthase, the iridoid scaffold-forming enzyme, is not orthologous to typical iridoid synthases but is derived from its conserved paralog. We discovered an enzymatic route from nepetalactol to diverse iridoids through the coupled activity of an iridoid oxidase cytochrome P450 and acetyltransferases, via an inferred acylated intermediate. This work provides a genomic resource for specialized metabolite research in mints and demonstration of the role of acetylation in T. marum iridoid diversity. This work will enable future biocatalytic or biosynthetic production of potent insect repellents, as well as comparative studies into iridoid biosynthesis in insects., (© 2024 The Authors. The Plant Journal published by Society for Experimental Biology and John Wiley & Sons Ltd.)

N6-methyladenosine (m 6 A) RNA modification is a new epigenetic molecular mechanism involved in various biological or pathological processes. Exposure to aluminum (Al) has been considered to promote neuronal apoptosis resulting in cognitive dysfunction, yet whether m 6 A modification participates in the underlying mechanism remains largely unknown. Here, rats exposed to aluminum-maltolate [Al(mal) 3 ] for 90 days showed impaired learning and memory function and elevated apoptosis, which were related to the increased m 6 A level and decreased fat mass and obesity-associated protein (FTO, an m 6 A demethylase) in the hippocampus. Accordingly, similar results presented in PC12 cells following Al(mal) 3 treatment and FTO overexpression relieved the increased apoptosis and m 6 A level in vitro. Next, we identified brain-derived neurotrophic factor (BDNF) as the functional downstream target of FTO in a m 6 A-dependent manner. Furthermore, it was found that as the onset of aluminum neurotoxicity, oxidative stress may be the upstream regulator of FTO in aluminum-induced apoptosis. Taken together, these results suggest that increased m 6 A modification of BDNF mRNA via FTO promotes neuronal apoptosis following aluminum-induced oxidative stress., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Thioredoxin reductase 1 (TrxR1) has emerged as a promising target for cancer therapy. In our previous research, we discovered several new TrxR1 inhibitors and found that they all have excellent anti-tumor activity. At the same time, we found these TrxR1 inhibitors all lead to an increase in AKT phosphorylation in cancer cells, but the detailed role of AKT phosphorylation in TrxR1 inhibitor-mediated cell death remains unclear. In this study, we identified the combination of AKT and TrxR1 inhibitor displayed a strong synergistic effect in colon cancer cells. Furthermore, we demonstrated that the synergistic effect of auranofin (TrxR1 inhibitor) and MK-2206 (AKT inhibitor) was caused by ROS accumulation. Importantly, we found that ATM inhibitor KU-55933 can block the increase of AKT phosphorylation caused by auranofin, and exhibited a synergistic effect with auranofin. Taken together, our study demonstrated that the activation of ATM/AKT pathway is a compensatory mechanism to cope with ROS accumulation induced by TrxR1 inhibitor, and synergistic targeting of TrxR1 and ATM/AKT pathway is a promising strategy for treating colon cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Catnip ( Nepeta cataria L.) plants produce a wide array of specialized metabolites with multiple applications for human health. The productivity of such metabolites, including nepetalactones, and natural insect repellents is influenced by the conditions under which the plants are cultivated. In this study, we assessed how field-grown catnip plants, transplanted after being propagated via either single-node stem cuttings or seeds, varied regarding their phytochemical composition throughout a growing season in two distinct environmental conditions (Pittstown and Upper Deerfield) in the state of New Jersey, United States. Iridoid terpenes were quantified in plant tissues via ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry (UHPLC-QqQ-MS), and phenolic compounds (phenolic acids and flavonoids) were analyzed via UHPLC with diode-array detection (UHPLC-DAD). The highest contents of total nepetalactones in Pittstown were found at 6 weeks after transplanting (WAT) for both seedlings and cuttings (1305.4 and 1223.3 mg/100 g, respectively), while in Upper Deerfield, the highest contents for both propagules were at 11 WAT (1247.7 and 997.1 mg/100 g, respectively) for seed-propagated and stem cuttings). The highest concentration of nepetalactones was associated with floral-bud to partial-flowering stages. Because plants in Pittstown accumulated considerably more biomass than plants grown in Upper Deerfield, the difference in nepetalactone production per plant was striking, with peak productivity reaching only 598.9 mg per plant in Upper Deerfield and 1833.1 mg per plant in Pittstown. Phenolic acids accumulated in higher contents towards the end of the season in both locations, after a period of low precipitation, and flavone glycosides had similar accumulation patterns to nepetalactones. In both locations, rooted stem cuttings reached their maximum nepetalactone productivity, on average, four weeks later than seed-propagated plants, suggesting that seedlings have, overall, better agronomic performance.

Background: Al exists naturally in the environment and is an important component in acidic soils, which harm almost all plants. Furthermore, Al is widely used in food additives, cosmetics, and medicines, resulting in living organisms ingesting traces of Al orally or dermally every day. Accordingly, Al accumulates in the body, which can cause negative bioeffects and diseases, and this concern is gaining increasing attention. Therefore, to detect and track Al in the environment and in living organisms, the development of novel Al-selective probes that are water-soluble and exhibit fluorescence at long wavelengths is necessary., Results: In this study, an Al 3+ -selective fluorescent probe PSP based on a novel pyrone molecule was synthesized and characterized to detect and track Al in biological systems. PSP exhibited fluorescence enhancement at 580 nm in the presence of Al 3+ in aqueous media. Binding analysis using Job's plot and structural analysis using 1 H NMR showed that PSP formed a 1:1 complex with Al 3+ at the two carbonyl groups of the dimethyl malonate of the pyrone ring. Upon testing in biological systems, PSP showed good cell membrane permeability, detected intracellular Al 3+ in human breast cancer cells (MDA-MB-231), and successfully imaged accumulated Al 3+ in Microcystis aeruginosa and the larvae of Rheocricotopus species., Significance: The novel Al 3+ -selective fluorescent probe PSP is highly effective and is expected to aid in elucidating the role of Al 3+ in the environment and living organisms., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally. Many herbal medicines and their bioactive compounds have shown anti-tumor properties. This study was conducted to examine the effect of psilostachyin C (PSC), a sesquiterpenoid lactone isolated from Artemisia vulgaris L., in the malignant properties of HCC cells. CCK-8, flow cytometry, wound healing, and Transwell assays revealed that 25 μM PSC treatment significantly suppressed proliferation, cell cycle progression, migration, and invasion of two HCC cell lines (Hep 3B and Huh7) while promoting cell apoptosis. Bioinformatics prediction suggests CREB binding protein (CREBBP) as a promising target of PSC. CREBBP activated transcription of GATA zinc finger domain containing 2B (GATAD2B) by binding to its promoter. CREBBP and GATAD2B were highly expressed in clinical HCC tissues and the acquired HCC cell lines, but their expression was reduced by PSC. Either upregulation of CREBBP or GATAD2B restored the malignant properties of HCC cells blocked by PSC. Collectively, this evidence demonstrates that PSC pocessess anti-tumor functions in HCC cells by blocking CREBBP-mediated transcription of GATAD2B., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacological Relevance: Xiaoke formulation (XKF) has been utilized in clinical practice for decades in China as a treatment option for mild to moderate type 2 diabetes. However, there is still a need for systematic research to uncover the key pharmacodynamic material basis and mechanism of XKF., Aim of the Study: Aim of to investigate the distribution and metabolism of XKF in normal and insulin resistant (IR) mice were different, and elucidate its key pharmacodynamic material basis and mechanism of action., Materials and Methods: Ultra performance liquid chromatography/time of flight mass spectrometry technology was employed to investigate the differences in XKF absorption, distribution, and metabolism between normal and IR mice across blood, liver, feces, and urine samples. Further, network pharmacology was used to predict target proteins and their associated signaling pathways. Then, molecular docking was utilized to validate the activity of key pharmacodynamic components and targets. Finally, IR HepG2 cells were used to detect the glucose consumption under the action of key pharmacodynamic material basis. In addition, the expression of phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT) and phospho-protein kinase B (p-AKT) was determined using western blotting., Results: The study demonstrates significant distinctions in plasma and liver number and abundance of alkaloids, organic acids, flavonoids, iridoids and saponins between normal and IR mice when XKF was administered. Further analysis has shown that the representative components of XKF, including berberine, chlorogenic acid, calycosin, swertiamarin and astragaloside IV have significantly different metabolic pathways in plasma and liver. Prototypes and metabolites of these components were rarely detected in the urine and feces of mice. According to the network pharmacological analysis, these differential components are predicted to improve IR by targeting key factors such as SRC, JUN, HRAS, NOS3, FGF2, etc. Additionally, the signaling pathways involved in this process include PI3K-AKT pathway, GnRH signaling pathway, and T cell receptor signaling pathway. In addition, in vitro experiments indicate that berberine and its metabolites (berberine and demethyleneberine), chlorogenic acid and its metabolites (3-O-ferulic quinic acid and 5-O-ferulic quinic acid), calycosin and swertiamarin could improve IR in IR-HepG2 cells by elevating the expression of PI3K and AKT, leading to an increase in glucose consumption., Conclusion: The key pharmacodynamic material basis of XKF, such as berberine and its metabolites (berberrubine and demethyleneberberine), chlorogenic acid and its metabolites (3-O-feruloylquinic acid and 5-O-feruloylquinic acid), calycosin and swertiamarin influence the glucose metabolism disorder of IR-HepG2 cells by regulating the PI3K/AKT signalling pathway, leading to an improvement in IR., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Capitalizing a synergy between late-stage C(sp 3 )-H alkynylation and a series of transition metal-catalyzed alkyne functionalization reactions, we reported herein enantioselective divergent synthesis of 10 diterpenoid pyrones within 14-16 steps starting from chiral pool enoxolone, including the first enantioselective synthesis of higginsianins A, B, D, E, and metarhizin C. Our synthesis also highlights an unprecedented biomimetic oxidative rearrangement of α-pyrone into 3(2H)-furanone, as well as applications of Echavarren C(sp 3 )-H alkynylation reaction and Toste chiral counterion-mediated Au-catalyzed intramolecular allene hydroalkoxylation in natural product synthesis.

Context: The molecular mechanism by which Swertiamarin (SM) prevents advanced glycation end products (AGEs) induced diabetic nephropathy (DN) has never been explored., Objective: To evaluate the effect of SM in preventing the progression of DN in high fat diet-streptozotocin-induced diabetic rats., Materials and Methods: After 1 week of acclimatisation, the rats were divided randomly into five groups as follows: (1) Control group, which received normal chow diet; (2) High-fat diet (HFD) group which was fed diet comprising of 58.7% fat, 27.5% carbohydrate and 14.4% protein); (3) Aminoguanidine (AG) group which received HFD + 100 mg/k.b.w.AG (intraperitoneal); (4) Metformin (Met) group which received HFD + 70 mg/k.b.w. the oral dose of Met and (5) SM group which was supplemented orally with 50 mg/k.b.w.SM along with HFD. After 12 weeks all HFD fed animals were given a single 35 mg/k.b.w. dose of streptozotocin with continuous HFD feeding for additional 18 weeks. Later, various biochemical assays, urine analyses, histopathological analysis of kidneys, levels of AGEs, expression of various makers, and in-silico analysis were performed., Results: The diabetic group demonstrated oxidative stress, increased levels of AGEs, decreased renal function, fibrosis in the renal tissue, higher expression of the receptor for advanced glycation end products (RAGE), which were ameliorated in the SM treated group. In-silico analysis suggests that SM can prevent the binding of AGEs with RAGE., Conclusions: SM ameliorated DN by inhibiting the oxidative stress induced by AGEs.HighlightsSM reduces the levels of hyperglycaemia-induced advanced glycation end products in serum and renal tissue.SM prevents renal fibrosis by inhibiting the EMT in the kidney tissue.The in-silico analysis proves that SM can inhibit the binding of various AGEs with RAGE, thereby inhibiting the AGE-RAGE axis.

Trypanosoma evansi is a flagellate protozoan that infects a wide range of hosts, especially horses. Clinically, the infection is characterized by rapid weight loss, anemia and mobility disorders. This study evaluated the efficacy of treatment gallium maltolate (GaM) in rats infected with T. evansi in the acute and chronic phases of the disease and its influence on the enzyme and blood parameters. 48 animals (Rattus norvegicus) were divided into 8 groups (A-H) of 6 animals each, namely: A: (negative control) uninfected; B: acutely infected positive control; C: chronically infected positive control; D: acutely infected, treated with GaM for 7 days post infection (p.i.); E: acutely infected treated with GaM for 3 days before infection (b.i) and 7 days p.i.; F: chronically infected, treated with GaM for 7 days p.i.; G: chronically infected, treated with GaM for 3 days b.i. and 7 days p.i.; and H: uninfected treated with GaM for 10 days. Acute infected animals (B, D and E) had a progressive increase in parasitemia and were died or euthanized before completing treatment days (5th days p.i.) as they had high parasitemia (over 100 field trypanosomes in the blood smear). Thus, it can be concluded that GaM was not effective against an acute infection. In untreated chronically infected animals (C) the parasitemia also increased progressively and they were euthanized on the 7th day p.i.. The chronically infected and treated animals (F and G) showed low parasitemia and after treatment became negative, showing no trypanosomes in the bloodstream until the 50th day of the experiment. Thus, we conclude that GaM was effective against chronic infections. In uninfected and treated animals (H) hematological, biochemical and enzymatic parameters had no significant changes when compared to the negative control group (A) demonstrating the low toxicity of GaM., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

An indium complex supported by a ferrocene-derived Schiff base ligand has an unprecedented high activity toward ε-caprolactone, δ-valerolactone, and β-butyrolactone. l-Lactide, d,l-lactide, and trimethylene carbonate polymerizations also showed moderate to high activity.