Search Results (807)

Nutraceuticals are gaining research interest due to their beneficial potential and their use to counter the impact of emerging contaminants on natural ecosystems. Particularly, during the COVID-19 pandemic, the use of personal hygiene/care products and disinfectants increased significantly. These products contain several substances in their formulations, including surfactants, which have proven to be hazardous to the entire aquatic ecosystem. In the present study, bergamot (Citrus bergamia) peel extract was used as a nutraceutical to counteract the toxicity of sodium lauryl sulphate (SLS), a common anionic detergent with antimicrobial activity. Specimens of Mytilus galloprovincialis, were exposed to SLS (0.01 mg/L), bergamot peels’ extract (BRG: 5 mg/L), and their mixture for 14 days. The cellular and physiological alterations in haemocytes, digestive gland (DG) and gill cells were analysed. The analyses included cell viability of haemocytes and DG cells (trypan blue exclusion assay and the neutral red retention test); the ability of DG cells to regulate their volume (RVD); haemocyte phagocytic activity; expression of genes involved in antioxidant response (Cu/ZnSOD, MnSOD, Hsp70, and CYP4Y) on gills and DG; the energy efficiency of the organism through byssus production; and the measurement of key macromolecules, including total lipid and fatty acid content, total protein, tocopherols and carotenoids, which play a key role in maintaining physiological and metabolic functions in the organism. Overall, significant differences emerged between the control (CTR) and treated groups, with the CTR and BRG groups resembling each other, while the SLS-treated groups showed significant alterations. Meanwhile, the groups exposed to the combination showed a recovery, suggesting the potential beneficial effect of the BRG. Full article

Background/Objectives: The ineffective delivery of drugs into tumors and the existence of multidrug resistance (MDR) are the primary causes of chemotherapy failure. Downregulation of the Sonic Hedgehog (Shh) pathway has been shown to reduce P-glycoprotein (P-gp) expression on cell membranes and to resist MDR. Methods: In this study, we combine cyclopamine (CYP, a potent Shh antagonist) with paclitaxel (PTX, an antitumor drug that can produce MDR) in a nano-drug delivery system (CYP NP and PTX NP) for the treatment of drug-resistant breast cancer. Nanoparticles were characterized for size, zeta potential, and encapsulation efficiency. P-gp expression, nanoparticle accumulation, cytotoxicity, and apoptosis were evaluated in MCF-7 and MCF-7/Adr cells. Penetration ability was assessed using 3D multicellular tumor spheroids. Antitumor efficacy and nanoparticle biodistribution were validated in MCF-7/Adr-bearing nude mice models. Results: Our engineered CYP nanoparticles (~200 nm) demonstrated prolonged intratumoral retention, enabling sustained Shh pathway inhibition and P-gp functional suppression. This size-optimized formulation created a favorable tumor microenvironment for the smaller PTX nanoparticles (~30 nm), facilitating deeper tumor penetration and enhanced cellular uptake. Meanwhile, by down-regulating P-gp expression, CYP NPs could convert drug-resistant cells to PTX-sensitive cells in both cytotoxicity and apoptosis induction through the Shh pathway. The combination of CYP NP and PTX NP augmented the antitumor effects in MCF-7/Adr-bearing nude mice models. Conclusions: The CYP NP and PTX NP combination offers a new therapeutic strategy in cancer treatment. Full article

Grifola frondosa, commonly known as turkey tail, is a valuable fungus with medicinal and culinary uses, rich in bioactive compounds like triterpenoid polysaccharides that contribute to health benefits. Here, we constructed a nearly complete genome of G. frondosa CH1 using Illumina, PacBio HiFi, and Hi-C sequencing technologies, resulting in a 35.74 Mb genome with 12,526 protein-coding genes. The genome spans 12 chromosomes, all with intact telomeric structures and no gaps. The BUSCO completeness scores of 95.1% and 99.1% for the genome and genes, respectively, indicate high assembly quality and high completeness of gene prediction. Phylogenetic analysis showed a close relationship between G. frondosa CH1 and Trametes cinnabarina. Transcriptomic analysis under varying light conditions showed changes in the expression of genes, especially those related to terpenoid synthesis, with several CAZymes and CYP450 genes also exhibiting light-induced variations. Ten triterpenoid secondary metabolite gene clusters were identified, three of which were light-sensitive, indicating that light exposure regulates triterpenoid metabolism. This study provides valuable data supporting the high-quality genome of G. frondosa and offers new insights into the light-induced regulation of its metabolism. Full article

MicroRNA-204-5p (miR-204-5p) is a critical regulator of differentiation, structural maintenance, and inflammation in limbal epithelial cells (LECs). This study examined the role of miR-204-5p in modulating the gene expression related to transcription factors, cell structure, extracellular matrix remodeling, and retinoic acid signaling under normal and lipopolysaccharide (LPS)-induced inflammatory conditions. Using qPCR, we analyzed the mRNA levels of FOSL2, FOXC1, Meis2, PPARγ, ABCG2, PTGES2, IL-1β, IL-6, KRT3, KRT12, MMP2, MMP9, RARA, RARB, RXRA, RXRB, CRABP2, RBP1, RDH10, ADH7, ADH1A1, FABP5, CYP1B1, and CYP26A1, while changes in protein levels were assessed via Western blot or ELISA. Our data revealed that the overexpression of miR-204-5p reduced the mRNA levels of FOXC1, KRT12, and RDH10 under normal and inflammatory conditions (p ≤ 0.039). Additionally, it decreased FOSL2 and RXRA mRNA under normal conditions (p = 0.006, p = 0.011) and KRT3 and FABP5 mRNA under inflammatory conditions (p = 0.010, p = 0.001). The IL-6 mRNA expression was significantly increased following the LPS treatment in cells overexpressing miR-204-5p (p = 0.029). A protein analysis revealed significant reductions in FOXC1 and KRT3 in the miR-204-5p-transfected cells during LPS-induced inflammation (p = 0.020, p = 0.030). These findings suggest that miR-204-5p modulates genes critical to the differentiation, migration, and inflammatory response of LECs. The modulation of FOXC1 and KRT3 by miR-204-5p highlights these proteins as novel targets under inflammatory conditions. Full article

In this study, red–blue light (7R3B) was used as the control (CK), while far-red (FR) and ultraviolet-A (UVA) light were supplemented to evaluate their effects on basil growth. The results showed that the FR treatment promoted plant height, stem diameter, and biomass, but reduced chlorophyll and carotenoid content, while the UVA treatment increased stem diameter and chlorophyll b content. Meanwhile, transcriptomic and metabolomic analyses were employed to examine changes in gene expression and metabolite accumulation in basil. The FR treatment reduced the levels of differentially accumulated metabolites (DAMs) in the carotenoid biosynthesis pathway, potentially contributing to the observed decrease in chlorophyll. The FR treatment upregulated the levels of five DAMs (gibberellin, cytokinin, brassinosteroid, jasmonic acid, and salicylic acid) and altered the differentially expressed genes (DEGs) such as gibberellin receptor (GID1) and jasmonate ZIM domain-containing protein (JAZ) in the plant hormone signal transduction pathway, thereby promoting plant growth and shade avoidance responses. The UVA treatment upregulated the 9-cis-epoxycarotenoid dioxygenase (NCED) expression in the carotenoid biosynthesis pathway, possibly indirectly promoting flavonoid synthesis. In the flavonoid biosynthesis pathway, the UVA treatment also promoted flavonoid accumulation by upregulating DEGs including flavonol synthase (FLS), anthocyanidin synthase (ANS), 5-O-(4-coumaroyl)-D-quinate 3′-monooxygenase (CYP98A), and flavanone 7-O-glucoside 2″-O-beta-L-rhamnosyltransferase (C12RT1), as well as increasing the levels of DAMs such as kaempferol, luteolin, apigenin, and leucopelargonidin. The accumulation of flavonoids improved antioxidant capacity and nutritional value in basil. Through a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, this study provided valuable insights into the molecular and metabolic mechanisms of the FR and UVA regulation of basil growth, providing guidance for optimizing supplementary lighting strategies in plant factories. Full article

Insulin-like growth factors (IGFs) play crucial roles in the regulation of animal growth and reproduction. However, the functional and regulatory mechanisms underlying ovarian growth and oocyte maturation in teleosts remain unclear. In this study, the expression profiles of lncRNAs and mRNAs were analyzed in the ovaries of golden pompano (Trachinotus ovatus) treated with IGF1 and IGF2 proteins to gain insights into the role of these two IGF ligands in the regulation of ovarian development and maturation. A total of 1494 lncRNAs and 8728 mRNAs were differentially expressed following IGF1 treatment compared with the control group. A total of 101 lncRNAs and 377 mRNAs were differentially expressed after IGF2 treatment compared to those in the control group. The results revealed that KEGG pathways enriched by target genes of the DE lncRNAs overlapped significantly with those enriched by the DE mRNAs in both the IGF1 and IGF2 groups. The key overlapping enriched pathways included ECM receptor interaction, gap junction, Hedgehog signaling pathway, Ras signaling pathway, Rap1 signaling pathway, TGF beta signaling pathway, Wnt signaling pathway, GnRH signaling pathway, progesterone-mediated oocyte maturation, oocyte meiosis, cell cycle, and MAPK signaling pathway. The differentially expressed genes (DEGs) involved in ovarian development and oocyte maturation were cyp17a1, cyp19a1, star, hsd17b3, hsd17b7, adam23, slc26a6, htr2b, h2ax, nanos3, krt18, pgr, and inhbb, following IGF1 and IGF2 treatment. Furthermore, four lncRNAs (MSTRG.66521.1, MSTRG.49969.1, MSTRG.59923.1, and MSTRG.13767.1) for IGF1 and two (MSTRG.20896.2 and MSTRG.58123.2) for IGF2 within the lncRNA–mRNA network were found to target DEGs related to ovarian development and maturation. This suggests that IGFs may affect reproductive processes by regulating the expression of lncRNAs and mRNAs. RT-qPCR analysis revealed that these six lncRNAs showed high expression levels in the brain, pituitary, liver, and gonad tissues, indicating their potential involvement in regulating ovarian growth and development. This study elucidates the lncRNA–mRNA regulatory mechanism in response to IGF1 and IGF2 treatment during stage III of ovarian development in golden pompano, thereby deepening our understanding of its functional role. Full article

Phytoalexins are specialized metabolites that are synthesized by plants in response to pathogens. A paradigm in transcription factor (TF) biology is that conserved TFs have dedicated roles across plant lineages in regulating specific branches of specialized metabolism. However, the Arabidopsis (Arabidopsis thaliana) NAC family TF ANAC042 (a.k.a. JUNGBRUNNEN1 or JUB1) regulates the synthesis of camalexin, a Trp-derived phytoalexin specifically produced by several Brassicaceae species, whereas its homolog in soybean (Glycine max) regulates the synthesis of glyceollins, which are Phe-derived phytoalexins specific to soybean. The question addressed by this research is whether ANAC042 broadly regulates phytoalexin biosynthetic pathways in Arabidopsis. Using a novel matrix-assisted laser desorption ionization high-resolution mass spectrometry (MALDI-HRMS) method, we found that the Arabidopsis loss-of-function mutant anac042–1 elicited with bacterial flagellin (Flg22) is deficient in lineage-specific Trp- and conserved Phe-derived phytoalexins—namely camalexin and 4-hydroxyindole-3-carbonyl nitrile (4OH-ICN), and pathogen-inducible monolignols and scopoletin, respectively. Overexpressing ANAC042 in the anac042-1 mutant restored or exceeded wildtype amounts of the metabolites. The expression of phytoalexin biosynthetic genes in mutant and overexpression lines mirrored the accumulation of metabolites. Yeast-one hybrid and promoter-reporter assays in Nicotiana benthamiana found that the ANAC042 protein directly binds and activates the promoters of CYP71B15, CYP71A12, and PAL1 genes for the synthesis of camalexin, 4OH-ICN, and pathogen-inducible monolignol/scopoletin, respectively. Our results demonstrate that ANAC042 regulates conserved and lineage-specific phytoalexin pathways in Arabidopsis. The latter suggests that it is an opportunistic TF that has coopted lineage-specific genes into phytoalexin metabolism, thus providing an exception to the current paradigm. Full article

Vitamin A (retinol) and its derivatives (retinoids) assume critical roles in neural development, cellular differentiation, axon elongation, programmed cell apoptosis and various fundamental cellular processes. Retinoids function by binding to specific nuclear receptors, such as retinoic acid receptors (RARs) and retinoid X receptors (RXRs), activating specific signalling pathways in the cells. The disruption of the retinoic acid signalling pathway can result in neuroinflammation, oxidative and ER stress and mitochondrial dysfunction and has been implicated in a wide range of neurodegenerative diseases. The present study explored the potential therapeutic application of our innovative CNS-permeable synthetic retinoid, Ellorarxine, for the treatment of neurodegenerative disorders in vitro. An MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay, lactate dehydrogenase (LDH) assay, enzyme-linked immunosorbent assay (ELISA), immunocytochemistry and immunofluorescence staining were performed. Ellorarxine increased Cyp26 and, selectively, RARβ protein expression in neurons, glia and microglia. Ellorarxine significantly reduced cell death (neurons, glia), increased mitochondrial viability (neurons), modulated cytokine release (microglia), and positively regulated cellular autophagy (neurons, glia, microglia). These results suggest that Ellorarxine is a promising drug candidate that should be further investigated in the treatment of neurodegenerative diseases. Full article

Ergosterol plays a dual role in fungal pathogenesis and azole resistance, driving key advancements in the understanding of its biosynthesis regulation. This review integrates the latest research progress on the regulation of fungal ergosterol biosynthesis and its role in drug resistance and pathogenicity. We comprehensively discuss the functions of key enzymes (such as Erg11p/Cyp51A, Erg6p, Erg3p, and Erg25p) in the mevalonate, late, and alternative pathways. Notably, we highlight the complex regulation of cyp51A expression by factors such as SrbA, AtrR, CBC, HapX, and NCT in Aspergillus fumigatus, and elucidate the distinctive roles of Upc2, Adr1, and Rpn4 in Candida species. Importantly, we summarize recent discoveries on the CprA-dependent regulation of Cyp51A/Erg11p and heme-mediated stability control. Based on these findings, we propose innovative antifungal strategies, including dual-target inhibition and multi-enzyme inhibition by natural products, which provide novel insights and potential directions for the development of next-generation antifungal therapies. Full article

Aspergillus flavus and its secondary metabolites aflatoxins pose a significant threat to the health of humans, animals, and plants. Therefore, there is an urgent need to control A. flavus contamination. AfverB plays a key role in the aflatoxin gene cluster; however, its function and mechanism in fungal development and virulence remain poorly understood. In this study, we constructed afVerB gene deletion mutants (∆afVerB−1 and ∆afVerB−2) and two CYP domain mutants (afVerB^∆D1 and afVerB^∆D2) through homologous recombination. Phenotype analysis revealed that, via its two CYP domains, AfVerB is deeply involved in fungal morphogenesis and aflatoxin synthesis. Insect and crop colonization models revealed that AfVerB plays a key role in the fungus’s ability to infect hosts, and stress experiments discovered that AfVerB plays a significant role in the response to various environmental stresses, which explains why AfVerB is a key factor in fungal infection to some extent. RT-qPCR analysis demonstrated that AfVerB performs its bio-function through corresponding regulatory factors. We ultimately discovered that AfVerB is deeply involved in cell membrane stress stability, thereby participating in the regulation of fungal drug resistance (sensitive to AMB and resistant to VOR in this study). The CYP domain of AfVerB, particularly its second CYP domain, is crucial for the execution of its biological functions. This study elucidated the regulatory mechanisms by which AfVerB regulates fungal pathogenicity and aflatoxin biosynthesis, providing potential strategies for controlling A. flavus and its aflatoxin contamination. Full article

Tumorigenesis and progression are closely associated with apoptosis and primarily regulated by mitochondria, which are considered major targets for cancer therapy. In this study, twelve novel icaritin (ICT) derivatives were designed and synthesized, four of which were specifically targeted to mitochondria. Biological studies demonstrated that all compounds containing triphenylphosphine (TPP⁺) exhibited a substantial increase in antitumor activity compared to ICT and control compounds while also exhibiting notable selectivity for tumor cells over normal cells. Among these derivatives, Mito-ICT-4 exhibited the strongest antiproliferative effect, with an IC₅₀ value of 0.73 ± 0.06 μM for BEL-7402 cells, which is 29 times lower than that of ICT, and an IC₅₀ value of 67.11 ± 2.09 μM for HEK293 cells, indicating approximately 33-fold selectivity for tumor cells. High-performance liquid chromatography (HPLC) analysis revealed that Mito-ICT-4 significantly accumulated in the mitochondria of BEL-7402 cells, with the level of accumulation approximately 2.5 times greater than that of ICT. Further investigations demonstrated that upon entering the mitochondria of tumor cells, Mito-ICT-4 downregulated SIRT3 protein expression, disrupted intracellular redox homeostasis, and led to a substantial increase in mitochondrial ROS levels, abnormal CypD-dependent MPTP opening, mitochondrial membrane potential depolarization, and ROS release into the cytoplasm, ultimately triggering ROS-mediated apoptosis in BEL-7402 cells. Transcriptomic analysis identified differentially expressed genes and enriched pathways, highlighting the ROS-mediated p38-MAPK signaling pathway as a key mediator of Mito-ICT-4-induced mitochondria-dependent apoptosis. The effects of Mito-ICT-4 on the expression of key genes (SIRT3, CypD, P-MKK6, P-P38, and DDIT3) were further validated by qRT-PCR and Western blot analysis, with results aligning with transcriptomic data. The novel ICT derivatives synthesized in this study, with mitochondria-targeting functionality, provide a basis for the development of targeted antitumor drugs. Full article

The CYP78A gene family, a plant-specific subfamily of cytochrome P450 enzymes, plays pivotal roles in plant growth, development, and stress responses. Although the CYP78A genes in many plants have been widely studied, little is known about them in Lycium. In this study, we identified six CYP78A genes in both Lycium barbarum and Lycium ruthenicum through comprehensive bioinformatics analysis. These genes exhibited high conservation in protein structure, gene organization, and conserved motifs. Phylogenetic analysis revealed they are close in terms of homology to CYP78A genes in Arabidopsis, tomato, and eggplant. Cis-acting element analysis of the promoter regions indicated that CYP78A genes are involved in light, hormone, and stress responses, with tissue-specific expression patterns observed across different developmental stages. Subcellular localization experiments confirmed that LrCYP78A5 is localized in the endoplasmic reticulum. Overexpression of LrCYP78A5 in L. ruthenicum resulted in a significant increase in chlorophyll content, indicating the former’s potential role in plant growth. These findings provide valuable insights into the functional roles of the CYP78A gene family in goji, highlighting their potential involvement in growth regulation and metabolic processes. Full article

Wolfberry (Lycium barbarum L.), as a kind of combination of medicine and food, is rich in antioxidant components. However, the deep-processed products of wolfberry need to be developed to improve its added value. This study aimed to investigate the nutrients, active antioxidant ingredients, and liver-protective mechanism of mixed-culture fermented wolfberry vinegar (MFV). The results showed that MFV had significantly higher protein and significantly lower fat content than wolfberry juice before fermentation, indicating that MFV was a healthy product. The active ingredient content, which included total phenolics, total flavonoids, polysaccharides, betaine, and antioxidant activities, was significantly increased in MFV after mixed-culture fermentation. Moreover, MFV improved histopathological changes and reduced liver biochemical indicators in alcohol-treated mice, indicating the improvement of liver function. In addition, MFV effectively alleviated alcohol-induced liver injury by increasing the expression of alcohol metabolizing enzymes and inhibiting CYP2E1 activity. MFV regulated the equilibrium between pro-oxidant and antioxidant levels by downregulating pro-oxidant markers and upregulating antioxidant markers. Furthermore, MFV reduced the levels of inflammatory indexes by inhibiting the PI3K/Akt/NF-κB signaling pathway. These results suggest that MFV is a healthy food for liver protection, which provides a strategy for deep-processed products of wolfberry. Full article

Indolic glucosinolates are a group of plant secondary metabolites found in Brassica vegetables, and their breakdown products could act as important anti-cancer and defense compounds against biotic stresses. Transcriptional regulation plays a key role in modulating the biosynthesis of indolic glucosinolates in the model plant Arabidopsis, but little is known about the transcriptional regulatory landscape of these glucosinolates in Brassica vegetables. In this study, we selected and functionally validated the important biosynthetic gene BolCYP83B1 from the indolic glucosinolate pathway in cabbage. Through a yeast one-hybrid assay, we systemically screened and identified upstream regulators of BolCYP83B1 in cabbage with BolANTs as the top candidates for further functional validation. Two homologs of BolANTs, BolANT1 and BolANT3, were confirmed to bind the promoter of BolCYP83B1 via both a yeast one-hybrid assay and an LUC assay. The overexpression of BolANT3 in cabbage significantly increased the accumulation of indolic glucosinolates, while the virus-induced gene silencing (VIGS) of BolANT3 significantly reduced the accumulation of indolic glucosinolates in cabbage. Our work provides valuable insights into the transcriptional regulatory mechanisms of indolic glucosinolates in Brassica vegetables. Full article

Antimony and copper can contaminate vegetables and enter the human body through the digestive tract, inducing severe and extensive biotoxicity. However, the role of bile acids (BAs) in the pathogenesis of liver inflammation by antimony or copper has not been elucidated. Our results indicated that antimony and/or copper induced liver inflammation, causing the disruption of gut microbiota, with the down-regulation of probiotics and up-regulation of harmful bacteria closely correlated to liver inflammation. Targeted metabolomics of BAs showed that antimony and/or copper significantly up-regulated the levels of taurine-β-muricholic acid (T-β-MCA) in serum and liver, which was due to the reduction of Lactobacillus spp. A farnesoid X receptor (FXR) antagonist, T-β-MCA inhibited the FXR-SHP pathway in liver and FXR-FGF15 pathway in ileum, thereby promoting the transcription of cholesterol 7-alpha hydroxylase (CYP7A1) and increasing total bile acid concentrations, ultimately leading to liver inflammation. These findings provide new insights into the underlying mechanisms of antimony- and/or copper-induced liver inflammation. Full article