Search Results (346)

Roselle beverage residue (RBR), a by-product of Hibiscus sabdariffa L. processing, retains bioactive compounds, including soluble and insoluble dietary fiber and polyphenols. Its antihyperglycemic effect in type 2 diabetes mellitus (T2DM) has been previously demonstrated; however, its role in lipid metabolism remains unknown. This study assessed the preventive and therapeutic potential of RBR on dyslipidemia and hepatic steatosis in a rodent model of late-stage T2DM characterized by hyperglycemia and hypoinsulinemia. Male Wistar rats with T2DM induced by a high-fat and high-fructose diet combined with streptozotocin received 6% RBR supplementation as either a preventive intervention (starting at week 1 in healthy rats or week 9 in insulin-resistant rats) or a therapeutic intervention (starting at week 14 in diabetic rats). After 17 weeks, RBR supplementation significantly reduced serum triglycerides and total cholesterol, attenuating hepatic lipid accumulation regardless of the timing of intervention. Hepatic Acadm expression, involved in fatty acid β-oxidation, was significantly upregulated in rats treated with RBR from week 1 and 9, whereas no significant modulation was observed for genes related to fatty acid synthesis or uptake. These findings suggest that RBR supplementation may contribute to improving lipid metabolism and hepatic steatosis in a rat model of late-stage T2DM. Full article

Background/Objectives: Benefiting from their outstanding tumor-penetrating ability and cytotoxic proteins and cytokines, natural-killer-cell-derived exosomes (NEX) show great potential for cell-free tumor immunotherapy. To meet the clinical tumor therapeutic need, engineered NEX are highly required to further enhance their tumor-tropism and antitumor abilities. Methods: We proposed a NEX engineering strategy, using a structure of AS1411-bivalent-cholesterol (B-Chol) anchor equipped with photosensitizer zinc phthalocyanine (ZnPc) attached on the membrane of NEX to form A-P-NEX. It not only preferably maintains the spatial structure of the AS1411 aptamer via a B-Chol anchor contributing to the tumor-tropism and stability of NEX but also significantly improves the photodynamic therapy (PDT) effect by firmly binding ZnPc in the unique G-quadruplex structure in the AS1411 aptamer. Results: The results showed that A-P-NEX could promote the precise uptake of NEX and ZnPc by tumor cells and produce obvious synergistic NEX-based immunotherapy and PDT upon laser irradiation, demonstrating excellent targeted antitumor effects both in vitro and in vivo. Conclusions: This study demonstrates a reliable NEX engineering strategy and paves the way for developing a useful tumor-tropism PDT method. Full article

Background/Objectives: Mexicans are disproportionately affected by dyslipidemia, specifically low high-density lipoprotein (HDL-C) and high triglyceride (TG) concentrations. Research on the genetic contributions to dyslipidemia, conducted primarily among European populations, has identified numerous single-nucleotide polymorphisms (SNPs) with small effect sizes and low replication rates. A genetic risk score (GRS) can examine the cumulative effects of multiple SNPs and potentially explain greater phenotypic variability than individual SNPs. GRS in Mexican populations and those without diagnosed dyslipidemia are limited. This study aims to construct a GRS from lipid metabolism-related SNPs and determine its associations with blood lipid concentrations in young Mexican college students. Methods: Adults (ages 18–25 years, n = 580) provided a fasting blood sample to determine TG and HDL-C concentrations. DNA was genotyped for 14 SNPs in lipid metabolism pathways (reverse cholesterol transport [RCT], cellular lipid uptake, and lipoprotein formation and transport). Additive (number of risk alleles) and weighted (regression-derived β coefficients) GRS were calculated for individual pathways, and their sum (total GRS) was explored. Associations among individual SNPs, GRS, and blood lipids were determined through general linear models in SAS. Results: The additive RCT and total GRS were associated with TG (both p < 0.05). The RCT pathway explained 3.4% of the variability in TG concentrations, and the total GRS explained 6.1%. The weighted RCT GRS was associated with HDL-C (p = 0.007). The ATP-binding cassette protein (ABCA1) rs9282541 variant was most strongly associated with HDL-C (p = 0.016). When this SNP was removed from the GRS, the association became non-significant. Conclusions: SNPs in lipoprotein metabolism pathways cumulatively associate with blood lipid concentrations in young Mexican adults. The ABCA1-rs9282541 variant, previously shown to be positively associated with low HDL-C concentrations in Amerindian populations, had the strongest association with HDL-C. Further work is needed to elucidate the roles of genetic admixture and lifestyle risk factors in dyslipidemia in this population. Full article

Background/Objectives: The gut–liver axis plays a central role in cholesterol homeostasis, linking intestinal absorption, microbial metabolites, and hepatic lipid regulation. Dysregulation of this axis contributes to hypercholesterolemia and cardiometabolic risk, beyond classical cholesterol synthesis pathways. This study evaluated a novel multi-botanical formulation (MIX) that combines Gastrodia elata, Black Garlic, Primula veris, and Emblica officinalis (AMLA) to integrate modulation of cholesterol metabolism through intestinal and hepatic mechanisms. Methods: Individual extracts were chemically characterised for polyphenols, flavonoids, polysaccharides, S-allyl-L-cysteine (SAC), and tannins. Caco-2 cells were treated with varying doses to determine optimal concentrations and for viability, transepithelial electrical resistance, and permeability analysis. Supernatants post-intestinal passage were applied to HepG2 cells under high-glucose conditions to assess viability, oxidative stress, SRC/ERK-MAPK signalling, cholesterol synthesis (HMGR), LDL uptake, PCSK9–LDLR–SREBP-2 axis, and bile acid production. Results: MIX enhanced intestinal barrier integrity (TEER, tight junctions, permeability) and preserved cell viability compared with single extracts. In HepG2 cells, MIX demonstrated synergistic effects: it reduced HMGR expression by 83–90% relative to individual extracts, increased LDLR expression by 43–97%, suppressed PCSK9 by up to 92%, and lowered total cholesterol and LDL uptake more effectively than RYRF. MIX also amplified bile acid production and free cholesterol excretion, indicating improved hepatic clearance pathways. SRC and ERK-MAPK signalling were favourably modulated, supporting hepatocyte survival under metabolic stress. Conclusions: The multi-botanical formulation exerts complementary and synergistic effects on intestinal absorption and hepatic cholesterol regulation, integrating suppression of cholesterol synthesis, enhanced LDL clearance, and stimulated elimination via bile acids. These findings highlight the potential of the MIX formulation to modulate metabolically induced cholesterol dysregulation, supporting further in vivo and clinical investigation. Full article

Lactic acid bacteria (LAB) have dominated food fermentation globally and are ingrained in many food cultures. Obesity is a global health concern, and LAB ingestion is known to exert anti-obesity effects in animals. However, the characteristics of individual bacterial strains and their underlying mechanisms require elucidation since the anti-obesity effects can differ with variations in the strain, host, and living environment. In this study, we aimed to evaluate the safety and anti-obesity effects of Lactiplantibacillus plantarum TO-A (LPTOA), isolated from silage, using Caenorhabditis elegans as the model organism. The study findings revealed that LPTOA was non-toxic to mice, as established via subacute toxicity tests, and extended the lifespan of C. elegans. Furthermore, both LPTOA and heat-killed LPTOA reduced fat accumulation in C. elegans by 60% and 58%, respectively. However, in vitro experiments suggested that LPTOA does not decompose cholesterol and triglycerides, nor does it inhibit lipase activity. We identified that pept-1 (a dipeptide transporter) in C. elegans is involved in the anti-obesity effects of LPTOA. PEPT-1 is a protein that controls proton influx into the intestinal tract and is involved in not only peptide uptake but also free fatty acid absorption. These results demonstrate the anti-obesity effects and probiotic potential of LPTOA for application in products, including foods and supplements. Full article

The prevalence of metabolic dysfunction-associated steatohepatitis (MASH) is rising worldwide. hFGF1^ΔHBS, a variant of human fibroblast growth factor 1 with three substitutions in its heparin-binding sites, was previously shown by our group to ameliorate fatty liver. However, hFGF1^ΔHBS also significantly modulates systemic metabolism, making it unclear whether its hepatic benefits arise from direct liver-specific actions. Additionally, its poor pharmacokinetic profile underscores the need for alternative delivery strategies. Here, we employed adeno-associated virus serotype 8 under the thyroxine-binding globulin promoter (AAV8-TBG) to achieve sustained, hepatocyte-specific expression of hFGF1^ΔHBS. In high-fat-, high-cholesterol-diet-fed apolipoprotein E knockout mice, liver-directed hFGF1^ΔHBS expression markedly reduced hepatic steatosis, inflammation, and fibrosis, independent of changes in body weight, blood glucose, insulin sensitivity, body composition, or circulating triglyceride and cholesterol levels. Mechanistically, hFGF1^ΔHBS gene transfer normalized fatty acid synthesis and suppressed fatty acid uptake by downregulation of stearoyl-CoA desaturase-1 and cluster of differentiation 36. Importantly, these therapeutic effects were achieved without inducing hepatic hyperproliferation, as evidenced by unchanged expression of proliferating cell nuclear antigen and antigen Kiel 67. Collectively, our findings demonstrate that hFGF1^ΔHBS exerts direct hepatoprotective effects and that AAV8-TBG-mediated liver-directed hFGF1^ΔHBS delivery represents a safe and effective strategy for treating MASH. Full article

Modulation of the gut microbiota represents a promising approach to counteract diet-induced metabolic alterations, with microalgae emerging as potential interventions. Building on our previous in vivo evidence that dietary supplementation with the marine microalga Tisochrysis lutea F&M-M36 (T. lutea) positively modulates selected metabolic alterations under high-fat feeding, the present study aimed to identify potential associations between these metabolic changes and coordinated modifications of the gut microbiota. Animals were fed normal-fat (NF), high-fat (HF), or HF supplemented with 5% T. lutea (HFTiso) diets for three months. Gut microbial profiles were analyzed by 16S rRNA sequencing and correlated with plasma lipids, glucose, blood pressure, fecal lipid excretion, and adiponectin levels. T. lutea supplementation was associated with significant modulation of selected metabolic parameters and coherent alterations in gut microbial communities. Multivariate analyses revealed treatment-dependent clustering of metabolic profiles, with HFTiso forming an intermediate group between HF and NF diets. Beta-diversity analyses showed marked treatment-specific shifts, while alpha-diversity remained stable. Linear discriminant analysis identified 31 discriminative genera, with the HFTiso group enriched in taxa associated with fermentative metabolism and lipid-related metabolic pathways including Anaerotruncus, Marvinbryantia, and Eubacterium coprostanoligenes, while the HF group was linked to Clostridium sensu stricto 1 and Terrisporobacter. Positive correlations between HFTiso-associated taxa and adiponectin levels were consistent with microbiota-associated metabolic signatures. In parallel, T. lutea supplementation was associated with downregulation of colonic Niemann-Pick C1-like 1 (NPC1L1) mRNA expression, a key mediator of intestinal cholesterol uptake. The bioactivity of T. lutea likely reflects its content of polyunsaturated fatty acids, oleic acid, phytosterols, and fucoxanthin; however, whether these components act synergistically or whether specific bioactive compounds are primarily responsible remains to be clarified. Together, these findings indicate that T. lutea supplementation is associated with coordinated changes in gut microbiota composition and transcriptional modulation of the intestinal cholesterol transporter NPC1L1 in the context of selected early-stage metabolic alterations under high-fat feeding. While direct extrapolation to humans remains limited, these results suggest potential translational relevance of T. lutea as a nutraceutical approach targeting early-stage metabolic dysregulation. Future studies will be required to determine the mechanistic contribution of individual bioactive components and to assess whether microbiota- and gene expression-associated changes play a causal role in mediating the observed metabolic outcomes, thereby informing the rational development of T. lutea-derived interventions. Full article

The tumor microenvironment (TME) plays a key role in driving tumor progression, metastasis, and resistance to therapy. The TME is a highly variable ecosystem composed of both cancer and surrounding normal cells, immune survey cells and the extracellular matrix, also composed of signaling molecules that mediate interactions between them. Blood cancer cells pose a unique challenge because of their circulation and widespread distribution along with their capacity to invade various niches, interacting with a wide range of host cells such as fibroblasts, immune cells, endothelial cells, and adipocytes. Metabolism reprogramming in this tumor context, notably referring to elevated cholesterol and fatty acid metabolism, emerges as a crucial event in shaping an immune-suppressive microenvironment that promotes tumor progression. Cholesterol and fatty acids are supplied by both de novo biosynthesis and exogenous uptake from lipoproteins. Lipoproteins are pseudo-micellar structures, designed to transport essential water-insoluble metabolites, including triacylglycerols and cholesterol, in the plasma, lymph, and interstitial fluids. A number of studies have reported abnormal circulating lipoprotein levels in leukemic patients and have suggested that lipoproteins are key for cancer cells to thrive. However, the role of lipoprotein metabolism in cancer cells in the context of the TME is still incompletely discussed so far. The aim of this review is to consider the importance of lipoprotein metabolism in shaping the tumor microenvironment in the context of hematological malignancies. Full article

Mutations in leucine-rich repeat kinase 2 (LRRK2) are among the most common genetic causes of Parkinson’s disease (PD), yet substantial heterogeneity exists among pathogenic variants. How mutations in distinct functional domains of LRRK2 differentially perturb cellular homeostasis remains incompletely understood. Here, we compared two pathogenic LRRK2 mutations—G2019S in the kinase domain and I1371V in the GTPase domain—across multiple cellular models, including SH-SY5Y and U87 cells, and healthy human iPSC-derived floor plate cells. We demonstrate that the I1371V mutation induces markedly more severe cellular dysfunction than G2019S. I1371V-expressing cells exhibited elevated LRRK2 autophosphorylation at S1292 and robust hyperphosphorylation of Rab8A and Rab10, indicating enhanced downstream signaling. These alterations impaired sterol trafficking, leading to selective depletion of membrane cholesterol without changes in total cellular cholesterol. Consequently, I1371V cells displayed increased membrane fluidity, disrupted microdomain organization, altered membrane topology, reduced caveolin-1 expression, and impaired dopamine transporter surface expression and dopamine uptake. Lipidomic profiling further revealed a broad disruption of lipid homeostasis, including reductions in cholesteryl esters, sterols, sphingolipids, and glycerophospholipids, whereas G2019S cells showed comparatively modest changes. Pharmacological intervention revealed mutation-specific responses, with the non-selective LRRK2 modulator GW5074 outperforming the kinase-selective inhibitor MLi-2 in restoring Rab8A phosphorylation, membrane integrity, and dopaminergic function. Collectively, these findings identify membrane lipid dysregulation as a central cell biological mechanism in LRRK2-associated PD and underscore the importance of variant-specific therapeutic strategies. Full article

Background/Objectives: Chronic heat stress impairs lipid mobilization from adipocytes, which reduces substrate availability for muscle metabolism. Systemic inflammation is a key facilitative response to heat stress, and we sought to determine if mitigating inflammation in heat-stressed wether lambs would improve lipid flux. Methods: Two cohorts of commercial feedlot lambs were heat stressed for 30 days. In study 1, heat-stressed lambs received dexamethasone injections every 3 days, fish oil capsules twice daily, or no intervention. In study 2, heat-stressed lambs received daily boluses of ω-3 polyunsaturated fatty acid Ca²⁺ salts (ω-3 PUFA) or no intervention. Results: In both studies, heat stress reduced ex vivo epinephrine-stimulated free fatty acid and glycerol mobilization from visceral adipose tissue. These deficits were partially resolved by fish oil and fully resolved by ω-3 PUFA. In study 1, fish oil recovered heat stress-induced deficits in circulating triglycerides and HDL-cholesterol but not in circulating free fatty acids. Fish oil and dexamethasone resolved the increase in muscle PPARα, indicating less lipid utilization for metabolism. In study 2, ω-3 PUFA resolved heat stress-induced deficits in muscle CD36 and PPARγ, indicating improved lipid uptake capacity. However, interventions did not resolve reduced intramuscular lipid content in either study. Conclusions: We conclude that inflammation was a primary facilitator of impaired lipid mobilization in heat-stressed lambs but was not the sole driver of lipid dysregulation. Nevertheless, targeting inflammation was a beneficial strategy for improving lipid flux during chronic heat stress. Full article

Background and Objective: Male individuals diagnosed with metabolic dysfunction-associated steatotic liver disease (MASLD) frequently present with decreased blood testosterone concentrations concomitant with increased levels of hepatic cholesterol, the fundamental substrate for testosterone synthesis; however, the mechanistic relationship between these phenomena remains inadequately elucidated. This study aimed to examine the involvement of hepatic cholesterol biosynthesis and testosterone metabolism in the pathogenesis of MASLD. Methods: An MASLD model was established in male C57BL/6J mice subjected to a high-fat diet (HFD). Comprehensive analyses, including hepatic transcriptomics, metabolomics, enzyme-linked immunosorbent assay, Western blotting, and quantitative polymerase chain reaction, were conducted. Additionally, in vitro experiments were performed using AML-12 hepatocytes treated with oleic acid and testosterone, with or without the presence of a uridine diphosphate-glucuronosyltransferase family 2 member B (UGT2B) enzyme inhibitor. Results: The HFD elevated cholesterol levels and activated cholesterol synthesis and testosterone metabolic pathways, notably characterized by upregulation of UGT2B enzymes and their transcriptional regulator, the aryl hydrocarbon receptor (AHR). Blood testosterone increased initially but decreased after 24 weeks of HFD. In vitro, testosterone alone did not affect oleic acid-induced lipid accumulation, but inhibiting UGT2B enabled testosterone levels to reduce lipid deposition and downregulate lipid uptake and synthesis pathways. Conclusions: The HFD induces dynamic, UGT2B-mediated hepatic testosterone metabolism. Compensatory early testosterone increase is offset by enhanced UGT2B-mediated clearance, resulting in eventual testosterone depletion and the loss of its protective effects against hepatic lipid accumulation. This explains the clinical paradox and suggests targeting the hepatic UGT2B enzymes as a potential MASLD treatment. Full article

The hypothalamic–pituitary–adrenal (HPA) axis plays a pivotal role in regulating stress responses through ACTH-stimulated glucocorticoid production. The transcriptional programmes underlying temporal adaptation to prolonged ACTH exposure and glucocorticoid feedback remain incompletely characterized. Adult male Wistar rats were subjected to acute ACTH stimulation (single injection, 1 h) to elicit an immediate transcriptional response, prolonged ACTH exposure (three injections over 36 h) as a repeated exposure, or Dexamethasone treatment (three injections over 36 h). Plasma corticosterone levels were subsequently measured using an enzyme-linked immunosorbent assay (ELISA). The adrenal transcriptome profiling was performed using Affymetrix arrays. Differentially expressed genes (DEGs; |fold change| ≥ 1.8, adjusted p < 0.05) were analyzed using limma, followed by pathway and network analyses. Acute ACTH exposure resulted in the induction of 569 DEGs (357 upregulated), including immediate-early genes (Nr4a family, AP-1 factors), cAMP-PKA-CREB signalling components, and heat shock proteins. Prolonged ACTH resulted in 98 DEGs (predominantly downregulated), including the suppression of mitochondrial genes and upregulation of Polycomb repressive complex 2 components, suggesting epigenetic transcriptional attenuation. Dexamethasone treatment yielded 75 DEGs with selective suppression of SREBP-mediated cholesterol biosynthesis and uptake pathways. Twelve genes were downregulated by both prolonged ACTH and Dexamethasone, including sterol metabolism and interferon-stimulated genes. Acute and prolonged ACTH exposure engage distinct transcriptional programmes. Acute stimulation activates immediate-early genes and stress responses, while prolonged exposure suppresses mitochondrial gene expression through transcriptional dampening mechanisms. Dexamethasone is associated with the inhibition of cholesterol metabolism via SREBP pathway suppression. These findings illuminate HPA axis adaptation and glucocorticoid-induced adrenal suppression. Full article

Prostate cancer (PCa) is the most common male cancer and the second leading cause of cancer death in men. Androgen deprivation therapy (ADT) has been widely used as the first-line treatment for PCa. However, most PCa will progress to castration-resistant PCa (CRPC) that resists ADT 1 to 3 years after the treatment. Steroidogenesis from cholesterol is one of the mechanisms leading to ADT resistance. In PCa cells, low-density lipoprotein (LDL) mediated uptake is the major venue to acquire cholesterol. However, the mechanism of regulating this process is not fully understood. Fibroblast growth factor receptor 1 (FGFR1) is a receptor tyrosine kinase (RTK) that is ectopically expressed in PCa cells and promotes PCa progression by activating downstream signaling pathways. To comprehensively determine the roles of FGFR1 in PCa, we generated FGFR1-null DU145 cells and compared the transcriptomes of FGFR1-null and wild-type cells. We found that ablation of FGFR1 reduced the expression of genes promoting LDL uptake and de novo synthesis of cholesterol, thereby reducing the overall cholesterol pool in PCa cells. Detailed mechanistic studies further revealed that FGFR1 boosted the activation of sterol regulatory element-binding protein 2 (SREBP2) through ERK-dependent phosphorylation and cleavage, which, in turn, increased the expression of low-density lipoprotein receptor (LDLR) and enzymes involved in de novo cholesterol synthesis. Furthermore, in silico analyses demonstrated that high expression of FGFR1 was associated with high LDLR expression and clinicopathological features in PCa. Collectively, our data unveiled a previously unrecognized therapeutic avenue for CRPC by targeting FGFR1-driven cholesterol uptake and de novo synthesis. Full article

Background/Objectives: Ginger (Zingiber officinale Roscoe) is a flowering plant widely used as a spice and natural medicine for millennia. Ginger demonstrates multiple protective effects, regulates cholesterol, and may reduce the risk of cancer and colitis. However, little attention has been paid to its potential to cause herb–drug interactions (HDIs). The aim of this study was to investigate the interaction of ginger extract and its major components [6]-gingerol and [6]-shogaol with clinically relevant uptake and efflux transporters in vitro. Methods: Transporter-overexpressing cell lines of 25 uptake transporters and inside-out membrane vesicles containing 8 efflux transporters were employed to measure potential interactions. Results: Zingiber officinale extract at 150 µg/mL interacted with 17 of 33 transporters examined. These were further investigated for interactions with the purified active components. Seven and 16 transporters interacted with pure [6]-gingerol (100 µM) and [6]-shogaol (100 µM), respectively. To evaluate the risk of in vivo inhibition, IC₅₀ values were determined for the affected transporters. Based on standard risk assessment calculations, we confirmed previously reported inhibitory effects of ginger components on MDR1 (67.64 µM) and BCRP (9.931 µM), and revealed novel potential interactions with renal OAT3 (0.956 µM) and URAT1 (5.887 µM), hepatic OCT1 (4.287 µM) and BSEP (25.45 µM), and the ubiquitously expressed ENT1 (11.62 µM) ([6]-shogaol IC₅₀ values are shown in parentheses). Strong and isoform-selective inhibition of OAT3 by [6]-shogaol is particularly intriguing. Additionally, via cell viability experiments on a set of human cervical, breast, and oropharyngeal cancer cell lines, we demonstrated the antiproliferative effect of [6]-shogaol in vitro. Conclusions: Prolonged consumption of high-dose ginger supplements may pose a risk of transporter-mediated HDIs when consumed concomitantly with conventional medications. Our study encourages follow-up of the suspected effects in vivo. Full article

Melanoma is the deadliest form of skin cancer, characterized by high metastatic potential and intrinsic heterogeneity. In addition to genetic mutations such as BRAF^V600E^ and NRAS, lipid metabolic reprogramming has emerged as a critical factor in tumor progression and therapy resistance. Lipid metabolism supports melanoma cell survival, phenotypic switching, immune evasion, and resistance to targeted therapies and immunotherapy, while also modulating susceptibility to ferroptosis. This review summarizes current knowledge on lipid dysregulation in melanoma, highlighting alterations in fatty acid synthesis, desaturation, uptake, storage, and oxidation, as well as changes in phospholipids, sphingolipids, cholesterol, and bioactive lipid mediators. These lipid pathways are tightly regulated by oncogenic signaling networks, including MAPK and PI3K–AKT–mTOR pathways, and are influenced by tumor microenvironmental stressors such as hypoxia and nutrient limitation. Advances in lipidomics technologies, particularly mass spectrometry-based approaches, have enabled comprehensive profiling of lipid alterations at bulk, spatial, and single-cell levels, offering new opportunities for biomarker discovery and therapeutic stratification. Targeting lipid metabolic vulnerabilities represents a promising strategy to improve melanoma diagnosis, prognosis, and treatment efficacy. Full article