Search Results (137)

Background/Objectives: The present study estimated the potential therapeutic effects of Borassus flabellifer immature endosperm extract (BFE) on the metabolic disorders of diabetes and hypothyroidism using a mixed research design. Methods: Characterization of phytochemicals via GC-MS demonstrated a highly abundant list of bioactive compounds, and it encompassed phenolic derivatives, methylxanthines, fatty acids, and inositol-related compounds. Molecular docking indicated that the major phytoconstituents showed positive binding affinities to the most vital metabolism and endocrine receptors, namely, TRβ1, PPARγ, and AMP-activated protein kinase (AMPK). Notably, both compounds C1 and C2 were highly affined towards TRβ1 (−7.8 and −7.6 kcal/mol), which is attributed to interactions in the active site through hydrogen bonding and hydrophobic responses, which means that the identified compounds were found to have good predicted interactions with some metabolic- and thyroid-associated targets and could be used to form preliminary hypotheses for further mechanistic studies. The in vivo data showed that the disease-induced groups were marked by hyperglycemia, imbalance in thyroid hormones, and dyslipidemia, as well as liver, kidney, and heart dysfunction. BFE caused significant decreases in these changes, which were also observed through improvements in fasting blood glucose, T3, T4, and TSH; partial restoration of lipid profiles; and dampening of liver and kidney injury signalers. The cardiac risk indices were also reduced significantly after BFE administration. Positive changes in body weight gain, feed ratio, and metabolic ratio further reflected better physiological stability. Results: These findings were corroborated by histopathological analysis, which showed that the tissue architecture of the pancreas, liver, kidney, and heart had significantly recovered in the study. BFE still showed constant therapeutic activity even though the magnitude of response was attenuated when combined disease conditions were used. Conclusions: Comprehensively, the results indicate that BFE potentially plays a role in the amelioration of metabolic and endocrine abnormalities of diabetic and hypothyroid conditions. These observations should be regarded as hypothesis-generating, as further mechanistic and translational studies are needed to substantiate their biological relevance. Full article

Background/Objectives: Whether anesthetic maintenance influences tumor biology in cervical cancer remains unsettled. We examined whether plasma extracellular vesicles (EVs) collected during sevoflurane or propofol anesthesia differentially affect HeLa cell behavior and explored lipidomic alterations associated with the biologically active EV condition. Methods: In a single-center prospective observational cohort, paired plasma samples were collected before anesthesia induction and before wound closure from 53 patients with stage II cervical cancer undergoing radical surgery under sevoflurane (n = 28) or propofol (n = 25) anesthesia. EV preparations were characterized by transmission electron microscopy, nanoparticle tracking analysis, and immunoblotting for EV markers. Their effects on HeLa cell proliferation, invasion, and wound closure, as well as HUVEC tube formation, were examined in vitro. EV miRNA profiles were analyzed by small-RNA sequencing. Lipidomic profiling by LC-MS and immunoblot analysis of EGFR/PKCα/NF-κB signaling were performed in recipient HeLa cells exposed to sevoflurane-associated EVs. Results: EVs collected after sevoflurane anesthesia increased HeLa cell proliferation, invasion, and wound closure and enhanced endothelial branching in HUVEC tube-formation assays, whereas post-propofol EVs showed no comparable phenotype. Small-RNA sequencing identified distinct anesthesia-associated EV miRNA changes, with the sevoflurane-related signature enriched in glycerolipid metabolism, glycerophospholipid metabolism, glycosylphosphatidylinositol-anchor biosynthesis, phosphatidylinositol signaling, and inositol phosphate metabolism. In HeLa cells treated with post-sevoflurane EVs, lipidomic analysis showed clear separation from pre-sevoflurane EV-treated cells and identified increased diacylglycerol (DG) species, including DG (16:1/18:2), DG (16:0/16:1), DG (18:2/18:2), DG (18:2/20:4), and DG (16:0/18:2). These changes were accompanied by higher p-EGFR, PKCα, and p-NF-κB p65 levels. Several DG species correlated positively with proliferation and invasion readouts and inversely with residual wound area. Conclusions: Plasma EVs collected after sevoflurane anesthesia were associated with a more aggressive phenotype in recipient cervical cancer cells and with lipid remodeling characterized by DG accumulation and altered EGFR/PKCα/NF-κB signaling. The data support an exploratory mechanistic model linking sevoflurane-associated EV cargo to metabolic reprogramming in cervical cancer cells. Full article

Fatty liver disease represents a major metabolic disorder affecting domestic animals worldwide, with significant implications for animal health, welfare, and agricultural productivity. Disrupted communication between mitochondria and other organelles—particularly the endoplasmic reticulum, lipid droplets, and lysosomes—plays a critical role in disease pathogenesis. This review synthesizes knowledge on inter-organellar communication across domestic animals, with emphasis on species-specific adaptations. We address the “Dairy Cow Paradox”—periparturient dairy cows develop severe hepatic steatosis (>30% liver fat), yet under sterile conditions, they have a higher threshold for progressing to sterile steatohepatitis compared to rodents and humans. However, it is critical to note that severe fatty liver in dairy cows is indeed associated with impaired autophagy, inflammation, and liver damage, particularly when accompanied by ketosis or concurrent infections, and 39% of transition cows exhibit moderate to severe lymphocytic hepatitis. We propose that the tolerance to severe steatosis in dairy cows arises from three adaptations: (1) attenuated innate immune sensing via the cGAS-STING pathway; (2) enhanced lipid buffering from perilipin 5 (PLIN5) with a hypothesized ruminant-specific Val152 substitution that may stabilize lipid droplet–mitochondria contacts; and (3) dampened calcium signaling due to ER–mitochondria membrane lipid raft rigidity, elevated inositol 1,4,5-trisphosphate receptor 2 (IP₃R2) expression, and reduced mitochondrial calcium uniporter (MCU) conductance. We contrast this with the inflammatory steatohepatitis common in rodent models driven by calcium overload and mitochondrial DNA (mtDNA) release, and glucocorticoid-mediated mitofusin 1 (MFN1) suppression, causing mitochondrial fragmentation in poultry. We identify critical knowledge gaps, including the need to define bovine and avian mitochondria-associated endoplasmic reticulum membrane (MAM) proteomes and spatially resolve hepatic zonal communication patterns. Targeting organellar communication hubs with nutraceuticals or pharmacological agents offers promising therapeutic strategies. Full article

Sterols and sphingolipids assemble into specialized membrane microdomains that are essential for membrane function, protein sorting, and signal transduction. Although coordinated regulation between sterol and sphingolipid metabolic pathways has long been recognized, the molecular mechanisms mediating this cross-talk remain incompletely defined. Here, we uncover an unanticipated role for the conserved yeast Orm proteins in controlling sterol and neutral lipid homeostasis. Deletion of ORM1 and ORM2 causes hypersensitivity to sterol biosynthesis inhibitors, accumulation of steryl esters, and an increase in lipid droplet number. Consistent with mutants lacking core neutral lipid hydrolases, orm1Δ orm2Δ cells display a marked defect in neutral lipid mobilization. These phenotypes depend on sphingolipid pathway perturbation but cannot be attributed to sphingolipid accumulation alone. Together, these findings position the Orm proteins as regulatory nodes linking sterol metabolism, lipid droplet dynamics, and sphingolipid biosynthesis. Full article

The global rise in obesity and metabolic disorders has intensified interest in dietary bioactives capable of improving glycemic control and metabolic health. Inositols, particularly D-pinitol, have emerged as insulin-sensitizing cyclitols with potential metabolic relevance. Carob (Ceratonia siliqua L.), one of the richest natural sources of D-pinitol, represents a promising nutritional matrix for metabolic regulation. This narrative review critically evaluates current evidence on the role of D-pinitol in glucose homeostasis and energy balance, integrating data from chemical characterization studies, mechanistic research, preclinical models, and human clinical trials assessing purified D-pinitol and D-pinitol–rich preparations, particularly from carob-derived sources. Available evidence suggests that D-pinitol may enhance insulin signaling efficiency, primarily through PI3K/Akt-dependent pathways, modulate hepatic metabolic flexibility, and influence endocrine balance without acting as a classical hypoglycemic agent. Preclinical models consistently report improvements in insulin sensitivity, lipid handling, oxidative stress parameters, and tissue-specific metabolic adaptations. In contrast, clinical trials in healthy, prediabetic, and type 2 diabetic individuals show more heterogeneous outcomes, including attenuation of postprandial glycemia, reductions in circulating insulin and HOMA-IR, and modest improvements in lipid and inflammatory markers. Overall, carob-derived D-pinitol appears to act as a potential insulin-sensitizing metabolic modulator with context-dependent effects influenced by metabolic phenotype and food matrix composition. However, available data remains limited and heterogeneous, with most data derived from preclinical studies and relatively small clinical trials. These findings should therefore be interpreted with caution. Larger, longer-term randomized controlled trials using standardized preparations are required to establish clinical relevance and translational applicability. Notably, the contribution of other bioactive components within the carob matrix cannot be excluded. Full article

Endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) represent fundamental cellular adaptive mechanisms that maintain protein homeostasis and metabolic balance. Many RNA viruses, particularly flaviviruses such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), extensively remodel the ER to establish replication compartments and assemble progeny virions. This massive reorganization disrupts ER homeostasis, leading to UPR activation. Emerging evidence reveals that flaviviruses not only trigger but also manipulate the three UPR branches—PERK, IRE1, and ATF6—to optimize viral translation, replication, and egress. In parallel, flavivirus infection profoundly alters host lipid metabolism and promotes dynamic changes in lipid droplets (LDs), key organelles that mediate lipid storage and serve as scaffolds for viral replication and assembly. The UPR intimately connects to LD biogenesis through transcriptional and translational programs mediated by XBP1, ATF4, and ATF6, thereby coupling ER stress responses to lipid remodeling and energy homeostasis. This intricate crosstalk between UPR and LDs creates a metabolic and structural niche favorable for viral replication but detrimental to host cell integrity. This review provides a comprehensive analysis of the molecular mechanisms by which flaviviruses exploit ER stress and the UPR to reprogram lipid metabolism and LD dynamics. We highlight the dual role of UPR signaling in promoting adaptive lipid synthesis and initiating cell death under prolonged stress, discuss recent insights into ER–LD interactions during flavivirus infection, and explore therapeutic opportunities targeting UPR–lipid metabolic pathways as broad-spectrum antiviral strategies. Understanding this interconnected network will advance our knowledge of viral pathogenesis and identify new avenues for host-directed antiviral intervention. Full article

Current models of the cell membrane assume a heterogenous environment such as sphingomyelin and cholesterol-enriched nano- and microdomains, which are thought to functionally sequester proteins. Besides lipid-ordered domains, membrane proteins can interact with protein complexes by transient binding—necessary for their functional role. Here, we show that an extension of k-space Image Correlation Spectroscopy applied to standard fluorescence microscopy image time series can be used to characterize the protein confinement in heterogeneous membranes. To validate this method, we simulated confined diffusion of tracer particles in a system of static microdomains where we varied the domain size, domain density, confinement probability and diffusion coefficients of tracer particles. We show how the kICS correlation function changes with these parameters and gives rise to emergent properties of the system such as apparent domain sizes and characteristic diffusion coefficients. As a validity check, we apply this analysis to study the dynamics of lipid domain-associated glycosylphosphatidyl inositol (GPI)-anchored proteins labeled by green fluorescent proteins (GPI-GFP) in intact COS-7 cell membranes, and upon domain-disrupting enzyme treatments. Full article

Background: Total parenteral nutrition (TPN) is widely used after major gastrointestinal surgery; however, its early systemic metabolic effects and temporal adaptation patterns remain incompletely characterized. This study applied a longitudinal plasma metabolomics approach to investigate time-dependent metabolic changes during early TPN administration. Methods: Plasma samples were collected from patients undergoing gastrointestinal surgery before TPN initiation (baseline, T0) and at 24 h (T1), 48 h (T2), and 72 h (T3). Untargeted metabolomic profiling was performed using complementary gas chromatography–mass spectrometry (GC–MS) and liquid chromatography–mass spectrometry (LC–MS) platforms. In total, 111 metabolites were detected. Analysis of variance (ANOVA) with baseline (T0) as the reference identified time-point–specific metabolic alterations during TPN administration. Results: At 24 h (T1), nominally significant increases were observed in glycine, tryptophan, isoleucine, and methionine, accompanied by decreases in sarcosine and oxalic acid. At 48 h (T2), elevated levels of glycine, isoleucine, valine, and phenylalanine persisted, while sarcosine, oxalic acid, and myo-inositol remained decreased. By 72 h (T3), sustained increases in glycine, isoleucine, valine, phenylalanine, proline, alanine, and tryptophan were accompanied by reduced levels of sarcosine, oxalic acid, and glucopyranose, reflecting coordinated alterations across multiple metabolite classes. Conclusions: Overall, the results demonstrated a distinct longitudinal metabolomic pattern characterized by increases in circulating amino acids and time-dependent changes in carbohydrate- and lipid-related metabolites within the first 72 h of TPN. This exploratory, time-resolved metabolomic study in 37 patients highlights the utility of untargeted metabolomics for characterizing early metabolic adaptation to parenteral nutrition and supporting postoperative metabolic monitoring. Full article

Myo-inositol, the most common stereoisomer of inositol, plays an important role in many physiological processes, such as cell signaling, regulation of glucose and lipid metabolism, and protection of cells against oxidative stress. The main focus has been on pharmacokinetics, and it has been studied in both animal models (Wistar rats, mice, and Danio rerio) and humans. It is characterized by high oral bioavailability and is primarily eliminated via the kidneys. Preclinical studies have shown that myo-inositol has hepatoprotective potential, reducing oxidative stress, inflammation, and lipid accumulation in hepatocytes, as well as stabilizing liver cell membranes. Animal models make it possible to assess mechanisms of action, toxicity, and efficacy, thereby laying the groundwork for clinical research. In clinical practice, myo-inositol is currently used mainly in the treatment of polycystic ovary syndrome, gestational diabetes, fertility disorders, and certain affective disorders. Based on the results of preclinical studies, its potential application in liver diseases and drug-induced injury has been suggested. Despite promising findings, further translational research and randomized clinical trials are necessary to evaluate the therapeutic efficacy and safety of myo-inositol in hepatology. In summary, myo-inositol is a natural, well-tolerated compound with a multidirectional mechanism of action that may represent a promising element of supportive therapy for liver diseases. Full article

Glycerophosphocholine (GPC) and glycerophosphoinositol (GPI) are phospholipid metabolites generated by phospholipase-mediated deacylation. In budding yeast, they enter cells via the Git1 permease; in fission yeast, the homolog is Tgp1. This study investigates why GPC is toxic to asp1-STF mutants, where Tgp1 is upregulated due to loss of Asp1 pyrophosphatase, resulting in elevated inositol pyrophosphate 1,5-IP₈. We show that S. pombe Tgp1 specifically transports GPC, explaining why GPC, but not GPI, impairs growth. Increased GPC uptake slows doubling time but does not reduce viability. Toxicity is relieved by deletion of Gde1, a phosphodiesterase that hydrolyzes GPC to choline and glycerol-3-phosphate. Mutations in either the Gde1 active site or SPX domain also suppress toxicity, and radiolabeling confirms both domains are required for enzymatic activity. GPC is toxic in cells vastly overexpressing Tgp1 even without elevated IP₈, but Gde1 loss does not suppress this effect. Similarly, in S. cerevisiae overexpressing the Candida albicans Git3 transporter, GPC provision causes toxicity independent of Gde1. Loss of Gpc1, the acyltransferase converting GPC to lysophosphatidylcholine, does not alter toxicity in either yeast. These findings highlight a conserved process by which GPC regulates growth and reveal a role for IP₈ in modulating this process. Full article

The combination of supported lipid bilayers (SLBs) with the Quartz Crystal Microbalance with Dissipation monitoring (QCM-D) has been proven to be a powerful tool to simultaneously monitor mass and viscoelastic changes related to membrane binding-events. In this work, the above methodology is employed for the study of the interaction of the Early Endosomal Antigen 1 (EEA1) to a model lipid bilayer that mimics the early endosome (EE) membrane, focusing on the membrane composition. Starting with the formation of a lipid bilayer through the vesicles fusion technique, we investigated the formation of SLBs that incorporate phosphatidylinositol 3-phosphate (PI(3)P), a key component for EEA1 binding, in combination with other lipids, e.g., (1,2-dioleoyl-sn-glycero-3)-phosphocholine (DOPC), -phosphoserine (DOPS), -phosphoethanolamine (DOPE), and cholesterol (Chol). The interaction of the full-length coiled-coil EEA1 to the formed SLBs was further studied in real time with the QCM-D and characterized with respect to the lipid composition and pH. Our findings confirm that PI(3)P is essential for the EEA1–membrane interaction, while it was shown that Chol and phosphatidylserine greatly influence the binding event. In fact, including 30% Chol in a PI(3)P (3%):PS (6%) SLB resulted in almost double EEA1 binding than in the absence of Chol. Moreover, we employed the QCM-viscoelastic model available to analyze the QCM-D data with emphasis on the study of the protein conformation. Our results showed that, in our in vitro system, EEA1 is not fully extended and/or highly packed, but is mainly in a bent, distorted conformation with an average size close to 100 nm. This study complements previous works employing in vitro assays, also demonstrating the ability to reconstitute more complex biomimetic EE membranes containing inositol phospholipids on a QCM surface for the study of EEA1 binding. Full article

Sepsis induces severe immune and metabolic dysfunction driven by mitochondrial failure. Mitochondrial transplantation (MT) has emerged as a promising strategy to restore mitochondrial bioenergetics, but its metabolic impact on immune cells remains unclear. Here, we used gas chromatography–time-of-flight mass spectrometry (GC-TOF-MS)-based metabolomics to evaluate metabolic alterations in peripheral blood mononuclear cells (PBMCs) and splenocytes from a rat polymicrobial sepsis model treated with MT. Principal component and partial least-squares discriminant analyses revealed distinct clustering between sham, sepsis, and MT groups. Sepsis markedly suppressed metabolites related to amino acid, carbohydrate, and lipid metabolism, including aspartic acid, glutamic acid, AMP, and myo-inositol, reflecting mitochondrial metabolic paralysis. MT partially restored these metabolites toward sham levels, reactivating tricarboxylic acid (TCA) cycle, nucleotide, and lipid pathways. Pathway analysis confirmed that exogenous mitochondria reversed sepsis-induced metabolic suppression and promoted bioenergetic recovery in immune cells. These findings provide direct metabolomic evidence that MT reprograms immune metabolism and restores oxidative and biosynthetic function during sepsis, supporting its potential as a mitochondrial-based metabolic therapy. Full article

Schwanniomyces etchellsii is an unconventional, halotolerant microorganism. Like some other yeasts, it can efficiently perform various biocatalytic transformations of organic compounds in seawater more effectively than in freshwater. In seawater, conversion rates are higher, by-product production is minimized, greater substrate loading is possible, and cells can be recycled for further use. To identify the molecular features that explain this behavior, comparative proteomic and lipidomic studies were conducted on cells grown in seawater and freshwater at various growth stages. The results showed higher expression of proteins involved in the stress response, such as glycerol-3-phosphate dehydrogenase, the glycerol transporter Stl1 and the P-type ATPase sodium pump Ena1, and several phospholipid biosynthesis proteins, including inositol-3-phosphate synthase and phosphatidate cytidylyltransferase, in seawater. Changes in metabolic enzymes and other proteins involved in responding to stimuli were also observed between the two conditions. Overall, cells grown in a freshwater medium exhibited higher levels of enzymes involved in biosynthetic processes. Differences in lipid profiles were also observed between cells grown in the two media. Higher levels of monoacyl and diacylglycerols were found in seawater, while higher levels of phospholipids containing serine and ethanolamine were found in freshwater. Consistent with more permeable membranes, cells grown in seawater exhibited lower levels of ergosterol. Full article

Calcium (Ca²⁺) is a signal messenger for ion flow in and out of microbial, parasitic, and host defense cells. Manipulation of calcium ion signaling with ion blockers and calcineurin inhibitors may improve host defense while decreasing microbial/parasitic resistance to therapy. Ca²⁺ release from intracellular storage sites controls many host defense functions (cell integrity, movement, and growth). The transformation of phospholipids in the erythrocyte membrane is associated with changes in deformability. This type of lipid bilayer defense mechanism helps to prevent attack by Plasmodium. Patients with sickle cell disease (SS hemoglobin) do not have this protection and are extremely vulnerable to massive hemolysis from parasitic infestation. Patients with thalassemia major also lack parasite protection. Alteration of Ca²⁺ ion channels responsive to environmental stimuli (transient receptor potential) results in erythrocyte protection from Plasmodium. Similarly, calcineurin inhibitors (cyclosporine) reduce heart and brain inflammation injury with Trypanosoma and Taenia. Ca²⁺ channel blockers interfere with malarial life cycles. Several species of parasites are known to invade hepatocytes: Plasmodium, Echinococcus, Schistosoma, Taenia, and Toxoplasma. Ligand-specific membrane channel constituents (inositol triphosphate and sphingosine phospholipid) constitute membrane surface signal messengers. Plasmodium requires Ca²⁺ for energy to grow and to occupy red blood cells. A cascade of signals proceeds from Ca²⁺ to two proteins: calmodulin and calcineurin. Inhibitors of calmodulin were found to blunt the population growth of Plasmodium. An inhibitor of calcineurin (cyclosporine) was found to retard population growth of both Plasmodium and Schistosoma. Calcineurin also controls sensitivity and resistance to antibiotics. After exposure to cyclosporine, the liver directs Ca²⁺ ions into storage sites in the endoplasmic reticulum and mitochondria. Storage of large amounts of Ca²⁺ would be useful if pathogens began to occupy both red blood cells and liver cells. We present scientific evidence supporting the benefits of calcium channel blockers and calcineurin inhibitors to potentiate current antiparasitic therapies. Full article

The abnormal barrier function of the stratum corneum is a significant characteristic of surface-active agent-induced inflammatory skin diseases, and its cause is closely related to the abnormal lipid components of the stratum corneum. Total saponins of Panax notoginseng (TSPN) have significant potential in improving inflammatory skin barrier function. This study aims to investigate the barrier repair efficacy of TSPN using the EpiKutis^® skin model and to explore the potential mechanisms through multi-omics analysis based on transcriptomics, proteomics, and lipid metabolomics. We found that TSPN could ameliorate Sodium dodecyl sulfate (SDS)-induced barrier impairment in the EpiKutis^® model, alleviating stratum corneum thickening and upregulating the expression of barrier-related proteins, e.g., Filaggrin, Involucrin, and Loricrin. Through an integrated multi-omics network, we identified seven key target proteins and screened six lipid metabolites, which are involved in lipid metabolism and exert barrier-repairing effects through five pathways. The result indicated that TSPN might repair the epidermal barrier by regulating the phosphatidylinositol 3 kinase (PI3K)-protein kinase B (AKT)-mediated proliferation pathway, Mitogen-activated protein kinase (MAPK)-mediated apoptotic pathways, sphingolipid synthesis, Calcium/calmodulin-dependent protein kinase II beta (CAMK2B)-mediated actin cytoskeleton regulation, and Inositol-trisphosphate 3-kinase B (ITPKB)-mediated phosphatidylinositol signaling system. Further study is needed to explore the mechanism of the molecular link between lipid abnormalities and skin barrier function. Full article