Search Results (305)

Cholesterol stress profoundly modulates cellular processes, but its underlying mechanisms remain incompletely understood. To investigate cholesterol-responsive networks, we performed integrated transcriptome (RNA-seq) and metabolome (LC-MS) analyses on HeLa cells treated with cholesterol for 6 and 24 h. Through transcriptomic analysis of cholesterol-stressed HeLa cells, we identified stage-specific responses characterized by early-phase stress responses and late-phase immune-metabolic coordination. This revealed 1340 upregulated and 976 downregulated genes after a 6 h cholesterol treatment, including induction and suppression of genes involved in cholesterol efflux and sterol biosynthesis, respectively, transitioning to Nuclear Factor kappa-B (NF-κB) activation and Peroxisome Proliferator-Activated Receptor (PPAR) pathway modulation by 24 h. Co-expression network analysis prioritized functional modules intersecting with differentially expressed genes. We also performed untargeted metabolomics using cells treated with cholesterol for 6 h, which demonstrated extensive remodeling of lipid species. Interestingly, integrated transcriptomic and metabolic analysis uncovered GFPT1-driven Uridine Diphosphate-N-Acetylglucosamine (UDP-GlcNAc) accumulation and increased taurine levels. Validation experiments confirmed GFPT1 upregulation and ANGPTL4 downregulation through RT-qPCR and increased O-GlcNAcylation via Western blot. Importantly, clinical datasets further supported the correlations between GFPT1/ANGPTL4 expression and cholesterol levels in Non-Alcoholic Steatohepatitis (NASH) liver cancer patients. This work establishes a chronological paradigm of cholesterol sensing and identifies GFPT1 and ANGPTL4 as key regulators bridging glycosylation and lipid pathways, providing mechanistic insights into cholesterol-associated metabolic disorders. Full article

Atherosclerosis (AS), a progressive inflammatory disease of coronary arteries, the aorta, and the internal carotid artery, is considered one of the main contributors to cardiovascular disorders. Blood flow is restricted by accumulating lipid-rich macrophages (foam cells), calcium, fibrin, and cellular debris into plaques on the intima of arterial walls. Butyrate maintains gut barrier integrity and modulates immune responses. Butyrate regulates G-protein-coupled receptor (GPCR) signaling and activates nuclear factor kappa-B (NF-κB), activator protein-1 (AP-1), and interferon regulatory factors (IFRs) involved in the production of proinflammatory cytokines. Depending on the inflammatory stimuli, butyrate may also inactivate NF-κB, resulting in the suppression of proinflammatory cytokines and the stimulation of anti-inflammatory cytokines. Butyrate modulates mitogen-activated protein kinase (MAPK) to promote or suppress macrophage inflammation, muscle cell growth, apoptosis, and the uptake of oxidized low-density lipoprotein (ox-LDL) in macrophages. Activation of the peroxisome proliferator-activated receptor γ (PPARγ) pathway plays a role in lipid metabolism, inflammation, and cell differentiation. Butyrate inhibits interferon γ (IFN-γ) signaling and suppresses NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) involved in inflammation and scar tissue formation. The dual role of butyrate in AS is discussed by addressing the interactions between butyrate, intestinal epithelial cells (IECs), endothelial cells (ECs) of the main arteries, and immune cells. Signals generated from these interactions may be applied in the diagnosis and intervention of AS. Reporters to detect early AS is suggested. This narrative review covers the most recent findings published in PubMed and Crossref databases. Full article

Alzheimer’s disease (AD), the most common form of dementia, is a progressive neurodegenerative disorder characterized by memory loss and cognitive decline. In addition to its two major pathological hallmarks, extracellular amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs), recent evidence highlights the critical roles of mitochondrial dysfunction and neuroinflammation in disease progression. Aβ impairs mitochondrial function, which, in part, can subsequently trigger inflammatory cascades, creating a vicious cycle of neuronal damage. Estrogen receptors (ERs) are widely expressed throughout the brain, and the sex hormone 17β-estradiol (E2) exerts neuroprotection through both anti-inflammatory and mitochondrial mechanisms. While E2 exhibits neuroprotective properties, its mechanisms against Aβ toxicity remain incompletely understood. In this study, we investigated the neuroprotective effects of E2 against Aβ-induced mitochondrial dysfunction and neuroinflammation in primary cortical neurons, with a particular focus on the role of AMP-activated protein kinase (AMPK). We found that E2 treatment significantly increased phosphorylated AMPK and upregulated the expression of mitochondrial biogenesis regulator peroxisome proliferator-activated receptor gamma coactivator-1 α (PGC-1α), leading to improved mitochondrial respiration. In contrast, Aβ suppressed AMPK and PGC-1α signaling, impaired mitochondrial function, activated the pro-inflammatory nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB), and reduced neuronal viability. E2 pretreatment also rescued Aβ-induced mitochondrial dysfunction, suppressed NF-κB activation, and, importantly, prevented the decline in neuronal viability. However, the pharmacological inhibition of AMPK using Compound C (CC) abolished these protective effects, resulting in mitochondrial collapse, elevated inflammation, and cell death, highlighting AMPK’s critical role in mediating E2’s actions. Interestingly, while NF-κB inhibition using BAY 11-7082 partially restored mitochondrial respiration, it failed to prevent Aβ-induced cytotoxicity, suggesting that E2’s full neuroprotective effects rely on broader AMPK-dependent mechanisms beyond NF-κB suppression alone. Together, these findings establish AMPK as a key mediator of E2’s protective effects against Aβ-driven mitochondrial dysfunction and neuroinflammation, providing new insights into estrogen-based therapeutic strategies for AD. Full article

Peroxisome proliferator-activated receptor α (PPARα, encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are the two prominent nutrient-sensing nuclear receptors essential for maintaining hepatic metabolism during fasting and fed states, respectively. These nuclear receptors comprehensively regulate the transcription of numerous genes involved in fatty acid oxidation (FAO), ketogenesis, bile acid (BA) biosynthesis, and other metabolic processes critical for liver energy homeostasis. These receptors have been shown to have opposite impacts on autophagy, which is triggered by PPARα activation but inhibited by FXR activation. Recent studies have further revealed that liver-specific genetic ablation of key autophagic genes tremendously impairs the activation of these nuclear receptors, thereby profoundly affecting hepatic metabolism in both fasting and feeding states. This review explores the roles and mechanisms of PPARα and FXR in regulating liver metabolism and autophagy, highlighting the necessity of basal autophagic activity in ensuring the proper signaling of these nutrient-sensing nuclear receptors. Finally, we examine the potential therapeutic strategies that leverage the interplay between PPARα, FXR, and autophagy for the treatment of metabolic liver disorders. We also delve into the clinical implications of this complex relationship, emphasizing its significance for translational medicine and future therapeutic interventions. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss and limited therapeutic options. Metal-based drugs have emerged as promising alternatives in the search for effective treatments, and vanadium coordination complexes have shown significant potential due to their neuroprotective and anti-aggregant properties. This review explores the advances in the development of vanadium-based metallodrugs for AD, focusing on their ability to modulate amyloid-beta (Aβ) aggregation, oxidative stress, and neuroinflammation. Recent in vitro and in vivo studies highlight the efficacy of oxovanadium (IV) and peroxovanadium (V) complexes in inhibiting Aβ fibril formation and reducing neuronal toxicity. Additionally, the interaction of vanadium complexes with key biological targets, such as peroxisome proliferator-activated receptor gamma (PPARγ) and protein-tyrosine phosphatase 1B (PTP1B), suggests a multifaceted therapeutic approach. While these findings underscore the potential of vanadium compounds as innovative treatments for AD, further research is needed to optimize their bioavailability, selectivity, and safety for clinical applications. Full article

Background/Objectives: Disruptions in adipose tissue dynamics contribute to obesity-related metabolic disorders, emphasizing the need for targeted therapies focusing on adipose tissue cells, including progenitor cells and adipocytes. Peroxisome proliferator-activated receptor gamma (PPARG) ligands are potent insulin sensitizers used in type 2 diabetes treatment. This study investigated the effects of rosiglitazone, a PPARG agonist, and betulinic acid, a PPARG antagonist, on adipogenesis and apoptosis in 3T3-L1 pre-adipocytes. Method: 3T3-L1 pre-adipocytes were treated with rosiglitazone or betulinic acid during adipogenic differentiation. Lipid droplet formation was used to evaluate adipogenesis. Cell growth and cell death were assessed using the resazurin-based cell viability assay, trypan blue exclusion assay, LDH assay, and Annexin V/PI staining. Quantitative PCR was conducted to examine the expression of genes associated with adipogenesis and apoptosis. Results: Betulinic acid reduced adipogenesis only when administered daily for eight days. Rosiglitazone did not alter the overall lipid quantity; however, it promoted a shift toward fewer but larger lipid droplets. Both compounds increased Adipoq and Cfd expression, and betulinic acid also elevated Fabp4. Rosiglitazone induced stronger cell aggregation. Despite increased cell death, overall viability was maintained. Apoptotic cell death was enhanced by both compounds and confirmed via Annexin V/PI staining and flow cytometry, accompanied by downregulation of Ccnd1 and Bcl2. Additionally, rosiglitazone markedly increased the expression of Cebpa, a key regulator that can modulate lipid droplet formation and the balance between cell growth and death. Conclusions: Rosiglitazone and betulinic acid differentially modulate adipogenesis and apoptosis in 3T3-L1 cells, revealing a complex interplay between lipid accumulation and programmed cell death. Together, the findings underscore the potential of dual PPARG-targeting approaches for metabolic disease interventions. Full article

Palmitoylethanolamide (PEA) is an endogenous lipid mediator belonging to the N-acyl-ethanolamine family, widely recognized for its multifaceted effects on neuroprotection, chronic pain management, and immune modulation. As a naturally occurring compound, PEA plays a crucial role in maintaining homeostasis under conditions of cellular stress and inflammation. Its pharmacological effects are primarily mediated through peroxisome proliferator-activated receptor-alpha (PPAR-α) activation, alongside indirect modulation of cannabinoid receptors CB1 and CB2, as well as interactions with novel targets such as GPR55 and TRPV1. These molecular mechanisms underpin its broad therapeutic potential, particularly in the management of neuroinflammatory and neurodegenerative disorders, pain syndromes, and immune dysregulation. A major advancement in PEA research has been the development of ultramicronized palmitoylethanolamide (umPEA), which significantly enhances its bioavailability and therapeutic efficacy by facilitating better tissue absorption and interaction with key molecular pathways. Preclinical and clinical studies have demonstrated that umPEA is particularly effective in reducing neuroinflammation, stabilizing mast cells, and enhancing endocannabinoid system activity, making it a promising candidate for integrative approaches in neuropsychiatric and chronic inflammatory diseases. Given its well-established safety profile, umPEA represents an attractive alternative or adjunct to conventional anti-inflammatory and analgesic therapies. This communication provides a comprehensive overview of the mechanisms of action and therapeutic applications of both PEA and umPEA, emphasizing their emerging role in clinical practice and personalized medicine. Full article

Type 2 diabetes mellitus represents a major global health burden and is often preceded by a prediabetic state characterized by insulin resistance and metabolic dysfunction. Mitochondrial alterations, oxidative stress, and disturbances in lipid metabolism are central to the prediabetes pathophysiology. Melatonin, a pleiotropic indolamine, is known to regulate metabolic and mitochondrial processes; however, its therapeutic potential in prediabetes remains poorly understood. This study investigated the effects of melatonin on energy metabolism, oxidative stress, and mitochondrial function in a rat model of prediabetes induced by chronic sucrose intake and low-dose streptozotocin administration. Following prediabetes induction, animals were treated with melatonin (20 mg/kg) for four weeks. Biochemical analyses were conducted to evaluate glucose and lipid metabolism, and mitochondrial function was assessed via gene expression, enzymatic activity, and oxidative stress markers. Additionally, hepatic mitochondrial dynamics were examined by quantifying key regulators genes associated with biogenesis, fusion, and fission. Prediabetic animals exhibited dyslipidemia, hepatic lipid accumulation, increased fat depots, and impaired glucose metabolism. Melatonin significantly reduced serum glucose, triglycerides, and total cholesterol levels, while enhancing the hepatic high-density lipoprotein content. It also stimulated β-oxidation by upregulating hydroxyacyl-CoA dehydrogenase and citrate synthase activity. Mitochondrial dysfunction in prediabetic animals was evidenced by the reduced expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and mitochondrial transcription factor A, both of which were markedly upregulated by melatonin. The indolamine also modulated mithocondrial dynamics by regulating fusion and fission markers, including mitosuin 1 and 2, optic atrophy protein, and dynamin-related protein. Additionally, melatonin mitigated oxidative stress by enhancing the activity of superoxide dismutase and catalase while reducing lipid peroxidation. These findings highlight melatonin’s protective role in prediabetes by improving lipid and energy metabolism, alleviating oxidative stress, and restoring mitochondrial homeostasis. This study provides novel insights into the therapeutic potential of melatonin in addressing metabolic disorders, particularly in mitigating mitochondrial dysfunction associated with prediabetes. Full article

Caigua (Cyclanthera pedata (L.) Schrad.) is a traditional herbal remedy traditionally used in Latin America for its health benefits and to treat metabolic disorders, including diabetes. Despite interest in its herbal use, the phytochemical properties of caigua’s secondary metabolites are poorly known. This study aimed to isolate the main flavone glycosides from the leaves of caigua landrace cultivated in the Camonica Valley (Italy) using flash chromatography and evaluate their potential activity toward peroxisome proliferator-activated receptors (PPARs) and transient receptor potential (TRP) ion channels through luciferase and intracellular calcium assays. We found that the caigua species-specific flavone glycoside, chrysin-6-C-fucopyranoside, showed potent and selective activity toward PPARγ, with no effects on other PPAR subtypes or TRP channels. These findings indicate that the caigua plant could offer a safer alternative to conventional PPARγ agonists, whose use as antidiabetic drugs is limited by severe side effects that currently restrict the clinical use of conventional PPAR agonists. Full article

Selenium-binding protein 1 (SeBP1) is an anticancer factor that affects lipid metabolism in mouse kidneys via the peroxisome proliferator-activated receptor-alpha (PPARA) pathway. However, its physiological role in the liver is difficult to explain because of the presence of the highly homologous selenium-binding protein 2 (SeBP2). To investigate the role of these proteins in the liver, we generated SeBP1 and SeBP2 double-knockout mice (SeBP1/2-DK). SeBP1/2 deletion did not significantly alter the mice phenotypic compared to that of the wild-type strain. Then, we identified the genes involved in hepatic lipid metabolism. The double knockout did not affect fatty acid and cholesterol synthesis, but inhibited fatty acid oxidation and cholesterol efflux. Furthermore, transfection of HepG2 cells with human selenium-binding protein 1 (hSeBP1) positively regulated PPARA and the genes controlled by it. Overexpression of hSeBP1 reduced the levels of non-esterified fatty acids in the culture medium. The serum levels of low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglycerides were significantly different among the three groups. In summary, we elucidated the potential signaling pathways of SeBP1 and SeBP2 in fatty acid oxidation and hepatic cholesterol efflux. Our findings provide insights relevant for developing new strategies to prevent and treat lipid metabolism disorders. Full article

Matrine, a quinoline alkaloid, possesses lipid-regulating effects, but the underlying mechanisms are rarely characterized in vivo. With a fat-accumulating Caenorhabditis elegans model, we show that matrine reduces the fat content and the DHS-3::GFP-labeled lipid droplets in high-glucose-diet N2 and transgenic LIU1 nematodes, respectively. Based on RNA-seq, this study demonstrates that a loss of AAK-2 function suppresses the fat-lowering effects of matrine, and the hyperactivated AAK-2 strain has a relatively lower fat content than N2. The involvement of NHR-49 in matrine’s fat-lowering effects further suggests that matrine impacts fat breakdown and storage via the AAK-2/NHR-49-governed pathway. Using the transgenic SJ4143 (ges-1::GFP(mit)) and VS10 (vha-6p::mRFP-PTS1), we show that matrine activates the AAK-2/NHR-49 pathway, coupling the alteration of mitochondrial and peroxisomal functions. Studies of aak-2 and nhr-49 mutants reveal that AAK-2 and NHR-49 modulate lipid metabolic homeostasis; meanwhile, matrine increases physical fitness and lifespan through activating the AAK-2/NHR-49 pathway in high-glucose-diet nematodes. Surprisingly, we found that β-amyloid (Aβ) induces lipid metabolic disorder in an Alzheimer’s disease (AD) C. elegans model, but matrine not only reduces Aβ aggregation but also alleviates Aβ-mediated lipid metabolic disorder. Our data suggest that matrine has promise as a fat-lowering agent, and also offer new insights into its therapeutic potential for AD. Full article

Metabolic-dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD), is a highly prevalent metabolic disorder characterized by hepatic steatosis in conjunction with at least one cardiometabolic risk factor, such as obesity, type 2 diabetes, hypertension, or dyslipidemia. As global rates of obesity and metabolic syndrome continue to rise, MASLD is becoming a major public health concern, with projections indicating a substantial increase in prevalence over the coming decades. The disease spectrum ranges from simple steatosis to metabolic-dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma, contributing to significant morbidity and mortality worldwide. This review delves into the molecular mechanisms driving MASLD pathogenesis, including dysregulation of lipid metabolism, chronic inflammation, oxidative stress, mitochondrial dysfunction, and gut microbiota alterations. Recent advances in research have highlighted the role of genetic and epigenetic factors in disease progression, as well as novel therapeutic targets such as peroxisome proliferator-activated receptors (PPARs), fibroblast growth factors, and thyroid hormone receptor beta agonists. Given the multifaceted nature of MASLD, a multidisciplinary approach integrating early diagnosis, molecular insights, lifestyle interventions, and personalized therapies is critical. This review underscores the urgent need for continued research into innovative treatment strategies and precision medicine approaches to halt MASLD progression and improve patient outcomes. Full article

Background/Objectives: Zellweger spectrum disorder (ZSD), a rare genetic disease characterized by defects in peroxisome biogenesis, results in dysfunction of all organ systems, including feeding difficulties, gastrointestinal bleeding, and reduced overall growth. Despite this nutritional impact, no published studies have assessed dietary intake in ZSD. The purpose of this study was to determine nutrient intake in individuals with ZSD or a related peroxisomal disorder using two methods of dietary assessment as provided by family caregivers. Methods: Family caregivers participated in multiple 24 h dietary recall interviews and completed 3-day food records for their child with ZSD or a related single-enzyme peroxisomal disorder over a 6-month period. Results: Twenty-one subjects (eleven orally fed and ten enterally fed), ranging from 1 to 33 years of age, were included in the study. Energy and nutrient intake as reported by dietary recall vs. 3-day food record were highly correlated for all nutrients (r² = 0.998, p < 0.0001). Mean nutrient intakes for subjects generally achieved or exceeded DRI requirements, except for fiber (about 50% of DRI). Conclusions: These results show that dietary assessment is feasible in individuals with ZSD using caregiver input, regardless of feed modality, and that dietary intake is consistent across different methods of assessment. These findings may be applicable in dietary assessments for individuals with ZSD and similar genetic disorders and a methodological consideration in clinical interventions. Full article

Background: Prenatal alcohol exposure (PAE) models can cause neurodevelopmental abnormalities like those observed in fetal alcohol spectrum disorder (FASD). Previous studies link experimental PAE effects in the brain to impaired signaling through insulin/IGF and Notch pathways that mediate neuronal survival, growth, migration, energy metabolism, and plasticity. Importantly, concurrent administration of peroxisome proliferator-activated receptor agonists or dietary soy prevented many aspects of FASD due to their insulin-sensitizing, anti-inflammatory, and antioxidant properties. Objective: To determine if dietary soy interventions during pregnancy would be sufficient to normalize central nervous system structure and function, we examined the effects of maternal gestation-limited dietary soy on cerebellar postnatal development, motor function, and critical signaling pathways. Methods: Pregnant Long Evans rats were fed isocaloric liquid diets containing 0% or 26% caloric ethanol with casein or soy isolate as the protein source. The ethanol and soy feedings were discontinued upon delivery. The offspring were subjected to rotarod motor function tests, and on postnatal day 35, they were sacrificed to harvest cerebella for histological and molecular studies. Results: Despite the postnatal cessation of alcohol exposure, chronic gestational exposure reduced brain weight, caused cerebellar hypoplasia, and impaired motor performance. Gestational dietary soy prevented the ethanol-associated reduction in brain weight and largely restored the histological integrity of the cerebellum but failed to normalize motor performance. Ethanol withdrawal abolished the impairments in insulin/IGF signaling that were previously associated with ongoing ethanol exposures, but ethanol’s inhibitory effects on Notch and Wnt signaling persisted. Soy significantly increased cerebellar expression of the insulin and IGF-1 receptors and abrogated several ethanol-associated impairments in Notch and Wnt signaling. Conclusions: Although gestation-restricted dietary soy has significant positive effects on neurodevelopment, optimum prevention of FASD’s long-term effects will likely require dietary soy intervention during the critical periods of postnatal development, even after alcohol exposures have ceased. Full article

Insulin resistance (IR) disrupts hepatic glucose metabolism and mitochondrial function, which contributes to metabolic disorders. The present study examined the effects of tomatine on glucose metabolism in high-glucose-induced IR hepatocytes and explored its underlying mechanisms using AML12 and HepG2 cell models. The results showed that tomatine did not exhibit cytotoxic effects. Under IR conditions, tomatine dose-dependently improved glucose metabolism by enhancing glucose consumption and restoring the mRNA expression of the glucose transporter Glut2 and gluconeogenesis-related genes (Pepck and G6pase). Mechanistically, tomatine activated the phosphorylation of AMP-activated protein kinase (AMPK) and upregulated the expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), reversing the IR-induced suppression of the AMPK/PGC1α pathway. In addition, tomatine enhanced mitochondrial oxidative function by restoring the oxygen consumption rate, increasing ATP production, and upregulating mitochondrial oxidative phosphorylation complex proteins. Both genetic and pharmacological inhibition of AMPK abolished these beneficial effects, confirming its central role in mediating tomatine’s actions. Overall, our findings suggest that tomatine is a promising therapeutic candidate for enhancing hepatic glucose metabolism and mitochondrial function in IR-associated metabolic disorders through AMPK activation. Full article