Deoxysphingolipids (dSLs) are atypical sphingolipids that accumulate in several pathological settings, yet their impact on hematologic malignancies is poorly understood. Here, we investigate the pathways and mechanisms of deoxysphinganine (dSA) cytotoxicity in lymphoma cells and its potential as a therapeutic agent. dSA exhibited markedly greater cytotoxicity than canonical sphingoid bases in lymphoma cell lines, yet induced only cytostatic effects in normal human T cells, indicating a therapeutically exploitable window. Inhibition of ceramide synthase blocked the generation of deoxy(dihydro)ceramides, prevented mitochondrial depolarization, caspase activation, ER stress, and DNA damage, establishing CerS-dependent deoxysphingolipids as essential mediators of dSA-induced death. Mechanistically, dSA engaged a mitochondrial apoptotic pathway, with DNA damage occurring downstream of mitochondrial permeabilization and caspase activation, while PERK-driven ER stress occurred in parallel and was dispensable for cytotoxicity. Subtype-specific engagement of ER stress and DNA damage further suggests that dSL signaling is shaped by lineage context. The differential sensitivity between malignant lymphoid cells and normal T cells, together with the central role of CerS-derived deoxy(dihydro)ceramides, highlights deoxysphingolipid metabolism as a druggable vulnerability in lymphoma. These findings support further exploration of dSA-based strategies and targeted modulation of dSL synthesis as a novel therapeutic avenue for non-solid hematologic malignancies.
Whether the fecal metabolome differs according to intensive low-density lipoprotein cholesterol (LDL-C) target achievement among statin-treated patients is unclear. In this cross-sectional study, 124 statin-treated adults with chronic disease were stratified by fasting LDL-C into a target-achieved group (< 70 mg/dL, n = 52) and a target-not-achieved group (≥ 70 mg/dL, n = 72). Stool samples were profiled by untargeted ultra-high-performance liquid chromatography-tandem mass spectrometry, and multivariable models adjusted for age, sex, chronic kidney disease, and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use were used to identify metabolites independently associated with target achievement. Statin dose, treatment duration and glucose-lowering therapy were also compared between the groups. Paired 16S rRNA gene sequencing data available for a subset (n = 86) were used for integrative correlation and network analyses. Partial least-squares discriminant analysis showed separation between the two groups. Eight annotated metabolites-glutamine, glutamate, phenylalanine, N-acetyl-L-phenylalanine, L-methionine, N-acetyl-L-methionine, lysine, and N-methyl-D-aspartic acid, predominantly amino acids and their derivatives-were present at lower fecal levels in participants who achieved the LDL-C target. Metabolite set enrichment analysis implicated amino acid and nitrogen metabolism, and multiomics network analysis identified an Anaerotruncus-centered amino acid module with high degree centrality. In conclusion, LDL-C target achievement under statin therapy was associated with a coherent "low fecal amino acid" signature and an Anaerotruncus-linked microbe-metabolite hub. These findings suggest that intestinal nutrient handling and gut microbial amino acid metabolism may contribute to variability in LDL-C response, and they warrant prospective mechanistic evaluation.
Metabolic dysfunction-associated liver disease (MASLD) arises from the accumulation of triglycerides within the liver. MASLD can advance to metabolic dysfunction-associated steatohepatitis (MASH), cirrhosis, and hepatocellular carcinoma. Monoacylglycerol acyltransferase 2 (MOGAT2) is essential for triglyceride synthesis and plays a significant role in regulating lipid metabolism. Here, we demonstrate the ability of a new human MOGAT 2 inhibitor, VB-85387, to inhibit the development of MASLD/MASH and further define its effects on the key metabolic pathways that progress MASH development. MASLD/MASH was induced using a methionine, choline-deficient diet (LMCD) or by streptozotocin treatment combined with high fat diet feeding (STAM-HFD). VB-85387 significantly mitigated the severity of MASLD and reduced signs of MASH in mice subjected to these two distinct diets. VB-85387-treated mice exhibited decreased fibrosis, evidenced by reduced hepatic triglyceride concentrations, hydroxyproline levels, and collagen deposition. NAS scores were consistently lower in VB-85387-treated mice across both models. VB-85387-treated mice showed induced PPARα signaling and reduced SREBP transcription, demonstrating a likely role for VB-85387 in regulating lipogenesis and fatty acid β-oxidation. STAM-HFD treated mice showed lower NF-κBp65 activation, which was associated with lower TNFα expression. IL-1β and IFNβ levels were also both reduced, suggesting VB-85387 can reduce pro-inflammatory pattern recognition receptor signaling. In addition, treatment suppressed IL-4/IL-6-dependent JAK activation. Overall, VB-85387 inhibited MASLD development by reducing liver triglyceride levels, fibrosis, and meta-inflammatory signaling. VB-85387 was as effective or superior to the MOGAT2 inhibitor phase I clinical trial drug BMS-963272 in reducing MASLD and fibrosis. VB-85387 has considerable potential for developing therapeutics targeting MASLD/MASH.
Glioma represents one of the most aggressive tumors in the central nervous system, with clinical management facing significant challenges including high recurrence rates and therapeutic resistance. Ferroptosis, an iron-dependent form of cell death, holds potential for glioma treatment, yet tumor cells frequently develop evasion mechanisms. This study elucidates the molecular mechanisms by which hypoxic microenvironment confers ferroptosis resistance in glioma cells, focusing on the pivotal role of the HIF-1α/SREBP1 signaling axis and its downstream effectors FASN and SCD1. Our experimental results demonstrate that hypoxic conditions significantly upregulate HIF-1α expression and confer resistance to RSL3-induced ferroptosis. Mechanistic studies reveal that HIF-1α promotes SREBP1 activation, which subsequently upregulates FASN and SCD1 expression to suppress lipid peroxidation.Furthermore, the HIF-1α-specific inhibitor PX-478 effectively reverses hypoxia-induced ferroptosis resistance and significantly enhances tumor cell sensitivity to ferroptosis inducers. In vivo experiments confirm the potent antitumor effects of PX-478 combined with RSL3. This study systematically elucidates the role of the HIF-1α-SREBP1-FASN/SCD1 signaling axis in ferroptosis regulation in glioma, providing important theoretical foundations and experimental support for developing HIF-1α-targeted ferroptosis therapies.
BACKGROUND:Lipoprotein(a) [Lp(a)] reflects inherited atherothrombotic risk, whereas the C-reactive protein-triglyceride-glucose index (CTI) integrates systemic inflammation, triglyceride-related lipid disturbance, and glucose-related metabolic stress. Their individual and joint association with angiographic coronary lesion burden in acute coronary syndrome (ACS) remain incompletely defined. We examined whether CTI complements Lp(a) in characterizing coronary lesion burden in ACS. MATERIALS AND METHODS:This retrospective, single-center study included 2,836 consecutive patients with ACS who underwent coronary angiography. Coronary lesion burden was assessed using continuous Gensini score, a high Gensini score, and multivessel disease (MVD). Multivariable regression, restricted cubic spline analyses, CTI-stratified analyses, incremental receiver operating characteristic analyses, and internally validated machine-learning analyses with SHAP interpretation were performed. RESULTS:Higher Lp(a) and CTI level were both associated with greater coronary lesion burden. Compared with Lp(a) <75 nmol/L, Lp(a) ≥175 nmol/L was associated with high Gensini score (OR, 1.51 [95% CI, 1.17-1.96]) and MVD (OR, 1.69 [95% CI, 1.27-2.26]). Each 1-SD increase in CTI was associated with high Gensini score (OR, 1.47 [95% CI, 1.35-1.60]) and MVD (OR, 1.18 [95% CI, 1.08-1.28]). Among inflammatory-lipid indices, CTI showed the most consistent associations and provided the largest numerical incremental discrimination beyond Lp(a). The associaton between ver high Lp(a) and coronary lesion burden was more pronounced at higher CTI levels, particular for MVD. Machine-learning analyses further supported the relevance of both CTI and Lp(a). CONCLUSIONS:In patients with ACS, higher Lp(a) and CTI level were associated with greater angiographic coronary lesion burden. CTI may complement Lp(a) by capturing inflammatory-metabolic status, supporting their joint assessment for more refined characterization of lesion-burden risk in ACS.
Lipoprotein metabolism is significantly different between mice and humans thus making it difficult to model disorders of human lipid metabolism in transgenic mice. Systemic lipoprotein metabolism is predominantly governed by hepatocytes, and mice with humanized livers display human-like lipid profiles. Here we report a highly efficient method to knock out genes in human hepatocytes while retaining their ability to repopulate immune deficient rodents. As proof-of-principle Fah deficient, immune compromised mice were repopulated with Apolipoprotein B (APOB) knockout human hepatocytes. Mice humanized with knockout cells recapitulated typical features of human hypobetalipoproteinemia. We conclude that at least some human lipid metabolism disorders can be modeled in liver chimeric mice using human knockout hepatocytes.
A systematic study of nuclear shape transitions in even-even 280−314Fl isotopes is performed within the framework of the relativistic Hartree-Bogoliubov (RHB) model using the density-dependent point-coupling (DD-PC1) interaction. Triaxially constrained calculations are carried out to explore the potential energy surfaces in this isotopic chain. The incorporation of γ degree of freedom plays an important role in determining the ground-state configurations. A significant prolate deformation is observed in this isotopic chain, followed by a sudden prolate to oblate shape transition at N = 178. Furthermore, we predict prolate-oblate shape coexistence in 290Fl. To elucidate the origin of deformation, the single-particle shell structure for these superheavy nuclei is also examined. Other ground-state properties such as two-neutron separation energies (S2n) and α-decay energies (Qα) are also calculated for 280−314Fl isotopes and compared with other theoretical models as well as available experimental data. Moreover, the single-particle energy spectrum is studied to examine the shell structure of 298Fl. The calculated ground-state properties, shell structure, and microscopic observables provide evidence consistent with a spherical doubly magic character of 298Fl.
High-altitude polycythemia (HAPC) remains prevalent among Tibetans despite genetic adaptations, including EPAS1/HIF2A. Excessive erythrocytosis elevates blood viscosity and increases cardiopulmonary risk, yet erythrocyte metabolic and membrane-lipid mechanisms of HAPC and of therapeutic erythrocytapheresis (TE) remain incompletely defined. We conducted integrated metabolomic and lipidomic profiling of washed erythrocytes from HAPC patients and non-HAPC (NHAPC), and from patients with HAPC after TE. Relative to NHAPC, HAPC showed coordinated erythrocyte remodeling spanning amino acid and purine metabolism together with membrane phospholipid and lipid structure (unsaturation and chain length) changes. The disease contrast was multiomic, whereas the acute post-TE contrast was lipid-dominant, consistent with apheresis acting primarily through erythrocyte removal. K-means stratification revealed clinically meaningful TE response heterogeneity, but erythrocyte omics did not define stable responder subtypes. These findings point to erythrocyte membrane lipids as a persistent molecular feature of HAPC and of the acute TE response.
Clinically, acute kidney injury (AKI) is one of the most frequent complications of Naja atra (N. atra) envenomation, primarily attributed to snake venom phospholipase A2 (SVPLA2). Although the SVPLA2 inhibitor varespladib shows great therapeutic promise, the underlying mechanisms remain incompletely understood. Herein, we integrated multi-omics and molecular biology approaches to investigate the critical role of SVPLA2 in N. atra venom-induced AKI as evidenced by pharmacological inhibition with varespladib. Proteomic profiling identified HRAS and CCND1 as key mediators of SVPLA2-induced nephrotoxicity. Mechanistically, SVPLA2 disrupts lipid raft integrity, impairing HRAS palmitoylation-dependent plasma membrane localization and GTPase activity. This defect suppresses phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling, causing apoptosis and cell cycle arrest in renal tubular epithelial cells, enforced activation of PI3K-AKT signaling effectively rescued cells from injury. Beyond direct cytotoxicity, SVPLA2 profoundly remodels the renal immune microenvironment. SVPLA2 enhances glycolysis by upregulating hexokinase 2 (HK2) while suppressing fatty acid oxidation through downregulation of carnitine palmitoyltransferase IA, thereby metabolically driving M1 polarization. This metabolic shift impairs macrophage efferocytosis and sustains inflammatory injury. HK2 knockdown reverses these effects in macrophages. Taken together, this study reveals a dual epithelial-immune mechanism by which SVPLA2 activity critically contributes to N. atra venom-induced AKI, as evidenced by pharmacological inhibition with varespladib. These findings highlight PI3K-AKT signaling and HK2 as potential therapeutic targets for N. atra-triggered AKI.
Pancreatic lipase is the major enzyme responsible for breaking down dietary triglycerides in the intestines. A previous report suggested that intestinal angiopoietin-like 4 (ANGPTL4) might serve as an endogenous inhibitor of pancreatic lipase and thus regulate fat absorption. As ANGPTL4 expression is reportedly induced by high-fat-diet feeding, we hypothesized that induction of ANGPTL4 by a high-fat diet would lead to an increased inhibition of pancreatic lipase, less breakdown of dietary triglycerides, and ultimately a reduced rate of postprandial triglyceride absorption. To test this hypothesis, we generated intestinal epithelial cell-specific ANGPTL4 knockout mice, fed them diets with varying levels of fat, and measured postprandial triglyceride absorption and intestinal triglyceride lipase activity. As we hypothesized, we found that chronic high-fat feeding reduced the rate of postprandial triglyceride absorption in mice. However, this regulation of postprandial triglyceride absorption appeared to be largely independent of ANGPTL4, as similar decreases were observed in both wild-type and intestinal epithelial cell-specific ANGPTL4 knockout mice. We conclude that there is mechanism by which chronic high-fat feeding reduces the rate of secretion of dietary triglycerides into the circulation, but that this mechanism does not require intestinal ANGPTL4.
The present study focuses on the radon and radium isotopic chains, specifically within the ranges 204 ≤ A ≤ 228 for radon and 212 ≤ A ≤ 232 for radium. These heavy nuclei undergo α, β, and γ decay. While the α-decay systematics are well established, the role of γ-transitions as probes of nuclear structure remains less understood. The main objective of this work is to explore the role of γ-transitions, the electric quadrupole moment Q0, and the deformation parameter β2 as effective probes into the internal structure of radon and radium nuclei, using a quantum electrodynamics framework combined with Fermi’s golden rule. Partial γ-decay widths, half-lives, mean lifetimes, and reduced transition probabilities B(E2) are derived from first principles and tabulated for all studied isotopes. The analysis reveals clear structural signatures across the chains, particularly near the neutron shell closure at N=126. A pronounced reduction in γ-decay half-lives is observed at and beyond this magic number, reflecting enhanced transition probabilities due to shell and collective effects. Our predictions for B(E2) values and deformation parameters are compared with existing experimental data and theoretical models (RMF, FRDM, global best-fit), showing overall good agreement while extending coverage to isotopes with limited experimental data. The evolution of Q0 and β2 indicates that nuclear deformation tends to be minimal when the neutron number approaches the magic value N=126, and increases progressively as the number of neutrons deviates from this closed-shell configuration. These results provide refined benchmarks for electromagnetic transition systematics in 204−228Rn and 212−232Ra, and demonstrate the predictive potential of quantum-transition models in regions critical for both nuclear structure and applied radiation science.
The excitation functions for eleven evaporation residues resulting from the interaction of 20Ne-ion beam with 124Sn target have been measured over an energy range of ≈ 127–165 MeV using the activation technique. The obtained excitation functions have been compared with theoretical predictions from the CASCADE code, which is based on the statistical model calculations. Both complete and incomplete fusion reaction channels have been identified through the analysis of experimental data, revealing the occurrence of incomplete fusion via the breakup of 20Ne into 16O + 4He and 12C + 8Be, followed by the fusion of one of these fragments with the 124Sn target nucleus. In these measurements, no significant pre-equilibrium particle emission has been found in the analysis with ALICE-91 code. On the other hand, the incomplete fusion fractions have been determined and analysed with different systems, considering parameters such as atomic number of target (ZT), mass number of target (AT), the fissionability parameter (Z2/A)T of the target, mass asymmetry, and target deformation. The lowest incomplete fusion fractions have been observed in the present system as compared to other systems at a constant normalizing parameter. Besides this, the analysis of ICF fractions with binding energy fraction (fB.E) shows an interesting valley of stability within the range 8.14 < fB.E < 8.77 MeV/nucleon. A relatively smaller suppression in the complete fusion function has been observed for the present system compared to other 20Ne-induced reactions when evaluated against the universal fusion function. Furthermore, the suppression factor has been analysed as a function of β2 to elucidate its systematic dependence of these parameters on CF. The present observations suggest that the suppression of ICF probability, even at energy higher than 30% above the Coulomb barrier, is associated with the shell closure effect of the magic nucleus target 124Sn.
This is a third, and so far conclusive, part of research project that seeks to determine candidate nuclear reactions for observation of a bound dineutron. Neutron capture reaction cross sections were calculated in the (0 - 30) MeV energy range with the TALYS-2.0 code for nuclei in the outgoing channel, which are expected to host bound dineutrons. Limiting to stable nuclides within the 90 < A < 210 mass range, criteria are calculated based on the (n, γ) resonance cross-section analysis to determine which nuclear reactions are the most suitable for bound dineutron generation. Two maxima were identified for A ≈ 120 and A ≈ 170, which are recommended as the most likely host nuclei for such nuclear reactions. This work initiates a new direction in dineutron research with the (p, 2n) and (p,2n+n) nuclear reactions.
Alpha-decay half-lives of odd-mass and odd-odd nuclei are sensitive to the α-daughter interaction, especially in the inner part of the tunneling barrier where density overlap and unpaired-nucleon effects can play an important role. We extend the double-folding model with a short-range repulsive core (DF+rep) to 49 odd-even, even-odd, and odd-odd nuclei in the heavy-mass region with Z=85-110 and A=202-267. The nuclear part of the α-daughter potential is calculated with the M3Y double-folding interaction and supplemented by a repulsive term. The resulting potential is used in the WKB approximation to calculate log10(T1/2α/s) under the favored-decay assumption ℓ=0. We systematically survey the effects of the repulsive-core diffuseness arep on the pocket region, the barrier shape, and the calculated half-lives. The repulsive core leaves the outer Coulomb barrier almost unchanged, but it reduces the overly deep attractive pocket of the pure folding potential and changes the effective barrier that controls tunneling. For the full data set, the optimized DF+rep calculation gives an rms deviation of 0.314, smaller than those obtained with the Denisov and Myers potentials and with the VSS, Royer, Brown, and Akrawy-Poenaru formulas. Since arep is optimized locally for each nucleus, this rms deviation should be regarded as a measure of descriptive accuracy rather than fully predictive performance. The correlation between arep and the neutron-proton asymmetry δ=(N−Z)/A is weak in odd systems, in contrast to the clearer trend found previously for even-even nuclei. These results show that the repulsive core is a useful degree of freedom for describing odd-nucleus α decay, while also indicating that a predictive implementation of the DF+rep model will require a systematic parametrization of arep beyond the local optimization used here.
Weight rebound remains the core challenge in the long-term management of obesity. Although current mechanistic understanding mainly focuses on physiological adaptations, the role of biomechanical factors remains largely unexplored. This study aims to investigate the contribution of lysyl oxidase (LOX)-mediated adipose tissue (AT) stiffening to the process of weight rebound. Our clinical analysis first established a correlation among obesity, elevated AT stiffness, and higher LOX levels. We then demonstrated that the weight rebound model mice displayed accelerated lipid accumulation and worsened metabolic functions. Importantly, AT stiffness dynamically increased during obesity, failed to normalize after weight loss due to persistent fibrosis, and reached its highest level during the regain stage. LOX expression followed an identical temporal pattern, showing a strong positive correlation with tissue stiffness. Mechanistically, mimicking a high-stiffness microenvironment in vitro promoted adipocyte differentiation and lipid accumulation in a LOX-dependent manner. Crucially, pharmacological inhibition of LOX in vivo significantly attenuated the rate of weight rebound. Our findings provide supportive evidence that LOX-mediated AT stiffening creates a pro-adipogenic mechanical microenvironment that contributes to accelerated weight rebound and metabolic deterioration, highlighting the LOX-stiffness axis as a potential therapeutic target for preventing weight rebound.
Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory and antioxidant properties. We therefore hypothesized that CBD may modulate atherosclerosis development; however, preclinical evidence remains limited and sex-specific effects are poorly understood. Male and female apolipoprotein E-deficient (ApoE-/-) mice were fed a Western-type diet for 12 weeks and received either a CBD nanoemulsion (≈80 mg/kg/day) or vehicle via drinking water. Atherosclerosis was quantified by aortic plaque area, and lipidomic profiling together with aortic root proteomics were used to characterize CBD-induced metabolic changes. CBD treatment significantly reduced aortic plaque area in male but not female mice, without affecting body weight or standard serum lipid parameters. Untargeted lipidomics revealed sex-specific remodeling of the serum lipidome in males, including enrichment of ether-linked triacylglycerols, a class connected to ether-lipid metabolism; however, no lipid class emerged as a robust correlate of plaque burden. Proteomic analysis identified male-specific downregulation of mitochondrial oxidative and stress-related pathways, consistent with reduced vascular oxidative burden. In vitro, CBD attenuated oxLDL-induced oxidative stress and inflammatory activation in endothelial cells, supporting a direct vascular effect. CBD elicited no comparable molecular or plaque changes in females. Collectively, chronic CBD administration exerts a sex-dependent, anti-atherogenic effect in male ApoE-/- mice, associated with downregulation of mitochondrial oxidative metabolism and attenuation of endothelial oxidative and inflammatory activation, alongside remodeling of ether-linked lipid metabolism whose contribution to plaque protection remains to be established. These findings highlight the importance of incorporating sex-specific responses in future mechanistic and translational studies of CBD in atherosclerosis.
A systematic study of α-decay half-lives along the decay chains of recently discovered 288Lv and 289Lv isotopes by Oganessian et al. [Phys. Rev. C 112 (2025) 014603], and 289Mc is carried out using different effective nucleon–nucleon (B3Y, M3YR, M3YP, and the density-dependent DD-M3YP and CD-M3YP) interactions within both spherical and deformed configurations. The α–daughter interaction potential is calculated using the double-folding model, with the folding integral evaluated in momentum space via a Fourier transform. The penetration probability for ground-state to ground-state α- transitions is evaluated within the semiclassical WKB approximation, while the preformation probability is determined using the cluster formation model (CFM). The calculated logarithmic half-lives are compared with experimental data, and the role of nuclear deformation is examined through multipole deformation parameters of the daughter nuclei. The results show that deformation significantly modifies the interaction barrier by lowering its height and width, leading to enhanced penetrability and improved agreement with experimental half-lives. A pronounced structural effect is observed around N=168, which is attributed to the presence of a deformed shell closure in the superheavy region. Benchmark comparisons with the semi-empirical modified Brown and Royer formulae demonstrate that the microscopic double-folding calculations achieve superior agreement with the experimental α-decay half-lives and provide a more reliable description of the underlying structural properties along the investigated decay chains.
