Search Results (520)

Regulated cell death is essential for tissue homeostasis, immune defense, and disease progression, yet the lipid-based regulatory mechanisms that coordinate cell death signaling remain incompletely understood. Protein palmitoylation is a dynamic and reversible lipid post-translational modification that controls protein membrane association, trafficking, stability, and signaling complex assembly. This review summarizes the regulatory roles of palmitoylation and depalmitoylation in major forms of regulated cell death, including apoptosis, necroptosis, pyroptosis, ferroptosis, and autophagy-related cell death. Particular attention is given to representative palmitoylated substrates, including Fas cell surface death receptor (Fas), receptor-interacting protein kinase 1 (RIPK1), NLR family pyrin domain containing 3 (NLRP3), gasdermin D (GSDMD), glutathione peroxidase 4 (GPX4), solute carrier family 7 member 11 (SLC7A11), autophagy-related 16 like 1 (ATG16L1), and Beclin1. These substrates illustrate how palmitoylation links membrane organization, metabolic status, inflammatory signaling, and cell fate decisions. Disease-oriented evidence further indicates that dysregulated palmitoylation contributes to cancer, neurodegenerative diseases, and inflammatory or immune-related disorders by modulating cell death resistance, inflammatory amplification, immune evasion, or impaired proteostasis. Current challenges include limited quantitative information on palmitoylation dynamics, incomplete evidence for some enzyme–substrate relationships, and insufficient distinction between disease-driving and secondary palmitoylation events. Targeting zinc finger Asp-His-His-Cys (zDHHC) palmitoyl acyltransferases, depalmitoylating enzymes, or specific palmitoylated substrates may provide new therapeutic opportunities. Overall, this review positions protein palmitoylation as a dynamic molecular switch linking lipid metabolism, membrane signaling, regulated cell death, and disease remodeling. Full article

Lauric acid is a characteristic component of Litsea cubeba seed oil, but FatB thioesterase candidates with predicted structural compatibility for C12 acyl-substrate accommodation remain insufficiently defined. In this study, seed oil content and fatty acid composition were examined during L. cubeba seed development. The fatty acid profile shifted from a C18:2-rich pattern at the early stage to a C12:0-dominated composition at later stages, providing the biochemical context for FatB candidate prioritization. Three FatB-like candidates were retrieved from a de novo seed transcriptome assembly and named LcFatB1, LcFatB2, and LcFatB3. Phylogenetic analysis, conserved motif comparison, sequence alignment, and homology modeling showed that LcFatB1 and LcFatB2 retained more complete FatB-like sequence and structural features than LcFatB3. S-dodecanoyl-4′-phosphopantetheine was used as a C12 acyl-4′-phosphopantetheine surrogate for molecular docking. Docking analysis indicated that LcFatB1 and LcFatB2 formed more interpretable C12-bound poses than LcFatB3. Subsequent 150 ns molecular dynamics simulations, free energy landscape analysis, residue–ligand interaction profiling, and catalytic tunnel analysis further distinguished the two main candidates. Compared with LcFatB2, LcFatB1 maintained a lower-displacement C12-bound state, a more compact contact environment involving Tyr116, Ser125, and Asn278, and a main tunnel with higher throughput and shorter length in the representative global-minimum conformation. LcFatB2 also retained the C12 surrogate but stabilized it in a distinct rearranged binding environment. These results support LcFatB1 as the strongest structurally prioritized FatB candidate among the three transcriptome-derived proteins, while LcFatB2 remains a plausible FatB-like candidate with a distinct C12-bound state. This prioritization provides computational structural clues for future biochemical testing but should not be interpreted as direct functional confirmation of FatB activity in vivo. Full article

This study integrated echocardiography with widely targeted metabolomics to decipher how plasma metabolic dynamics couple with cardiac geometry in Yili horses during incremental treadmill exercise. Nine speed-type horses underwent a graded exercise test (6% incline; 0 to 9 m/s). Jugular venous blood samples collected at rest (0 m/s) and at 3, 5, 7, and 9 m/s were profiled by LC-MS, and Pearson correlation analysis was applied to relate differentially expressed metabolites (DEMs) to twenty echocardiographic structural indices. A core set of 314 shared DEMs (124 upregulated, 190 downregulated) was identified across all exercise comparisons, spanning amino acids, organic acids, and fatty acyls. These metabolites were mapped to ABC transporter, thermogenesis, aldosterone-regulated sodium reabsorption, steroid hormone biosynthesis, and one-carbon folate metabolism pathways. At rest (0 m/s), right ventricular end-diastolic dimension correlated positively with arginyl-isoleucine (p < 0.001), whereas left ventricular free wall thickness (diastolic and systolic) correlated positively with undecanedioic acid (p < 0.001) and proline-hydroxyproline (p < 0.01). At peak exercise (9 m/s), left ventricular mass and left ventricular mass index correlated positively with succinic acid (p < 0.05) and methylmalonic acid (p < 0.05), while left ventricular minor axis correlated with carnitine C14:2 and carnitine C12:1 (p < 0.05). Left ventricular end-systolic dimension and left atrial end-diastolic dimension correlated negatively with cysteine-glutathione disulfide and N2-(1-carboxyethyl)-L-arginine, respectively. These findings illuminate a robust metabolic–cardiac structure axis: amino acid metabolites support collagen matrix turnover and redox homeostasis, organic acids sustain mitochondrial energy flux and antioxidant defense, and fatty acyls fuel continuous contractile activity via enhanced fatty acid oxidation. This metabolome-informed framework furnishes a mechanistic basis for precision training and performance phenotyping in equine athletes. Full article

Background/Objectives: Protein–carbohydrate interactions are implicated in amyloid aggregation pathways associated with Alzheimer’s disease (AD). Designing glycomimetics that modulate amyloid assembly represents a promising strategy. In addition, the interaction of Aβ_1–42 oligomers (Aβo) with prion protein (PrP^C) activates Fyn kinase and leads to Tau hyperphosphorylation, another process characterizing AD. Thus, we generated a library of phenyl 2-acetamidoselenogalactoside mimetics to evaluate their interactions with Aβo and disruption of Aβo–PrP^C binding, and consequently their potential to inhibit Fyn kinase activation. Methods: The synthetic approach comprised azidophenylselenylation, a modified one-pot Staudinger reduction–acylation, a selective α-glycosylation, and deacetylation. Structural diversity was achieved mainly via acylation or ureation. The compounds were screened for binding to Aβo using STD-NMR, ¹⁹F-NMR, and rapid equilibrium dialysis (RED). ADME properties were assessed through microsomal metabolism and solubility assays, while cytotoxicity was evaluated by MTT assays in human embryonic kidney (HEK) cells. Results: Several compounds bound Aβo in STD-NMR experiments, mainly through aromatic and anomeric protons, and phenyl 2-deoxy-2-phenylureido-1-seleno-α-d-galactopyranoside (34) showed the most consistent response, with >50% increase in relative binding signal in competition assays, demonstrating also some inhibition of Aβo–PrP^C interactions (12%). Selenium at the anomeric position enhanced binding compared to sulphur and oxygen analogs. RED experiments confirmed weak binding interactions, consistent with STD-NMR results. ADME revealed that acetylated compounds undergo microsomal metabolism, whereas deacetylated derivatives displayed high aqueous solubility (>100 μM) and showed no cytotoxicity. Conclusions: Phenyl 2-acetamidoselenogalactosides are a novel class of amyloid-binding glycomimetics. Among them, 34 emerges as the most promising compound, combining favorable solubility, metabolic stability, low toxicity, and measurable interference with Aβo and Aβo–PrP^C interactions, thus supporting further developments toward therapeutic applications in AD. Full article

Magnolia cavaleriei var. platypetala ‘Tanchun’ is a newly registered flower variety in China, known for its characteristic floral aroma that intensifies toward full bloom. However, the composition of the volatiles of this aromatic flower remains uncharacterized. Here, we compared the volatile organic compound composition of Tanchun through gas chromatography–mass spectrometry and comparative transcriptome sequencing analyses of the stamen (S), pistil (P), and petals (T) during flower development, i.e., the bud (S1), semi-opened (S2), and bloom (S3) stages. We present a first comprehensive profile of 1395 metabolites from Tanchun’s floral organs. Terpenoids (26.2%) constituted the largest chemical group, followed by esters (17.52%), nitrogen compounds (9.83%), hydrocarbons (8.11%), alcohols (7.97%), aldehydes (6.53%), and others. We found that volatile organic compound (VOC) accumulation was both spatiotemporal and stage-specific. The S1 and S2 transition was characterized by scent notes of green, herbal, and waxy aromas, while the S2 and S3 shift exhibited a richer profile of fruity, sweet, and creamy notes, primarily in petals. A comparative VOC and transcriptomic analysis revealed that petals activate pathways for structural expansion and precursor mobilization, stamens enhance lipid and terpenoid metabolism, and pistils maintain a conserved profile. Importantly, the S1 and S2 transition in petals establishes the biochemical foundation by activating acyl-CoA, phenylpropanoid, and terpenoid synthesis pathways, which enables the activation of the butanoate metabolism pathway at S3, leading to the production of ester-rich compounds that define the floral scent. The transition to full bloom involves a shift to energy-efficient volatile biosynthesis, supported by carbohydrate restructuring and phytohormonal regulation. Our results provide the first comprehensive volatilome and transcriptome resource for ‘Tanchun’, revealing a highly efficient, multi-stage strategy for floral fragrance biosynthesis. This work lays a molecular foundation for future horticultural improvement and biotechnological applications in the flavor and fragrance industries. Full article

L-carnitine is a crucial quaternary ammonium compound widely used in the pharmaceutical, food, and feed industries. Microbial biosynthesis of L-carnitine, compared with chemical synthesis, offers milder conditions, higher stereoselectivity, and a lower environmental impact. However, highly efficient strains and mechanistic insights into the bioconversion of γ-butyrobetaine (γBB) to L-carnitine remain limited. This study focuses on strain WQ-1, a newly screened strain capable of converting γBB to L-carnitine. Based on morphological, physiological, and phylogenetic analyses of 16S rRNA and housekeeping genes, the strain was identified as Ensifer sp. WQ-1. Under the condition of 30 °C, initial pH 8.5, 10% inoculum, 6 g/L initial γBB, shake-flask fermentation reached molar conversion rate of 88%. In a 5 L bioreactor fed-batch fermentation, the L-carnitine titer achieved 13.98 g/L with a 78.7% molar conversion rate. Genomic analysis revealed a 6.97 Mb genome harboring 6568 protein-coding genes, including candidates for quaternary ammonium transport, CoA-dependent transformation, and transcriptional regulation. Comparative transcriptomics identified 58 differentially expressed genes, highlighting the significant upregulation of genes related to acyl-CoA activation, dehydrogenation, carnitine metabolism, and thioester hydrolysis in the presence of γBB. Multi-omics analyses support a putative CoA-dependent metabolic pathway for conversion of γBB to L-carnitine in Ensifer sp. WQ-1. Full article

Lyophilized black goji berry powder (LBGBP) cultivated in Serbia was evaluated and optimized as a fortification agent in cookie formulation. Nutritional, chemical, technical and biological characteristics, in vitro release and storage stability were analyzed. LBGBP is characterized by a phenolic-rich profile dominated by acylated anthocyanins, 5-O-caffeoylquinic acid (5-O-CA), and spermidine-based phenylamides (S1, S2), which are partially retained in LBGBP-enriched cookies and enhance their functional properties. The substitution of different white flour shares with LBGBP in cookies statistically significantly improved their overall nutritional profile by increasing protein, dietary fiber, minerals and bioactive compounds, concurrently reducing fat, sugar and sodium levels. With the increase in the LBGBP in cookies, total phenolics and total anthocyanin content increased to the levels of 58.09 mg GAE/100 g and 10.12 mg CGE/100 g of cookies, respectively. The overall effect of LBGBP cookie fortification led to softer, more crumbly cookies with significant improvement in antioxidant and antidiabetic activity. The Z-score analysis was chosen to perform multi-criteria cookie formulation optimization with the goal of maximal functional enrichment, with minimal decrease in technological quality. The 10% LBGBP substitution was calculated to produce optimal overall quality, obtaining 65.96% of maximal score in comparison to the control sample of only 32.91%. Full article

(1) Aim: The incidence of high-altitude pulmonary hypertension (HAPH) has risen in recent years and is expected to continue increasing; however, its diagnosis remains challenging. In this study, we employed proteomics and metabolomics to identify the proteins and metabolic biomarkers that contribute to the development of HAPH. (2) Methods: We applied integrated proteomics and metabolomics to match blood samples from 40 HAPH patients and 40 healthy controls in Yunnan’s high-altitude regions to characterize molecular profiles, identify biomarkers, and develop a predictive model. (3) Results: Proteomic analysis identified four proteins (A2IPH7, K1C14, PSME2, SERPINE2) commonly dysregulated in HAPH patients from two high-altitude regions. SERPINE2 was notably downregulated and showed a negative correlation with clinical severity, which was further validated in HAPH rat lung tissues and supported by UK Biobank data for idiopathic PAH. Concurrent metabolomics uncovered 11 shared metabolites, largely acyl fatty acids, enriched in pathways such as unsaturated fatty acid synthesis. Integration of these multi-omics data enabled the development of a robust predictive model. (4) Conclusion: Our study identified key protein and metabolic biomarkers involved in HAPH development, which were validated in animal models. Based on these findings, a predictive model was developed, highlighting SERPINE2 and 11 metabolites as promising targets for the prediction and prevention of HAPH. Full article

Human neutrophil elastase (HNE) is a key driver of inflammatory lung disorders, promoting extracellular matrix degradation and tissue damage. Although inhibitors such as Sivelestat and Alvelestat are clinically relevant, their performance within the oxidative microenvironment of diseased lungs remains poorly understood. Here, we employed an integrated in vitro and in silico approach to investigate their behavior under physiological and oxidative conditions and to provide a molecular-level interpretation. Under physiological conditions, enzymatic assays and steady-state kinetics confirmed that both compounds act as competitive inhibitors, with Sivelestat displaying higher baseline potency. Under oxidative stress, however, Sivelestat exhibited a marked reduction in inhibitory potency, whereas Alvelestat retained its efficacy. Molecular modeling and molecular dynamics simulations of native and oxidized HNE variants provided a structural rationale for this divergence. Alvelestat, as a non-covalent inhibitor, maintains stable binding despite increased flexibility of the active site, whereas Sivelestat, acting via a reversible covalent mechanism, requires a precise pre-acylation geometry. Oxidation-induced remodeling of the S1 pocket disrupts the near-attack configuration required for covalent bond formation, thereby impairing inhibition. Overall, these findings indicate that oxidative stress may selectively compromise covalent inhibition while preserving enzymatic activity, and suggest that context-dependent redox-related structural effects may represent a consideration for the design of next-generation HNE inhibitors. Full article

Autophagy dysfunction is implicated in the pathogenesis of Alzheimer’s disease (AD), and enhancing autophagic flux has been proposed as a potential strategy for addressing neurodegenerative diseases. To expand the structural diversity of ingenol esters and systematically evaluate their autophagic flux activation activity, a systematic phytochemical investigation of ingenane diterpenoids from Euphorbia peplus was conducted. A total of 13 ingenane-type compounds were isolated and identified, including two previously undescribed compounds, euphingenol A and B (1–2), together with 11 known analogs (3–13). Their structures were elucidated by extensive spectroscopic analyses (HRESIMS and NMR) and comparison with literature data. The compounds were evaluated for their bioactivity with flow cytometry in assays of autophagic flux in HM Cherry-GFP-LC3 (human microglia cells stably expressing the tandem monomeric mCherry-GFP-tagged LC3) cells. 17-O-benzoyl-20-deoxyingenol (3) significantly activated autophagic flux at concentrations of 10 μM and 40 μM, while euphingenol A (1) induced a dose-dependent increase, with structure-activity relationship analysis indicating that C-17 acylation enhances this bioactivity. These findings suggest that compound 3 warrants further investigation as a potential modulator of autophagic flux, possibly through binding to PKCδ (protein kinase C), with relevance to autophagy-related neurodegenerative conditions. Full article

De-S-acylation enzymes mediate the reversible S-acylation cycle and play critical roles in plant development and stress responses. However, the precise origin and evolutionary dynamics of this gene family in plants remain poorly understood. In this study, a total of 718 ABAPT genes were identified across 73 plant genomes, including 622 ABHD17 and 96 ABHD13 homologs, which share only a 20–30% conserved sequence identity between them. We further performed comprehensive analyses of gene duplication and structure, protein properties, synteny networks, and expression profiles to establish a systematic framework by classifying ABAPT genes in land plants. Our results revealed that ABHD13 genes have been retained as a single copy in most angiosperm genomes, whereas ABHD17 genes have undergone extensive expansion. ABAPT genes formed three major evolutionary clades: Clade 1 contained ABHD13 homologs, while Clades 2 and 3 harbored ABHD17 homologs. The three clades showed distinct disparities in intron–exon structural patterns and IDR properties. Phylogenomic synteny network analyses revealed the deeply conserved genomic syntenies within each of the six ABAPT subclades among the three clades, while Cluster4-Monocot was more dynamic and showed distinct lineage-specific duplication patterns restricted to Poaceae. ABHD13s exhibited constitutive expression patterns, while the tissue-specific expression genes were predominantly found within the ABHD17s subfamily. Notably, the ABAPT8/9 subgroups were specifically expressed in reproductive organs, and the weighted gene co-expression network identified specific groups to find ABAPT-specific regulatory features, implying the presence of potential modules for the protein S-acylation cycle during pollen development. Additionally, our results suggested that C-terminal Cys-rich region was required for ABAPT10 localization. Altogether, this study sheds light on the evolutionary divergence of the ABAPT subclades across major green plant lineages and emphasizes the need for future functional characterizations. Full article

Styela plicata, an edible ascidian rich in diverse bioactive constituents, represents a promising source of marine natural products for therapeutic discovery. Here, bioactive components from a 95% ethanol extract of S. plicata (ESP) were characterized by HPLC-MS/MS, showing that the major constituents were oxygenated small molecules dominated by fatty acyls and carboxylic acid derivatives. In a mouse model of alcohol-induced liver injury, H-ESP treatment (300 mg/kg) significantly reduced serum levels of AST, ALT, and TG (p < 0.01), while effectively ameliorating pathological changes in liver tissue, reducing lipid accumulation and inflammatory responses. Transcriptome sequencing (H-ESP vs. model group) identified 1097 differentially expressed genes (172 upregulated and 925 downregulated), and KEGG analysis highlighted significant enrichment of the Toll-like receptor signaling pathway. ESP modulated hepatic metabolite expression, suppressed inflammation via TLR-4/NF-κB pathway inhibition, and boosted antioxidant defenses by activating Nrf2/HO-1 signaling, which was further confirmed by RT-qPCR and immunohistochemistry. ESP increased intestinal SCFAs (acetate, propionate, isobutyrate; p < 0.05), improved α-diversity and the Firmicutes/Bacteroidetes ratio, reversed shifts in Lactobacillus and Bifidobacterium, and partly restored Odoribacter, supporting a gut–liver axis mechanism. Overall, these findings indicate that ESP exerts hepatoprotective effects by modulating the gut–liver axis, and they provide insights for developing natural therapeutics against alcoholic liver disease. Full article

Background/Objectives: Differences between rural and urban settings, as well as between emergency medical service (EMS) systems, may influence short-term mortality among patients attended in the prehospital setting. The aim of this study was to determine the associations of rurality and the US and Spanish EMS health systems with patient mortality. Methods: This was a multicenter, EMS-based, observational study involving a prospective dataset, the Salud de Castilla y Leon dataset (SACYL) from Spain, and a retrospective dataset, the National Emergency Medical Services Information System (NEMSIS) from the US. All consecutive EMS activations of adult patients (≥18 years) requiring high-priority transport to emergency departments were included in the analysis. The collected variables included demographic characteristics, EMS transport characteristics, case characteristics, and rural or urban origin. The primary outcome was 2-day, short-term mortality. Results: A total of 54,981 EMS activations were considered from both datasets. The mortality rate was 8.47% for rural areas and 11.8% for urban areas (p < 0.001). Multivariable analyses showed that mortality patterns differed according to geographic setting and EMS system. Male sex and the use of advanced life support were associated with higher odds of mortality in several models, while prehospital time intervals and call characteristics showed context- and system-dependent associations, including protective effects in specific subgroups. Conclusions: Short-term mortality differed between rural and urban settings, with heterogeneous patterns across EMS systems. These findings highlight the importance of considering both geographic context and system-level organizational characteristics when evaluating prehospital care and mortality outcomes. Full article

This study reports the first isolation of Elizabethkingia miricola from cultured river puffer (Takifugu obscurus) in South Korea under low-salinity aquaculture conditions. A total of 5000 juvenile T. obscurus were reared for 20 months in a recirculating aquaculture system with salinity maintained at 3–5 ppt. During the rearing period, fish exhibited a cumulative mortality rate of 58.17%, presenting clinical signs such as lethargy, fin rot, hepatic hemorrhage, and white nodules in the spleen and kidney. Biochemical and molecular analyses identified E. miricola in the internal organs of diseased fish. All isolates exhibited multidrug resistance and showed 98.8–99.8% 16S rRNA gene sequence similarity to E. miricola, forming a distinct phylogenetic cluster. Additionally, several virulence-associated genes (fabG, fabV, wecB, ureB, aceA, acyl) were detected in the isolates. Histopathological examination revealed granulomatous lesions in multiple organs, including the gill, heart, kidney, and spleen. This study represents the first report of E. miricola isolated from cultured river puffer in South Korea and suggests its potential association with disease in this species, as well as its possible zoonotic relevance. These findings highlight the importance of disease monitoring and pathogen surveillance in low-salinity aquaculture systems. Full article

Apis cerana is widely managed in apiculture in Southern China but experiences substantial colony losses during prolonged summer heat. Developing effective strategies to support colony over-summering is therefore critical. This study demonstrates that dietary supplementation with melatonin significantly enhances thermal tolerance and extends worker lifespan in A. cerana under heat stress. Laboratory bioassays revealed that melatonin supplementation (20 µg/mL) markedly improved worker survival at both 35 °C and 37 °C, with the most pronounced effect at 37 °C, where mortality was significantly reduced. Consistently, field trials demonstrated that melatonin supplemented colonies gained significantly more weight during summer heatwaves than colonies without melatonin supplementation. Mechanistically, melatonin orchestrates a biphasic adaptive response. In an early phase (day 4), melatonin rapidly upregulates heat shock proteins (HSC70-4, CRYAA, l(2)efl) and detoxification enzymes (GST-like), accompanied by reduced reactive oxygen species (ROS) accumulation and enhanced proboscis extension response (PER), indicative of preserved sensory function. This is followed by a later maintenance phase (day 11), characterized by sustained upregulation of fatty acyl-CoA reductases (FAR1, FAR11-like, FARwat) and peroxisomal components (PMP34), which promote lipid remodeling and membrane stabilization. RNA-seq analysis identified differentially expressed genes (DEGs) significantly enriched in pathways related to redox homeostasis, lipid metabolism, detoxification (GSTs, CarEs, CYP450s), and longevity. These molecular responses were associated with enhanced antioxidant capacity, reduced oxidative damage, and sustained foraging activity under thermal stress. Collectively, these results indicate that melatonin serves as a potent nutritional intervention that reprograms redox metabolic networks to mitigate heat-induced damage, extend worker longevity, and enhance colony productivity under climate warming. These findings highlight melatonin’s potential as a practical tool to reduce summer colony losses in apiculture. Full article