Molecules最新文献

Drug repurposing is a cost-effective and innovative strategy for identifying new therapeutic applications for existing drugs, thereby shortening development timelines and accelerating the availability of treatments. Applying this approach to the development of cosmeceutical ingredients enables the creation of functional compounds with proven safety and efficacy, adding significant value to the cosmetic industry. This study evaluated the potential of rifampicin, a drug widely used for the treatment of tuberculosis and leprosy, as a cosmeceutical agent. The anti-melanogenic effects of rifampicin were assessed in B16F10 melanoma cells, showing no cytotoxicity at concentrations up to 40 µM and a significant reduction in intracellular tyrosinase activity and melanin content. Mechanistically, rifampicin reduced the expression of melanogenic enzymes, including tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, via a protein kinase A (PKA)-dependent pathway, leading to the suppression of microphthalmia-associated transcription factor (MITF), which is a key regulator of melanogenesis. Additionally, rifampicin inhibited the p38 signaling pathway but was independent of the PI3K/protein kinase B (Akt) pathway. Furthermore, it decreased Ser9 phosphorylation, enhancing glycogen synthase kinase-3β (GSK-3β) activity, promoted β-catenin phosphorylation, and facilitated β-catenin degradation, collectively contributing to the inhibition of melanin synthesis. To evaluate the topical applicability of rifampicin, primary human skin irritation tests were conducted, and no adverse effects were observed at concentrations of 20 µM and 40 µM. These findings demonstrate that rifampicin inhibits melanogenesis through multiple signaling pathways, including PKA, MAPKs, and GSK-3β/β-catenin. This study highlights the potential of rifampicin to be repurposed as a topical agent for managing hyperpigmentation disorders, offering valuable insights into novel therapeutic strategies for pigmentation-related conditions.

In this study, we investigated the inhibitory potential of 60 flavonoids from six distinct subgroups on the programmed cell death ligand 1 (PD-L1) dimer through molecular docking and dynamics simulations. Using AutoDock Vina for docking, the binding poses and affinities were evaluated, revealing an average binding affinity of -8.5 kcal/mol for the flavonoids. Among them, ginkgetin exhibited the highest binding free energy of -46.73 kcal/mol, indicating a strong interaction with PD-L1, while diosmin followed closely, with -44.96 kcal/mol. Molecular dynamics simulations were used to further elucidate the dynamic interactions and stability of the flavonoid-PD-L1 complexes, with the analyses showing minimal root mean square deviation (RMSD) and favorable root mean square fluctuation (RMSF) profiles for several compounds, particularly formononetin, idaein, and neohesperidin. Additionally, contact number and hydrogen bond analyses were performed, which highlighted ginkgetin and diosmin as key flavonoids with significant binding interactions, evidenced by their stable conformations and robust molecular interactions throughout the simulations. Ultimately, a cell-based assay confirmed their ability to inhibit the proliferation of cancer cells. These results, validated through cell-based assays, indicate that the strategy of identifying natural compounds with anticancer activity using computational modeling is highly effective.

Biological sex is a fundamental determinant of physiological differences, including metabolic processes and disease susceptibility. β-carotene (BC), a provitamin A carotenoid, is known for its health benefits, but its sex-specific effects on its metabolism remain largely unexplored. This study investigated male and female BALB/c mice receiving BC or vehicle control via oral gavage for 11 weeks. Hepatic and circulating lipid levels, serum retinol, and the expression of BC cleavage enzymes (Bco1 and Bco2) and estrogen receptors (Esr1 and Esr2) in the liver and gonadal fat were analyzed. BC supplementation increased the hepatic Bco1 and Bco2 expression in males, accompanied by higher serum retinol, while downregulating expressions of these enzymes in male gonadal fat. Additionally, BC supplementation significantly reduced gonadal fat mass and adipogenic gene expression in males, with Cebpa and Esr1/Esr2 positively correlated, suggesting a role for estrogen receptor signaling in adipogenesis. These findings demonstrate that BC exerts sex- and tissue-specific effects on lipid metabolism, with strong regulatory interactions between BC metabolism, lipid homeostasis, and sex hormone signaling in males. The results provide novel insights into the mechanisms underlying sex-dependent differences in lipid metabolism following BC supplementation, with potential implications for metabolic health and disease prevention.

Hydrogels, renowned for their hydrophilic and viscoelastic properties, have emerged as key materials for flexible electronics, including electronic skins, wearable devices, and soft sensors. However, the application of pure double network hydrogel-based composites is limited by their poor chemical stability, low mechanical stretchability, and low sensitivity. Recent research has focused on overcoming these limitations by incorporating conductive fillers, such as liquid metals (LMs), into hydrogel matrices or creating continuous conductive paths through LMs within the polymer matrix. LMs, including eutectic gallium and indium (EGaIn) alloys, offer exceptional electromechanical, electrochemical, thermal conductivity, and self-repairing properties, making them ideal candidates for diverse soft electronic applications. The integration of LMs into hydrogels improves conductivity and mechanical performance while addressing the challenges posed by rigid fillers, such as mismatched compliance with the hydrogel matrix. This review explores the incorporation of LMs into hydrogel composites, the challenges faced in achieving optimal dispersion, and the unique functionalities introduced by these composites. We also discuss recent advances in the use of LM droplets for polymerization processes and their applications in various fields, including tissue engineering, wearable devices, biomedical applications, electromagnetic shielding, energy harvesting, and storage. Additionally, 3D-printable hydrogels are highlighted. Despite the promise of LM-based hydrogels, challenges such as macrophase separation, weak interfacial interactions between LMs and polymer networks, and the difficulty of printing LM inks onto hydrogel substrates limit their broader application. However, this review proposes solutions to these challenges.

Branched-chain amino acid aminotransferases (BCATs), existing as the two isoforms BCAT1 and BCAT2, are responsible for the catabolism of branched-chain amino acids (BCAAs) and are highly upregulated and implicated in a diverse range of cancers. BCAT1 inhibitors represent a potential class of therapeutic agents for cancers; however, none have yet progressed to clinical development. Our earlier research identified WQQ-345 as a novel BCAT1 inhibitor featuring a unique bridged bicyclic skeleton and demonstrating both in vitro and in vivo antitumor activity against tyrosine kinase inhibitor (TKI)-resistant lung cancer with high BCAT1 expression. In the present study, we proceeded to modify the structure of WQQ-345 by two-round structure-activity relationship (SAR) exploration, leading to the discovery of a bicyclo[3.2.1]octene-bearing GABA derivative 7. Compound 7 exhibited a 6-fold enhancement in BCAT1 enzymatic inhibitory activity compared to the parent compound WQQ-345 and could effectively suppress the growth of 67R cells that highly expressed BCAT1 and was resistant to third-generation TKIs. GABA derivatives are an important chemical class of BCAT1 inhibitors, and therefore, the findings in the present study represent great progress both in the discovery of potent BCAT1 inhibitors with new chemical structures and in the treatment of cancer resistance.

Simple urea-based chemicals have been used in the textile industry for "ironing-free clothes" for decades. One of the most used chemicals is 1,3-dimethylol-4,5-dihydroxyethyleneurea (DMDHEU), which consists of urea, glyoxal and formaldehyde. DMDHEU and related chemicals are considered safe and environmentally benign. We have therefore synthesized these compounds and studied their properties as H₂S scavengers as alternatives to the "triazine" compounds used in the offshore industry today. Several derivatives are easily available, and we have evaluated their scavenging properties using Raman spectroscopy. This study reveals that this class of compounds scavenges H₂S under conditions similar to the triazine-based scavengers and gives insight into the structural requirements needed.

Small peptides with aromatic nuclei at the N-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle-dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by using S-(benzo[b]thiophene) and N,S-(thieno [2,3-b]pyridine and thieno[2,3-b]quinoline) heterocycles as N-protective groups for dipeptides l-Phe-l-Phe and l-Phe-l-Leu. The synthesis involved coupling heterocyclic carboxylic acids with trifluoroacetate salts of ethyl l-phenylalanyl-l-phenylalaninate and ethyl l-phenylalanyl- l-leucinate using HBTU and Et₃N, producing the corresponding six N-heterocycle-dipeptide ester conjugates, which were then hydrolyzed to the carboxylic acids. These conjugates were subjected to gelation tests in water starting from 0.4 wt% concentration of the conjugates, using a pH-lowering method with GdL. Among them, only the conjugate of benzo[b]thiophene with l-Phe-l-Phe-OH formed a hydrogel, with a gelation critical concentration of 0.15 wt% (GdL 0.6%) and a final pH of 6.8, which is important for biological applications. The hydrogel was characterized by STEM, revealing nanofibers with an average thickness of 17 nm that assemble into a 3D network capable of trapping water. Further rheological analysis demonstrated its viscoelastic behavior (G' = 3.03 × 10³ Pa; G″ = 3.28 × 10² Pa), comparable to the extracellular matrix of certain human tissues, crucial for biomedical applications.

A significant number of silent biosynthetic gene clusters (BGCs) within the Burkholderia genome remain uncharacterized, representing a valuable opportunity for the discovery of new natural products. In this research, the recombineering system ETh1h2e_yi23, which facilitates recombination in Burkholderia and was developed in our previous study, was used for mining the BGCs of B. plantarii DSM9509. By using this recombineering system, the constitutive promoter was precisely inserted into the genome, resulting in the activation of the silent pla BGC, which led to the production of a new lipopeptide named plantariitin A. A distinctive characteristic of this lipopeptide is the incorporation of a non-proteinogenic amino acid residue, i.e., amino-1,2,3,6-tetrahydro-2,6-dioxo-4-pyrimidinepropanoic acid (ATDPP), which has not been identified in other natural products. A biological activity assay demonstrated that plantariitin A exhibits anti-inflammatory activity. This study further substantiates the notion that the in situ activation of silent BGCs is a crucial strategy for the discovery of new natural products within the genus Burkholderia. With the increasing availability of genomic data and the development of bioinformatics tools, Burkholderia is poised to emerge as a prominent source for the development of new lipopeptides.

γ-aminobutyric acid, a critical neurotransmitter, is experiencing an increasing demand in the medical and health fields. Conventional processes for γ-aminobutyric acid purification from fermentation broth encounter significant challenges, such as high ethanol usage, low yield, complex process flow, and environmental pollution. Therefore, a purification process based on crystallization techniques was developed to address the above issues. The process was implemented in two stages: desalination and γ-aminobutyric acid treatment. Na₂SO₄ was effectively removed through a cooling crystallization technique. γ-aminobutyric acid with a purity of 98.66% and a yield of 67.32% was further obtained through a designed "antisolvent-cooling" crystallization process in a 3.2 L system. Moreover, the new process reduced ethanol usage compared to conventional processes, streamlined the purification process flow, and was more environmentally sustainable. Furthermore, we established an industrial-scale model for γ-aminobutyric acid production. Techno-economic analysis indicates that an investment in a plant with an annual capacity of 74.16 tons of γ-aminobutyric acid is projected to achieve payback in 1.98 years. In conclusion, the crystallization-based purification process is poised for industrial-scale γ-aminobutyric acid production due to its high efficiency, economic viability, energy conservation, and environmental compatibility.

The relentless consumption of fossil fuels and soaring CO₂ emissions have plunged the world into an energy and environmental crisis. As society grapples with these challenges, the demand for clean, renewable, and sustainable energy solutions has never been more urgent. However, even though many efforts have been made in this field, there is still room for improvement concerning efficiency, material stability, and catalytic enhancement regarding kinetics and selectivity of photoelectrochemical (PEC) processes. Herein, we provide the experimental proof for the enhancement of the photocurrent efficiency by the critical focus on semiconductor-electrolyte interface (SEI) properties. By tailoring electrolyte composition, researchers can unlock significant improvements in catalytic efficiency and stability, paving the way for advanced PEC technologies. In this study, we investigate the influence of electrolyte composition on SEI properties and its impact on PEC performance. By employing electrolytes enriched with carbonates, borates, sulphates, and alkali cations, we demonstrate their profound role in optimising photoelectrochemical CO₂ reduction reaction (CO₂RR) efficiency. Central to this work is Cu₂O-an affordable, highly promising photocatalyst. While its potential is undeniable, Cu₂O's inherent instability and diverse reduction products, ranging from CH₃OH to CO, HCOOH, CH₃COOH, and CH₃CH₂OH, have hindered its widespread adoption in PEC CO₂ reduction (CO₂RR). Our approach leverages a straightforward yet powerful electrodeposition method, enabling a deeper exploration of SEI dynamics during photocatalysis. Key parameters, such as carbonate concentration, local pH, alkali cation presence, anionic geometry, CO₂ solubility, and electrolyte conductivity, are systematically investigated. The findings reveal the formation of a unique "rigid layer" at the photocatalyst surface, driven by specific cation-anion interactions. This rigid layer plays a pivotal role in boosting PEC performance, offering a new perspective on optimising, among other PEC processes, CO₂RR catalytic efficiency. This profound study bridges a critical knowledge gap, shedding light on the dual influence of cations and anions on SEI properties and PEC CO₂RR. By unravelling these intricate interactions, we provide a roadmap for designing next-generation PEC systems. These insights pave the way for sustainable energy advancements, inspiring innovative strategies to tackle one of the most pressing challenges of our time.