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Selective laser sintering (SLS) is an emerging three-dimensional (3D) printing technology that uses a laser to fuse powder particles together, which allows the fabrication of personalized solid dosage forms. It possesses great potential for commercial use. However, a major drawback of SLS is the need to heat the powder bed while printing; this leads to high energy consumption (and hence a large carbon footprint), which may hinder its translation to industry. In this study, the concept of cold laser sintering (CLS) is introduced. In CLS, the aim is to sinter particles without heating the powder bed, where the energy from the laser, alone, is sufficient to fuse adjacent particles. The study demonstrated that a laser power above 1.8 W was sufficient to sinter both KollicoatIR and Eudragit L100-55-based formulations at room temperature. The cold sintering printing process was found to reduce carbon emissions by 99% compared to a commercial SLS printer. The CLS printed formulations possessed characteristics comparable to those made with conventional SLS printing, including a porous microstructure, fast disintegration time, and molecular dispersion of the drug. It was also possible to achieve higher drug loadings than was possible with conventional SLS printing. Increasing the laser power from 1.8 to 3.0 W increased the flexural strength of the printed formulations from 0.6 to 1.6 MPa, concomitantly increasing the disintegration time from 5 to over 300 s. CLS appears to offer a new route to laser-sintered pharmaceuticals that minimizes impact on the environment and is fit for purpose in Industry 5.0.
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Quaternary phosphonium salts (QPS) are significant structural motifs in drugs, materials, and catalysts. Here, a photoactivated approach for the selective late-stage synthesis of QPS utilizing organothianthrenium salts and tertiary phosphines is presented with high yields and broad functional group compatibility. Additionally, the synthetic utility of this protocol is demonstrated by in situ generation of QPS via C-H functionalization and its fluorescence confocal imaging of mitochondrial localization in cells.
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Cuproptosis, as a newly identified form of programmed cell death, shows great promise in cancer treatment. Efficient Cu+ delivery while avoiding systemic toxicity and elimination of the resistance from over-expressed intracellular copper chelator glutathione (GSH) are critical for cuproptosis. Herein, this work innovatively constructs a biocompatible and defect-rich copper hydroxide nanowire (HCu nanowire) through a human serum albumin (HSA) mediated biomineralization method. This work finds that the morphology and size of HCu nanowires can be controlled adjusted by the feed ratio of HSA and Cu2+. Remarkably, except for outstanding biocompatibility, HSA coordination endows HCu nanowires abundant oxygen vacancies (OVs), and the defect-rich HCu nanowire possesses excellent GSH consumption efficiency. Density functional theory studies indicate that OVs change GSH absorption energy on defective HCu nanowires. In cancer cells, HCu nanowires deplete GSH and simultaneously produce sufficient free Cu+ for enhanced cuproptosis. Meanwhile, Cu+ can catalyze endogenous H2O2 into hydroxyl radicals (·OH) via a Fenton-like reaction. Thus, synergetic cuproptosis and ROS mediated apoptosis against tumor are achieved. The experimental results show that HCu nanowires have a better performance in both antitumor efficiency and safety compared with chemotherapeutic drug Dox at the same dose, demonstrating its great potential in clinical applications.
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Bioassay-guided purification of the xanthine oxidase (XOD) inhibitory extract of the roots of Ampelopsis japonica resulted in the isolation of two new triterpenoids (1-2), designated Ampejaponoside A and B, along with sixteen known compounds (3-18). The structures of Ampejaposide A and B were elucidated by comprehensive analysis of spectroscopic data with the structures of the known compounds 3-18 confirmed by comparison the spectral data with corresponding values reported in literatures. All the isolates were evaluated for their XOD inhibitory activity in vitro. As a result, compounds 2, 8, and 14-16 displayed significant XOD inhibitory effect, particularly 16 being the most potent with an IC50 value of 0.21 µM, superior to positive substance allopurinol (IC50 1.95 µM). Molecular docking uncovered a unique interaction mode of 16 with the active site of XOD. The current study showed that the triterpenoids and polyphenols from A. japonica could serve as new lead compounds with the potential to speed up the development of novel XOD inhibitors with clinical potential to treat hyperuricaemia and gout.
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As a plant hormone, salicylic acid (SA) has diverse regulatory roles in plant growth and stress resistance. Although SA is widely found in plants, there is substantial variation in basal SA among species. Tea plant is an economically important crop containing high contents of SA whose synthesis pathway remains unidentified. The phenylalanine ammonia-lyase (PAL) pathway is responsible for basal SA synthesis in plants. In this study, isotopic tracing and enzymatic assay experiments were used to verify the SA synthesis pathway in tea plants and evaluate the variation in phenylalanine-derived SA formation among 11 plant species with different levels of SA. The results indicated that SA could be synthesized via PAL in tea plants and conversion efficiency from benzoic acid to SA might account for variation in basal SA among plant species. This research lays the foundation for an improved understanding of the molecular regulatory mechanism for SA biosynthesis.
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Camellia sinensis , Ácido Salicílico , Ácido Salicílico/metabolismo , Fenilalanina/metabolismo , Plantas/metabolismo , Fenilanina Amoníaco-Liasa/genética , Camellia sinensis/metabolismo , Té , Regulación de la Expresión Génica de las PlantasRESUMEN
The fruit of Lycium barbarum (Lb), known as red goji berry, is a "superfruit" due to its abundance of bioactive compounds. Among these compounds, dicaffeoylspermidine derivatives (DCSPDs) have anti-oxidant and anti-Alzheimer's Disease activity. This study employed ultra-high-performance liquid chromatography with tandem mass spectrometry to investigate metabolic changes during the development and ripening stages of red goji berries. Totally 97 compounds, including 51 DCSPDs, were tentatively identified. Correlation analysis of these DCSPDs revealed that glycosyltransferases (GTs) play an important role in the formation of glycosylated DCSPDs. In vitro experiments characterized 3 novel GTs could add a glucosyl moiety to N1-caffeoyl-N10-dihydrocaffeoyl spermidine. Homologous GTs from L. ruthenicum (Lr) exhibited similar activity, despite the absence of abundant glycosylated DCSPDs in Lr. These findings provide insights into the metabolic changes and interconnections among active compounds in red goji berries. The identified GTs hold potential for metabolic engineering of DCSPDs and functional food development.
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Lycium , Lycium/química , Frutas/química , Glucosiltransferasas/metabolismo , Espectrometría de Masas en Tándem , Antioxidantes/químicaRESUMEN
Artificial intelligence (AI) is a revolutionary technology that is finding wide application across numerous sectors. Large language models (LLMs) are an emerging subset technology of AI and have been developed to communicate using human languages. At their core, LLMs are trained with vast amounts of information extracted from the internet, including text and images. Their ability to create human-like, expert text in almost any subject means they are increasingly being used as an aid to presentation, particularly in scientific writing. However, we wondered whether LLMs could go further, generating original scientific research and preparing the results for publication. We taskedGPT-4, an LLM, to write an original pharmaceutics manuscript, on a topic that is itself novel. It was able to conceive a research hypothesis, define an experimental protocol, produce photo-realistic images of 3D printed tablets, generate believable analytical data from a range of instruments and write a convincing publication-ready manuscript with evidence of critical interpretation. The model achieved all this is less than 1 h. Moreover, the generated data were multi-modal in nature, including thermal analyses, vibrational spectroscopy and dissolution testing, demonstrating multi-disciplinary expertise in the LLM. One area in which the model failed, however, was in referencing to the literature. Since the generated experimental results appeared believable though, we suggest that LLMs could certainly play a role in scientific research but with human input, interpretation and data validation. We discuss the potential benefits and current bottlenecks for realising this ambition here.
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Inteligencia Artificial , Biofarmacia , Humanos , VibraciónRESUMEN
Bioactive peptides derived from proteins found in various foods provide significant health benefits, including regulating blood sugar levels by inhibiting carbohydrate-hydrolyzing enzymes. Hydrolysates of peanut protein were prepared using alcalase (AH) or trypsin (TH) to generate antidiabetic peptides with high activity against α-amylase (IC50 of 6.46 and 5.71 mg/mL) and α-glucosidase (IC50 of 6.30 and 5.57 mg/mL), as well as antiradical activity to scavenge DPPH⢠(IC50 of 4.18 and 3.12 mg/mL) and ABTSâ¢+ (IC50 of 2.87 and 2.56 mg/mL), respectively. The bioactivities of hydrolysates were greatest in the ultrafiltration-generated F3 fraction (< 3 kDa). The most active fraction was TH-F3, which was purified by gel filtration chromatography to generate sub-fractions (SF). With IC50 values of 1.05 and 0.69 mg/mL, the F3-SF8 fraction was the most effective at inhibiting the activity of α-amylase and α-glucosidase, respectively. This fraction was further purified using RP-HPLC to generate sub-subfractions (SSF), the most active of which were F3-SF8-SSF9 and SSF10. The peptide sequences F3-SF8-SSF9 and SSF10 were determined using LC-MS/MS. Two novel antidiabetic peptides with the potential to inhibit α-amylase and α-glucosidase were identified, with the sequences Asp-Trp-Arg (476.22 Da, IC50 of 0.78, and 0.35 mg/mL) and Phe-Tyr (329.15 Da, IC50 of 0.91, and 0.41 mg/mL). These results suggest that peptides derived from peanut protein are attractive natural ingredients for diabetes management applications.
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Arachis , Hipoglucemiantes , Hipoglucemiantes/farmacología , Hipoglucemiantes/química , Arachis/metabolismo , alfa-Glucosidasas/metabolismo , Cromatografía Liquida , Espectrometría de Masas en Tándem , Péptidos/farmacología , alfa-AmilasasRESUMEN
Spring green tea is usually considered to be better than summer green tea. Whether this phenomenon applies to black tea is unknown. Black tea produced using Camellia sinensis var. Yinghong No. 9 leaves is popular in South China and analyzed in the study. The taste and color quality of the infusion was higher for spring tea than for summer tea. Compared with summer tea, the main catechin contents were lower in spring tea, whereas caffeine and total amino acid contents were higher, especially glutamic acid, which may be responsible for the differences between teas. Moreover, spring tea had a higher theabrownin content and a lower L* value. The compounds contributing to the infusion taste and color were correlated with the chromaticity value (i.e., useful indicator of black tea quality). This study revealed the seasonal differences in Yinghong No. 9 black tea quality and the key underlying factors.
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Eleven new phenyltetracenoid polyketides, streptovertimycins U (1) and V (2), 14-bromo-streptovertidione (3), streptovertimycins W-Y (4-6), and streptovertimycins Z1-Z5 (7-11), together with the known congeners fasamycins R (12) and S (13) and accramycins A (14) and B (15), were isolated from the NaBr-supplemented rice-grown cultures of Streptomyces morookaense SC1169. Their structures were elucidated by extensive spectroscopic analysis, single-crystal X-ray diffraction analysis, and theoretical computations of ECD spectra. Compounds 1 and 2 are methylene-bridged dimers of accramycin A, and compounds 3 and 7-11 are brominated fasamycin congeners. Compounds 5 and 8-14 exhibited activity against the drug-resistant bacteria MRSA and VRE (MIC = 0.6-5.0 µg/mL), and the dimer 1 displayed activity against MRSA (MIC = 2.5 µg/mL). Compounds 6-15 showed cytotoxicity against the human carcinoma A549, HeLa, HepG2, and MCF-7 cells in the IC50 range between 1.7 and 9.2 µM.
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Streptomyces , Humanos , Streptomyces/química , Células HeLa , Análisis Espectral , Células MCF-7 , Antibacterianos/química , Estructura MolecularRESUMEN
Herbivore-induced plant volatiles (HIPVs) are critical compounds that directly or indirectly regulate the tritrophic interactions among herbivores, natural enemies and plants. The synthesis and release of HIPVs are regulated by many biotic and abiotic factors. However, the mechanism by which multiple factors synergistically affect HIPVs release remains unclear. Tea plant (Camellia sinensis) is the object of this study because of its rich and varied volatile metabolites. In this study, benzyl nitrile was released from herbivore-attacked tea plants more in the daytime than at night, which was consistent with the feeding behaviour of tea geometrid (Ectropis grisescens Warren) larvae. The Y-tube olfactometer assay and insect resistance analysis revealed that benzyl nitrile can repel tea geometrid larvae and inhibit their growth. On the basis of enzyme activities in transiently transformed Nicotiana benthamiana plants, CsCYP79 was identified as a crucial regulator in the benzyl nitrile biosynthetic pathway. Light signalling-related transcription factor CsPIF1-like and the jasmonic acid (JA) signalling-related transcription factor CsMYC2 serve as the activator of CsCYP79 under light and damage conditions. Our study revealed that light (abiotic factor) and herbivore-induced damage (biotic stress) synergistically regulate the synthesis and release of benzyl nitrile to protect plants from diurnal herbivorous tea geometrid larvae.
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Camellia sinensis , Lepidópteros , Animales , Camellia sinensis/metabolismo , Herbivoria , Nitrilos/metabolismo , Larva/fisiología , Té/metabolismoRESUMEN
Although cancer immunotherapy has made encouraging progress, clinical therapeutic efficiency is often modest due to inadequate immunogenicity and immune resistance. Developing promising nanoagents for simultaneously activating tumor-specific immunity and suppressing immune resistance to achieve efficient immunotherapy is still challenging. Herein, we developed a biomimetic nanozyme consisting of a gold nanorod@mesoporous ceria core-shell scaffold with gold nanoparticle deposition and cancer cell membrane camouflage. The nanozyme exhibited near-infrared (NIR)-enhanced GOx-mimicking activity at high temperatures and performed well under hypoxic environments due to an increased in situ oxygen supply. In cancer cells, the nanozyme induced and amplified hyperthermia by triggering self-accelerating cascade reactions to deplete glucose and inhibiting the expression of heat shock protein under NIR irradiation, which can cause mitochondrial dysfunction and redox balance disruption to activate pyroptosis and elicit a robust immune response. Additionally, the immune checkpoint blockade caused by encapsulated JQ1-mediated PD-L1 downregulation synergistically contributed to excellent immune therapeutic effects. Besides, we demonstrated that cancer cell membrane coating endows the nanozyme targeting ability to tumor. The proposed nanozyme will broaden the application of GOx and have the potential as the nanoplatform for imaging-guided and O2-consuming combined treatments.
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Nanopartículas del Metal , Neoplasias , Humanos , Oro , Membrana Celular , Inmunoterapia , Neoplasias/terapiaRESUMEN
Sour rot, caused by Geotrichum citri-aurantii, is a major postharvest disease in citrus and results in significant economic losses. The genus Beauveria is recognized as a promising source of biocontrol agents for agricultural applications. Herein, we established a targeted strategy by integrating genomics and metabolomics to accelerate the discovery of new cyclopeptides from antagonistic metabolites produced by the marine-derived fungus Beauveria felina SYSU-MS7908. As a result, we isolated and characterized seven cyclopeptides, including six new molecules, isaridins I-N (1-6). Their chemical structures and conformational analysis were extensively elucidated using spectroscopic techniques (NMR, HRMS, and MS'MS data), modified Mosher's and Marfey's methods, and single-crystal X-ray diffraction. Notably, isaridin K (3) contains a peptide backbone with an N-methyl-2-aminobutyric acid residue rarely found in natural cyclopeptides. Bioassays showed that compound 2 could significantly inhibit the mycelial growth of G. citri-aurantii by destroying the cell membrane. These findings provide an effective strategy for searching for new fungal peptides for potential agrochemical fungicides and also pave the way for further exploration of applications in agriculture, food, and medicine.
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Beauveria , Citrus , Antifúngicos/farmacología , Beauveria/química , Péptidos Cíclicos/farmacología , Metabolómica , Citrus/microbiologíaRESUMEN
Five previously undescribed specialized metabolites, including three 9,11-seco-pimarane diterpenoids, nodulisporenones A-C, and two androstane steroids, nodulisporisterones A and B, together with previously described ergosterol derivatives, dankasterone A and demethylincisterol A3, were isolated from solid cultures of the endophytic fungus Nodulisporium sp. SC-J597. Their structures including absolute configurations were elucidated by extensive spectroscopic analysis and theoretical calculations of electronic circular dichroism spectra. Among them, nodulisporenones A and B are the first examples of seco-pimarane diterpenoids that is cyclized to form an unprecedented diterpenoid lactone scaffold and nodulisporisterones A and B represent the first normal C19 androstane steroids of fungal origin. Nodulisporisterone B exhibited potent inhibitory effect on the production of NO in LPS-stimulated RAW264.7 macrophages (IC50 = 2.95 µM). This compound, together with the two known ergosterol derivatives, also displayed cytotoxicity against A549, HeLa, HepG2 and MCF-7 cancer cell lines with IC50 values of 5.2-16.9 µM.
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Abietanos , Diterpenos , Humanos , Abietanos/química , Estructura Molecular , Esteroides , Diterpenos/química , Androstanos , Hongos , ErgosterolRESUMEN
Two new cyclopropane derivatives (1-2) and seven undescribed α-pyrone derivatives (3-9), along with one known congener (10) were obtained from the marine fungus Stagonospora sp. SYSU-MS7888, which was isolated from the South China Sea. Their planar structures were established through extensive spectroscopic analyses including 1D and 2D NMR and HR-ESIMS. The absolute configurations were identified on basis of the quantum chemical calculations of ECD and NMR, as well as the modified Mosher's method. It's particularly noteworthy that the tetrasubstituted furopyrans, chenopodolans A-F, possessing phytotoxicity and zootoxicity, were structural misassignments. The structures of chenopodolans featuring with furopyran skeleton were revised as common trisubstituted α-pyrones by computational chemistry, NMR spectroscopic method, and empirical rule. Compounds 1, 2, 7, and 9 showed significant anti-inflammatory activity with IC50 values ranging from 3.6 to 22.8 µM, which is better than the positive control indomethacin (IC50 = 26.5 ± 1.13 µM). This discovery holds potential for the development of new anti-inflammatory agents.
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Ascomicetos , Pironas , Pironas/farmacología , Pironas/química , Estructura Molecular , Ascomicetos/química , Espectroscopía de Resonancia Magnética , Antiinflamatorios , CiclopropanosRESUMEN
An effective identification and discovery of fungal pigments is very important to illustrate the role of fungal pigments in the life process and conduce to the discovery of new bioactive and edible pigments. The phenotype combined with metabolomic and genomic (PMG) strategy led to the discovery and characterization of three new sorbicillinoid pigments, stasorbicillinoids A-C (1-3), and five known analogues (4-8) from the sponge-derived fungus Stagonospora sp. SYSU-MS7888. Their structures were elucidated by the application of spectroscopic methods (NMR, MS, UV, IR, and ECD) and modified Mosher's method. Compounds 1 and 2 featured novel naphthone nuclei linked by two alkyl side chains possibly undergoing inter- and intramolecular Michael reactions. Compounds 1-8 exhibited potent anti-inflammatory activity with IC50 values in the range of 3.56-22.8 µM. Furthermore, compound 2 inhibited the production of IL-1ß, IL-6, and TNF-α in a dose-dependent manner. This study provides an effective strategy to accelerate the discovery of new fungal pigments and further exploration of their potential applications in different fields such as medicine and food industries.
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Genómica , Metabolómica , Antiinflamatorios/farmacologíaRESUMEN
Cordyceps sinensis, as an expensive traditional Chinese medicine and edible fungus mycelium, lacks an effective quality evaluation method, especially and cultivated Cordyceps sinensis. In this study, a feasible workflow method was developed for traceability evaluation of wild and cultivated Cordyceps sinensis, based on mass spectrometry-based metabolomics. Mass spectrometry data were firstly acquired from Cordyceps sinensis, samples by liquid chromatography-quadrupole and time of flight mass spectrometry. Characteristic mass spectrometry peaks were extracted by applying the MZmine. Then significant markers were obtained from Cordyceps sinensis samples by orthogonal partial least square discriminant analysis. Then, identification of significant markers were identified by MS-FINDER data analytics. The results showed that Changdu, the other four wild origins (Naqu, Xinghai, Yushu and Guoluo) and cultivated samples could be significantly distinguished. This identified significant markers of Cordyceps sinensis, including 174 special significant markers for the wild samples, 204 special significant markers for the cultivated samples and 87 share significant markers. Number of 87 shared significant markers were identified in the wild and cultivated Cordyceps sinensis, especially 28 confident significant compounds, such as adenosine, riboflavin, tyrosine, arginine and glutamine. These shared significant markers might support the quality control of multi-targets of Cordyceps sinensis, compared with a single target in the Chinese Pharmacopoeia. The special significant markers indicated that cultivated Cordyceps sinensis was different from the wild based on mass spectrometry-based metabolomics. In the comparison of chromatographic fingerprint technology, it was found that the established feasible workflow method was easy to acquire significant markers and traceability of Cordyceps sinensis. This feasible workflow method has great potential to be successful for comprehensive and traceability evaluation of the wild and cultivated Cordyceps sinensis.
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Cordyceps , Cordyceps/química , Flujo de Trabajo , Espectrometría de Masas , Metabolómica , Micelio/químicaRESUMEN
Six previously undescribed cytochalasans, ueckerchalasins A-E and 4'-hydroxycytochalasin J3, together with eight known congeners, were isolated from solid cultures of the endophytic fungus Diaporthe ueckerae SC-J0123 which was originally isolated from the leaves of Pteris vittata L. Their structures were elucidated by extensive spectroscopic analysis, single-crystal X-ray diffraction, and theoretical simulations of ECD spectra and 13C NMR shifts. Ueckerchalasins A-C have a carbon-carbon bridge between C-14 and C-20, forming a rare 5/6/6/7-fused heterocyclic core. Ueckerchalasins C and D displayed selective activity against human carcinoma HeLa and HepG2 cells. Ueckerchalasins C was also active against Staphylococcus aureus and methicillin-resistant S. aureus (MRSA).
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Ascomicetos , Helechos , Staphylococcus aureus Resistente a Meticilina , Pteris , Contaminantes del Suelo , Ascomicetos/química , Carbono , Citocalasinas/química , Humanos , Pteris/microbiologíaRESUMEN
Four new pestalone-type benzophenones, pestalotinones A-D (1-4), along with six known congeners, pestalone, pestalone E-F, SB87-Cl, SB87-H, and pestalachloride B, were isolated from the endophytic fungus Pestalotiopsis trachicarpicola SC-J551 cultivated on rice grains. Their structures were established by extensive spectroscopic analysis. Compounds 1-3 exhibited potent activity against Staphylococcus aureus and MRSA (MIC: 1.25-2.5 µg ml-1) while no cytotoxicity against Vero cells (IC50 > 50 µM). The activity profile of this group of compounds suggested that replacement of the C-14 aldehyde with an oxymethyl greatly increases their activity and selectivity towards the bacteria and chlorine substitutions result in the increase of antibacterial activity and slight decrease of cytotoxicity against the mammalian cells.
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Antibacterianos , Benzofenonas , Animales , Antibacterianos/química , Benzofenonas/química , Benzofenonas/farmacología , Chlorocebus aethiops , Hongos , Estructura Molecular , Pestalotiopsis , Células VeroRESUMEN
Different microbial aggregates show substantial differences in morphology, and extracellular polymer substances have been confirmed to play a key role in the formation of aggregates. In this study, three different microbial aggregates and their exopolysaccharides were compared. The results show that the granular sludge was largest in size and the most compact in shape. Biofilms with a certain thickness had the next greatest density, and flocculent sludge, with the smallest particle size, was the loosest. The extended Derjaguin-Landau-Verwey-Overbeek analysis shows that hydrogen bonding, hydrophobic and electrostatic interactions affect the aggregation of microorganisms. A comparison of exopolysaccharides shows that granular sludge exopolysaccharides show the highest hydrophobicity (38.08%) and lowest surface charge (-20.5â mV), followed by biofilm exopolysaccharides (27.9% and -24.8â mV respectively). The results of Fourier transform infrared spectroscopy and X-ray photoelectron spectroscopy show that the contents of hydrophilic and hydrophobic functional groups and charged functional groups of exopolysaccharides affect the above properties of exopolysaccharides, thereby affecting microbial aggregation. In addition, the hydrogen bond content of exopolysaccharides in granular sludge (19.3%), biofilm (19.2%) and activated sludge (18.9%) decreased sequentially. This also affects the cross-linking of microbial exopolysaccharides to form hydrogels. Finally, the results of confocal laser scanning microscopy showed that, different from the other two aggregates, the extracellular α-polysaccharides of granular sludge are mainly distributed in the nucleus, which is more conducive to aggregation. The research results of this thesis provide a new understanding of the differences in the aggregation morphology of different aggregates from the perspective of exopolysaccharides.