Search Results (249)

Salinity is a key environmental factor regulating lipid metabolism in marine oleaginous protists. This study examined the impact of NaCl concentration on growth, glucose utilization, and lipid biosynthesis in Thraustochytrium sp. ATCC 26185. Moderate salinity (20 g/L) enhanced biomass and glucose uptake, while high salinity (45 g/L) induced osmotic stress yet significantly promoted squalene accumulation (17.27 mg/g), a 3.26-fold increase compared with 0 g/L NaCl (5.29 mg/g). Integrated transcriptomic and metabolomic analyses revealed that salinity-dependent activation of glycolysis, the TCA cycle, and the pentose phosphate pathway increased cellular ATP, NADH, and NADPH levels. Under salt stress, the mevalonate (MVA) pathway was transcriptionally upregulated, with key enzymes, including ACAT, HMGR, and IDI, showing marked induction, which supports enhanced carbon flux toward squalene biosynthesis. Despite SQS downregulation, squalene accumulation increased, likely due to elevated precursor availability and reduced flux to downstream sterol pathways. Concurrently, high salinity repressed expression of ACC, FAS-α, and FAS-β, reducing saturated fatty acid levels, while upregulation of PKSB-favored polyunsaturated fatty acid (PUFA) synthesis. These findings suggest that high-salt stress triggers transcriptional reprogramming, redirecting acetyl-CoA from fatty acid synthesis toward squalene and PUFA production. This study offers new insights into the metabolic plasticity of thraustochytrids and highlights salinity modulation as a promising strategy for enhancing high-value lipid yields in marine biotechnology. Full article

Forest ginseng (FG) is a rare medicinal and culinary plant in China, and its drying quality is heavily dependent on the drying method. This study investigated the effects of traditional hot air drying (HAD) and the self-developed negative-pressure circulating airflow-assisted desiccator drying (PCAD) method on the quality of FG using metabolomics and enzyme activity. The results revealed that the enzyme activities of dried FG were reduced considerably. PCAD preserved higher enzyme activity than HAD. Metabolomics data demonstrate that HAD promotes the formation of primary metabolites (amino acids, lipids, nucleotides, etc.), whereas PCAD promotes the formation of secondary metabolites (terpenoids, phenolic acids, etc.). A change-transformation network was built by combining the metabolites listed above and their biosynthetic pathways, and it was discovered that these biosynthetic pathways were primarily associated with the mevalonate (MVA) pathway, lipid metabolism, phenylpropane biosynthesis, and nucleotide metabolism. It is also believed that these findings are related to the chemical stimulation induced by thermal degradation and the ongoing catalysis of enzyme responses to drought stress. The facts presented above will give a scientific basis for the selection of FG drying processes, as well as helpful references for increasing the nutritional quality of processed FG. Full article

Fritillaria unibracteata is a rare and endangered medicinal plant in the Liliaceae family, whose bulbs have been used in traditional Chinese traditional medicine for over 2000 years. The mevalonate (MVA) pathway is involved in the growth, development, response to environmental stress, and active ingredient production of plants; however, the functional characterization of MVA-pathway genes in the Liliaceae family remains poorly documented. In this study, an Acetyl-CoA C-acetyltransferase gene (FuAACT) was first cloned from F. unibracteata. It exhibited structural features of the thiolase family and showed the highest sequence identity with the Dioscorea cayenensis homolog. The K_m, V_max, and K_cat of the recombinant FuAACT were determined to be 3.035 ± 0.215 μM, 0.128 ± 0.0058 μmol/(min·mg), and 1.275 ± 0.0575 min⁻¹, respectively. The optimal catalytic conditions for FuAACT were ascertained to be 30 °C and pH 8.9. It was stable below 50 °C. His361 was confirmed to be a key amino acid residue to enzymatic catalysis by site-directed mutagenesis. Subsequent subcellular localization experiments demonstrated that FuAACT was localized in chloroplasts and cytoplasm. FuAACT-overexpressing transgenic Arabidopsis thaliana plants showed higher drought tolerance than wild-type plants. This phenotypic difference was corroborated by significant differences in seed germination rate, lateral root number, plant height, and leaf number (p < 0.05). Furthermore, the FuAACT transgenic plants resulted in the formation of a more developed fibrous root system. These results indicated that the FuAACT gene revealed substantial biological activity in vitro and in vivo, hopefully providing the basis for its further research and application in liliaceous ornamental and medicinal plants. Full article

Background: Statins exhibit pleiotropic anti-inflammatory, antioxidant, and immunomodulatory effects, suggesting their potential in non-cardiovascular conditions. However, evidence supporting their repurposing remains limited, and off-label prescribing policies vary globally. Objective: To systematically review evidence on statin repurposing in oncology and infectious diseases, and to assess Hungarian regulatory practices regarding off-label statin use. Methods: A systematic literature search (PubMed, Web of Science, Scopus, ScienceDirect; 2010–May 2025) was conducted using the terms “drug repositioning” OR “off-label prescription” AND “statin” NOT “cardiovascular,” following PRISMA guidelines. Hungarian off-label usage data from the NNGYK (2008–2025) were also analyzed. Results: Out of 205 publications, 12 met the inclusion criteria—75% were oncology-focused, and 25% focused on infectious diseases. Most were preclinical (58%); only 25% offered strong clinical evidence. Applications included hematologic malignancies, solid tumors, Cryptococcus neoformans, SARS-CoV-2, and dengue virus. Mechanisms involved mevalonate pathway inhibition and modulation of host immune responses. Hungarian data revealed five approved off-label statin uses—three dermatologic and two pediatric metabolic—supported by the literature and requiring post-treatment reporting. Conclusions: While preclinical findings are promising, clinical validation of off-label statin use remains limited. Statins should be continued in cancer patients with cardiovascular indications, but initiation for other purposes should be trial-based. Future directions include biomarker-based personalization, regulatory harmonization, and cost-effectiveness studies. Full article

Background: Exposure to per- and polyfluoroalkyl substances (PFAS, including 7H-Perfluoro-4-methyl-3,6-dioxaoctanesulfonic acid (PFESA-BP2), perfluorooctanoic acid (PFOA), and hexafluoropropylene oxide (GenX), has been associated with liver dysfunction. While previous research has characterized PFAS-induced hepatic lipid alterations, their downstream effects on energy metabolism remain unclear. This study investigates metabolic alterations in the liver following PFAS exposure to identify mechanisms leading to hepatoxicity. Methods: We analyzed RNA sequencing datasets of mouse liver tissues exposed to PFAS to identify metabolic pathways influenced by the chemical toxicant. We integrated the transcriptome data with a mouse genome-scale metabolic model to perform in silico flux analysis and investigated reactions and genes associated with lipid and energy metabolism. Results: PFESA-BP2 exposure caused dose- and sex-dependent changes, including upregulation of fatty acid metabolism, β-oxidation, and cholesterol biosynthesis. On the contrary, triglycerides, sphingolipids, and glycerophospholipids metabolism were suppressed. Simulations from the integrated genome-scale metabolic models confirmed increased flux for mevalonate and lanosterol metabolism, supporting potential cholesterol accumulation. GenX and PFOA triggered strong PPARα-dependent responses, especially in β-oxidation and lipolysis, which were attenuated in PPARα^−/− mice. Mitochondrial fatty acid transport and acylcarnitine turnover were also disrupted, suggesting impaired mitochondrial dysfunction. Additional PFAS effects included perturbations in the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and blood–brain barrier (BBB) function, pointing to broader systemic toxicity. Conclusions: Our findings highlight key metabolic signatures and suggest PFAS-mediated disruption of hepatic and possibly neurological functions. This study underscores the utility of genome-scale metabolic modeling as a powerful tool to interpret transcriptomic data and predict systemic metabolic outcomes of toxicant exposure. Full article

Dryopteris fragrans (L.) Schott synthesizes volatile sesquiterpenes through the mevalonate pathway (MVA), in which 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) serves as the key rate-limiting enzyme. Although HMGR plays a crucial role in terpenoid biosynthesis, its functional characteristics in D. fragrans and its involvement in stress responses remain unclear. This study identified three HMGR genes (DfHMGR1/2/3) from the transcriptome data of D. fragrans. Bioinformatics analysis revealed that the encoded proteins are localized to the endoplasmic reticulum and share high sequence similarity with fern homologs. Under abiotic stress conditions, DfHMGRs exhibited differential expression patterns, with marked upregulation under salt and drought stress. To validate the functions of these genes, we generated transgenic Nicotiana tabacum L. plants overexpressing DfHMGRs. Compared with wild-type controls, the transgenic lines showed enhanced tolerance to drought and heat stress. Promoter analysis identified functional regulatory regions controlling DfHMGR expression, and co-expression network analysis predicted 21 potential transcriptional regulators. This study validates the function of D. fragrans HMGRs in a heterologous system and provides candidate genes for improving stress resistance in plants. Full article

Nitrogen-containing bisphosphonates (N-BPs) are commonly used drugs in the treatment of bone diseases due to their potent inhibition of the mevalonate pathway, leading to disrupted protein prenylation and reduced osteoclast activity. Although N-BPs are effective in reducing bone resorption, increasing evidence indicates their side effects on various non-skeletal cells. The aim of this review is to synthesize the current knowledge on the cellular and molecular effects of N-BPs outside the skeletal system, with particular emphasis on their impact on mitochondrial function and energy metabolism. At the cellular level, N-BPs may reduce viability, modulate inflammatory responses, trigger apoptosis, disrupt cytoskeletal organization, and influence signaling and energy metabolism. N-BPs may also impair the prenylation of proteins essential for mitochondrial dynamics and quality control, and may disrupt Ca²⁺ homeostasis. As we have shown in endothelial cells, by inhibiting the mevalonate pathway, N-BPs may lead to a reduction in key components of the mitochondrial respiratory chain, such as coenzyme Q (CoQ) and a-heme. These effects can contribute to impaired mitochondrial respiratory function, increased oxidative stress, and mitochondria-dependent apoptosis, affecting cellular energy metabolism and viability. These findings underscore the multifaceted impact of N-BPs beyond bone, emphasizing the importance of mitochondrial health and energy metabolism in understanding their broader biological effects and potential adverse outcomes. Full article

The mevalonate pathway is crucial for synthesizing isopentenyl pyrophosphate (IPP), the universal precursor of terpenoids, with 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) serving as the rate-determining enzyme that catalyzes the reduction of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonate, requiring NAD(P)H as an electron donor. Improving the cofactor promiscuity of HMGR can facilitate substrate utilization and terpenoid production by overcoming cofactor specificity limitations. In this study, we heterologously expressed rpHMGR from Ruegeria pomeroyi in Escherichia coli BL21(DE3) for the first time and established that it predominantly utilizes NADH. To broaden its cofactor usage, we employed Molecular Operating Environment (MOE)-assisted design to engineer the cofactor binding site, creating a dual-cofactor-utilizing mutant, D154K (the substitution of aspartic acid with lysine at residue 154). This mutant exhibited a significant 53.7-fold increase in activity toward NADPH, without compromising protein stability at physiological temperatures. The D154K mutant displayed an optimal pH of 6, maintaining over 80% of its catalytic activity across the pH range of 6–8, regardless of whether NADH or NADPH was the cofactor. These findings highlight the value of rational design, enhance our understanding of HMGR-cofactor recognition mechanisms, and provide a foundation for future efforts to optimize and engineer HMGR for broader cofactor flexibility. Full article

Background/Objectives: Bisphosphonates may influence vascular calcification and atheroma formation via farnesyl pyrophosphate synthase inhibition in the mevalonate pathway regulating bone and lipid metabolism. However, the clinical impact of NCB use on cardiovascular outcomes remains uncertain, largely due to methodological heterogeneity in prior studies. We aimed to evaluate the association between nitrogen-containing bisphosphonate (NCB) therapy and coronary artery calcium (CAC) progression, as well as the incidence of cardiovascular disease (CVD) and coronary heart disease (CHD) events. Methods: From 6814 participants in MESA Exam 1, we excluded males (insufficient male NCB users in the MESA cohort), pre-menopausal women, baseline NCB users, and users of hormone replacement therapy, raloxifene, or calcitonin. Among 166 NCB initiators and 1571 non-users with available CAC measurements, propensity score matching was performed using the available components of FRAX, namely age, race, BMI, LDL cholesterol, alcohol, smoking, and steroid use, and baseline CAC yielded 165 NCB initiators matched to 473 non-users (1:3 ratio). Linear mixed-effects models evaluated CAC progression, and Cox models analyzed incident CVD and CHD events. Results: In the overall cohort, NCB use was not significantly associated with CAC progression (annual change: −0.01 log Agatston units; 95% CI: −0.05 to 0.01). However, among participants with a baseline estimated glomerular filtration rate (eGFR) < 65 mL/min/1.73 m², NCB use was associated with attenuated CAC progression compared with non-users (−0.06 log Agatston units/year; 95% CI: −0.12 to −0.007). No significant association was observed between NCB use and incident CVD events in the overall cohort (HR: 0.90; 95% CI: 0.60−1.36) or within kidney function subgroups. Conclusions: Incident NCB use among postmenopausal women with mild or no CAC at baseline was associated with reduced CAC progression only in women with impaired kidney function. However, this association did not correspond to a decreased risk of subsequent cardiovascular events, suggesting that the observed imaging benefit may not translate into meaningful clinical association. Full article

Granulosa cell (GC) dysfunction contributes to diminished ovarian reserve (DOR). We collected GC and follicular fluid samples from the patients of normal ovarian reserve (NOR) and DOR. RNA-seq of GCs showed that cholesterol/sterol metabolism and biosynthesis and extracellular matrix organization were enriched in the DOR group. Metabolomics of follicular fluid revealed enrichment in steroid hormone biosynthesis, tryptophan metabolism, and fatty acid β-oxidation in DOR. The apoptosis rate was increased, whereas the proliferative rate was decreased in GCs of DOR. The Prussian blue staining rate was increased whilst GPX4 and SLC7A11 expression were downregulated in GCs of DOR. Mitochondrial morphology displayed the features of ferroptosis in GCs of DOR. FSHR, CYP19A1, NR5A1, and phosphorylated CREB levels were substantially downregulated in GCs, accompanied by increased androgen levels in follicular fluids in DOR. The key factors linked to the mevalonate pathway, HMGCR, SQLE, and SREBF2, were robustly increased in DOR. FSHR and NR5A1 levels were correlated with CYP19A1 levels, whilst CYP19A1 levels were positively correlated with GPX4 and SLC7A11 levels. Our findings indicate ferroptosis and dysregulation of cholesterol/sterol metabolism and biosynthesis occurrence in GCs of DOR, which might be associated with reduced FSHR signaling and decreased conversion of androgen to estrogen. Full article

γδ T cells are among the first line of defense in the immune system, playing a crucial role in bridging innate and adaptive immunity. Although γδ T cells are crucial for tumor immune surveillance, the complete mechanism by which γδ T cell receptors identify molecular targets in target cells remains unknown. Target cells can produce phosphoantigens (PAgs) via the mevalonate pathway or the methylerythritol phosphate pathway. The BTN3A1–BTN2A1 complex undergoes conformational changes in its extracellular domains upon binding to PAgs, leading to Vγ9Vδ2 T cell recognition. However, the structural basis of how Vγ9Vδ2 T cells recognize changes in this complex remains elusive. This review provides a detailed overview of the historical progress and recent discoveries regarding how Vγ9Vδ2 T cells recognize and target tumor cells. We also discuss the potential of γδ T cells immunotherapy and their role as antitumor agents. Full article

Volatile terpenoids (VTs) are key secondary metabolites that play dual roles as endogenous antioxidants and airborne signals in plants under abiotic stress. Their biosynthesis is orchestrated via the mevalonate (MVA) and 2-C-methyl-D-erythritol 4-phosphate (MEP) pathways, with metabolic plasticity regulated by transcription factors, phytohormonal crosstalk, and stress-responsive elements. Recent advances have revealed that VTs such as isoprene, monoterpenes, and sesquiterpenes help mitigate oxidative stress by scavenging reactive oxygen species (ROS) and modulating antioxidant enzyme systems. However, regulatory mechanisms of stress-induced VT emissions remain fragmented and species-dependent. This review synthesizes current knowledge of VT biosynthesis and emission under abiotic stress, highlights their antioxidant functions and regulatory architecture, and underscores their protective roles in redox homeostasis and stress signal transduction. By identifying key metabolic nodes (e.g., TPS, DXS and MYC2) and stress-responsive pathways, we propose potential molecular targets for the development of stress-resilient cultivars. The integration of VT-based traits into breeding strategies and production-oriented metabolic engineering offers promising avenues for improving crop performance, reducing oxidative damage, and supporting sustainable agricultural systems. Full article

The characteristic minty-like aroma of ‘Rucheng Baimaocha’ black tea (RCBT) enhances the tea’s unique flavor profile, driving high demand among consumers. The dynamic changes in key aroma compounds in minty-like RCBT were elucidated by sensory evaluation and gas chromatography olfactometry quadrupole time of flight mass spectrometry (GC × GC-O-Q-TOF-MS). The results indicated that during processing, the aroma of RCBT transitions from a fresh to floral, sweet, and minty-like aroma. Among the 189 identified volatile compounds, alcohols constitute the predominant category (over 50%), with 71 compounds identified as key differential compounds across all stages. Aroma analysis revealed that 28 compounds with odor activity values (OAV) > 1 were the primary contributors during RCBT processing. Notably, minty-like odorants in RCBT were primarily derived from the metabolic pathways of the methylerythritol phosphate (MEP) and mevalonic acid (MVA), lipid oxidation, and phenylalanine. These findings offer theoretical insights for improving unique black tea quality and optimizing processing techniques. Full article

Plants have evolved complex terpene defenses. Terpenoids accumulate in plant tissues or release as volatile in response to ever-changing environment, playing essential roles in chemo-ecological functions as defense against pathogen and insect, improving pollination and seed dispersal, facilitation plant-to-plant communication. They are also gaining attention in pharmaceuticals, nutraceuticals, fragrance, and biofuels. Here, we highlight the recent progress in the fundamental pathways of terpenoid biosynthesis, key enzymes, and their corresponding genes involved in terpenoid synthesis. We identified the further exploration of biosynthetic networks and the development of novel terpenoid resources, proposed the need for further exploration of biosynthetic networks and the development of novel terpenoid resources. Based on that knowledge, future research should be directed towards the mechanisms governing terpenoid biosynthesis dependent environmental change and molecular breeding. Full article

Background: Rhabdoid tumours (RTs) are aggressive neoplasms most often characterised by biallelic loss of the SMARCB1 gene, encoding a core subunit of the SWI/SNF chromatin-remodelling complex. Despite their relative genetic stability, RTs exhibit a highly malignant phenotype and poor prognosis. Methods: This review explores the mechanisms underlying SMARCB1 aberrations, their role in driving hallmarks of cancer, and emerging therapeutic strategies for RTs. Ongoing clinical trials listed on ClinicalTrials were reviewed to evaluate the translational potential of targeted therapies in SMARCB1-deficient rhabdoid tumours. Results: Loss of SMARCB1 drives multiple cancer hallmarks by disrupting key regulatory pathways. It promotes unchecked cell proliferation through alterations in p16INK4a and Myc signalling. SMARCB1-deficient tumours possess immune-evading capabilities via PD-L1 overexpression and immune checkpoint activation. SMARCB1 deficiency also alters cellular energetics. The nucleotide biosynthesis pathway has been demonstrated to be upregulated in RT organoids, as shown by increased levels of pathway metabolites. Enzymes of the mevalonate pathway such as HMG-CoA reductase and mevalonate kinase are also dysregulated. Targeting glutathione metabolism with eprenetapopt may induce oxidative stress and apoptosis. Widespread epigenetic aberrations, including increased EZH2 activity, are being targeted with inhibitors such as tazemetostat. Conclusions: SMARCB1 loss is a central driver of cancer hallmarks in RTs, enabling proliferation, immune evasion, metabolic reprogramming, and epigenetic dysregulation. Future horizons in RT treatment include immunotherapies, epigenetic modifiers, and gene therapies. The synergy and optimal timing of targeted therapy with conventional treatment requires further characterisation for clinical translation. Full article