Search Results (1,663)

Statins are the drugs most commonly used for lowering plasma low-density lipoprotein (LDL) cholesterol levels and reducing cardiovascular disease risk. Although generally well-tolerated, statins can induce myopathy, a major cause of non-adherence to treatment. Impaired mitochondrial function has been implicated in the development of statin-induced myopathy, but the underlying mechanism remains unclear. We have shown that simvastatin downregulates the transcription of TOMM40 and TOMM22, genes that encode major subunits of the translocase of the outer mitochondrial membrane (TOM) complex. Mitochondrial effects of knockdown of TOMM40 and TOMM22 in mouse C2C12 and primary human skeletal cell myotubes include impaired oxidative function, increased superoxide production, reduced cholesterol and CoQ levels, and disrupted markers of mitochondrial dynamics and morphology as well as increased mitophagy, with similar effects resulting from simvastatin exposure. Overexpression of TOMM40 and TOMM22 in simvastatin-treated mouse and human skeletal muscle cells rescued effects on markers of mitochondrial dynamics and morphology, but not oxidative function or cholesterol and CoQ levels. These results show that TOMM40 and TOMM22 have key roles in maintaining both mitochondrial dynamics and function and indicate that their downregulation by statin treatment results in mitochondrial effects that may contribute to statin-induced myopathy. Full article

Long-duration space missions expose astronauts to galactic cosmic radiation (GCR), a complex spectrum of high-charge, high-energy (HZE) ions that pose significant risks of chronic tissue injury. To model these effects, we examined intestinal outcomes in wild-type mice 5 months after low-dose (50 cGy) 33-ion mixed-field GCR simulation (GCRsim). GCRsim induced sustained DNA double-strand breaks (DSBs) and oxidative stress, as shown by elevated γH2AX foci and 4-HNE staining. Intestinal epithelial cells (IECs) exhibited pronounced senescence, marked by increased SA-β-gal activity, p16 upregulation, LaminB1 loss, and induction of senescence-associated secretory phenotype (SASP) cytokines (Cxcl10, IL-6, IL-1β, Icam1). GCRsim also elevated circulating LINE-1 DNA and reduced expression of DNA-degrading nucleases (DNase2, TREX1), indicating impaired extracellular DNA clearance. Targeted molecular study revealed persistent activation of the cGAS–STING pathway, with elevated cGAS, STING, pTBK1, pIKKα/β, and nuclear pIRF3, pIRF7, and p65, consistent with chronic innate immune signaling. Functionally, GCRsim altered nutrient absorption gene expression—upregulating glucose transporters (Slc2a2, Slc2a5, Slc5a1) and gut hormones (Cck, Gip), while downregulating cholesterol/fat transporters (Npc1, Npc1l1). Biochemical markers supported intestinal injury, with decreased serum citrulline and increased intestinal fatty acid-binding protein (I-FABP), indicating barrier compromise. Collectively, these findings demonstrate that GCRsim drives sustained intestinal dysfunction, highlighting the need for countermeasures to protect GI health during deep-space missions. Full article

Background: Familial hypercholesterolemia (FH) is a monogenic disorder causing markedly elevated low-density lipoprotein cholesterol (LDL-C) and premature atherosclerosis. Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in antioxidant defense via NADPH production. G6PD deficiency, an X-linked disorder impairing redox homeostasis, may contribute to cardiovascular disease (CVD) risk. This study examined whether G6PD deficiency increases CVD risk in FH patients. Methods: We retrospectively analyzed 217 FH patients. Clinical data included demographics, lipid profiles, G6PD status, and atherosclerotic CVD outcomes (coronary, cerebrovascular, or peripheral arterial disease). In a subset, FH was confirmed by LDLR gene sequencing, and G6PD Mediterranean and Seattle variants were genotyped. Cumulative CVD prevalence was compared between G6PD-deficient and G6PD-normal FH patients. Multivariable logistic regression was adjusted for age, sex, body mass index, high blood pressure, and smoking. Results: Participants (mean age 47 years, 60% female) had markedly elevated LDL-C (mean 292 mg/dL at diagnosis). Atherosclerotic CVD was present in 119 (55%) patients. G6PD-deficient FH patients had a significantly higher CVD prevalence than those with normal G6PD activity (77.4% vs. 39.8%, p < 0.0001). LDL-C levels were higher in the G6PD-deficient group than in the non-deficient group, and this difference reached statistical significance in the univariate analysis. In the multivariable analysis, G6PD deficiency remained an independent CVD predictor (adjusted OR 3.57, 95% CI 1.30–9.83) after controlling for conventional risk factors. Conclusions: In FH, hereditary G6PD deficiency is associated with a markedly increased risk of atherosclerotic CVD. A pro-oxidative state in G6PD-deficient FH patients may play a role in premature atherogenesis. G6PD status may represent a cardiovascular risk modifier in FH, warranting further research into underlying mechanisms and targeted management. Full article

Backgrounds: Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder that has become a prominent public health problem worldwide. As a traditional Chinese medicine formula, the ErChen decoction (ECD) possesses significant effects on metabolic syndrome. Methods: To determine whether ECD can relieve lipid accumulation and insulin resistance (IR) in liver cells, NAFLD and IR cell models were established by treating HepG2 cells with free fatty acids and an overdose of insulin, respectively. Bioinformatics and experimental evidence demonstrated that ECD could ameliorate NAFLD by modulating multiple pathways. The optimal combination of the key compounds in ECD was identified by the orthogonal experiment. Results: For lipid homeostasis, ECD suppressed de novo lipogenesis and reduced the cholesterol level by activating the AMPK signaling pathway. Concurrently, ECD enhanced hepatic β-oxidation by inducing PPARα-mediated upregulation of ACOX-1 and CPT-1α. ECD also resolved hepatic insulin resistance by activating the IRS1-Akt-FoxO1 pathway. The combined treatment with 100 μM liquiritin (LQ), 200 μM glycyrrhizic acid (GA) and 200 μM hesperidin (HEN) exhibited the best effect in reducing TG content in NAFLD model cells. Conclusions: ECD exhibited superior activities in activating the AMPK signaling pathway compared to the optimal compound combination. The comparison between the ECD and its key compounds demonstrated the superior synergistic effects of the herbs in ECD. Full article

Momordica charantia L. (Cucurbitaceae) has been widely recognized for its pharmacological potential, although studies on its leaves remain scarce. In this study, the hydroethanolic leaf extract (MCHLE) was chemically characterized by LC–MS/MS, revealing the presence of octopamine, ferulate, vitexin-2-O-rhamnoside, and other bioactive phenolics. Toxicological evaluation in Wistar rats demonstrated that both acute (2000 mg/kg) and repeated oral administration (up to 400 mg/kg for 28 days) caused no clinical or behavioral signs of toxicity. Notably, treatment significantly reduced glucose and cholesterol levels, in addition to attenuating lipid peroxidation and enhancing antioxidant defenses. In vivo, MCHLE inhibited leukocyte and neutrophil infiltration in the LPS-induced peritonitis model, with efficacy comparable to dexamethasone. It also reduced TNF-α secretion and nitric oxide generation in peritoneal fluids. In vitro assays with LPS-stimulated RAW 264.7 macrophages confirmed these effects, showing dose-dependent inhibition of TNF-α, IL-1β, and NO production. Gene expression analysis further demonstrated downregulation of TNF-α and MAPK, with marked suppression of NF-κB transcripts. Collectively, these results suggest that MCHLE exerts anti-inflammatory activity by targeting both mediator release and upstream signaling pathways, while maintaining a favorable safety profile, supporting its potential for further investigation as a promising source of bioactive compounds. Full article

Guava fruit is widely consumed in tropical countries and beyond. The phenolic fraction of guava pulp and processing waste (a single fraction containing seeds, skins, and pulp residues) have been reported to carry in vitro biological activities, acting on biomarkers of metabolic diseases such as type 2 diabetes and obesity (enzymatic inhibition of α-glucosidase and pancreatic lipase), atherosclerosis (mitigation of LDL-cholesterol oxidation), and mutagenesis (suppression of DNA strand scission). However, such bioactivities may be compromised by the exposure of guava phenolics to the harsh conditions found along the human gastrointestinal (GI) tract. To overcome this limitation, guava phenolic extracts were microencapsulated with maltodextrin through freeze-drying. The effect of crude and microencapsulated extracts on biomarkers of metabolic diseases was compared before and after in vitro simulated GI digestion. Moreover, guava waste extracts were tested for their ability to interfere with the intracellular redox status of Caco-2 and HeLa cells incubated with free radicals. Microencapsulation considerably improved the bioaccessibility of guava phenolics across digestion stages, which reflected on the enhancement of most bioactivities measured, with the exception of pancreatic lipase inhibition (both pulp and waste extracts) and LDL oxidative protection (pulp extract). Meanwhile, microencapsulation accentuated intracellular antioxidant activity in Caco-2 cells induced by guava waste extract whereas a prooxidant effect in HeLa cells was intensified. This highlights the selectivity of the same extract toward different cell lines. Overall, microencapsulation was demonstrated as a promising tool for protecting and even enhancing the nutraceutical power of guava phenolics, reinforcing their relevance in the development of functional foods and nutraceutical products. Full article

A hypercaloric diet is associated with oxidative stress and the dysfunction of ATP-Binding Cassette transporter A1 (ABCA1), a key element in high-density lipoprotein (HDL) biogenesis and reverse cholesterol transport. Nicotinamide (NAM) presents antioxidant properties, which may contribute to maintaining lipid metabolism. Therefore, we aimed to evaluate the effect of NAM on HDL-cholesterol (HDL-C) level, oxidative stress markers, and the gene expression and protein levels of ABCA1 in Sprague-Dawley rats fed a hypercaloric diet. Forty male rats were divided into five groups: one group received a standard diet, and the remaining groups received a single high-fat, high-fructose diet (HFDF). Three of the HFDF groups received NAM treatment (5, 10, and 15 mM) in drinking water for 16 weeks (5 h/day). While HDL-C and oxidative stress were measured in serum samples, oxidative stress markers, and the gene expression and protein levels of ABCA1 were quantified in liver samples. The HDL-C level altered by the HFDF was improved by treatment with NAM. Furthermore, NAM reduces systemic lipid peroxidation levels and enhances the hepatic antioxidant response affected by the HFDF. In addition, NAM modulates the hepatic ABCA1 gene expression and protein level, altered by the HFDF. Our results suggest that NAM may modify the serum HDL-C level by an improvement of antioxidant response, and a possible modulation of the hepatic ABCA1 gene and protein expression. Further metabolic and molecular studies are needed to support the potential therapeutic role of NAM to prevent or treat lipid alterations promoted by a hypercaloric diet. Full article

Bile acids, the primary components of bile, are cholesterol-derived molecules synthesized in the liver and secreted to the small intestine. Besides their primary digestive roles, bile acids have antimicrobial properties and serve as an environmental cue for intestinal pathogens, modulating the expression of virulence factors, e.g., toxins and effector proteins. Whereas timely recognition and neutralization of pathogenic toxin effectors by the host is critical, our understanding of the effects of bile on their structure and function is limited. In this work, we found that bile effectively protected cultured IEC-18 enterocytes from the mixture of Aeromonas hydrophila secreted toxins, containing hemolysin, aerolysin, and RtxA (MARTX). To explore whether these effects have broad specificity, we employed biochemical and biophysical techniques to test the in vitro effects of bile and bile acids on several effector domains of MARTX and VgrG toxins from Vibrio cholerae and Aeromonas hydrophila, and catalytic domains of TcdA and TcdB toxins from Clostridioides difficile. Bile compromised the structural integrity of the tested effectors to various degrees in a protein charge-dependent manner. Bile and bile acids promoted exposure of hydrophobic residues and the unfolding of most, but not all, of the tested effectors, facilitating their precipitation and cleavage by chymotrypsin. Bile also inhibited specific activities of the tested effector enzymes, partially due to imposed oxidation of their catalytic residues. To summarize, this work validated bile as a non-proteinaceous factor of innate immunity, capable of compromising the structural integrity and function of the effector domains of various bacterial toxins. Full article

Previous studies have demonstrated that high-yielding dairy cows experience endoplasmic reticulum (ER) stress in the liver during early lactation. To date, most insights into the role of ER stress in metabolism and disease pathophysiology have been derived from rodent and human models. In dairy cattle, however, the specific impact of ER stress on metabolic pathways and its contribution to disease development remain insufficiently characterized. The objective of this study was therefore to investigate the molecular effects of ER stress using a bovine liver cell model (BFH12 cells). ER stress was induced by incubation with Tunicamycin (TM) and Thapsigargin (TG). Molecular responses to ER stress were assessed via a whole-genome array analysis and PCR targeting genes involved in selected metabolic pathways. Incubation with both ER stress inducers resulted in a marked upregulation of genes associated with the unfolded protein response (UPR) within a 4 to 24-h time frame, indicative of the production of robust ER stress in these cells. Unexpectedly, treatment with TM led to a downregulation of numerous genes involved in lipid biosynthesis, including those related to lipogenesis and cholesterol synthesis. Furthermore, incubation with TM and TG induced upregulation of genes involved in fatty acid oxidation and was accompanied by a reduction in intracellular triglyceride concentrations. Genes associated with inflammatory responses were upregulated by both TM and TG, whereas genes encoding antioxidant enzymes were downregulated. Genes involved in ketogenesis did not exhibit a consistent pattern of regulation. Overall, several effects of ER stress previously described in rodent models could not be replicated in this bovine liver cell system. Extrapolating these findings to dairy cows suggests that while ER stress may contribute to hepatic inflammation, it is unlikely to play a significant role in the development of hepatic lipidosis or ketosis. Full article

Background and Objectives: Midlife represents a critical window for the emergence of metabolic risk factors. This study aimed to investigate age- and sex-related changes in lipid profiles, body composition, oxidative stress, and fatty acid content. Materials and Methods: This cross-sectional study included adults grouped by age: <30, 30–39, and 40–49 years. The assessments covered body composition (fat mass, fat distribution, and lean mass), fasting lipids, inflammation markers measurements, and platelet fatty acids evaluation. Results: In total, 169 adults took part in this study (60 men and 109 women), aged 36.30 ± 6.25 years. Fat mass and its regional distribution were higher after age 40, especially in females. In women, fat mass was lower in the thirties and higher again in the forties, while, in men, fat accumulation was progressive. Participants aged 40–49 had a significantly worse metabolic profile than younger individuals. Statistically significant higher total cholesterol, LDL cholesterol, triglycerides, and glucose were shown in the 40–49-years group when compared to younger groups. Malondialdehyde was higher in the 40–49-years vs. 30–39-years group (105.83 vs. 99.72, p = 0.034). In women aged 40–49, a more adverse lipid and glycemic profile was observed compared to younger groups. Platelet fatty acids in the 40–49-years group showed higher polyunsaturated fatty acids and ω6 percentages (12.85% vs. 10.14%, p = 0.046 and 11.44% vs. 8.79%, p = 0.031), including higher linoleic (8.80 ± 5.18 vs. 6.97 ± 5.05, p = 0.045), arachidonic (2.64 ± 2.64 vs. 1.82 ± 1.73, p = 0.030), and docosahexaenoic (0.61 ± 0.86 vs. 0.31 ± 0.49, p = 0.008) acids, when compared to younger groups. Fat mass strongly correlated with insulin resistance, triglycerides, and CRP, and inversely with HDL-C. Conclusions: Significant age-related changes in body composition, metabolic biomarkers, and platelet fatty acid profiles occur after the age of 40, with distinct gender-specific patterns. The fifth decade of life is a transitional period characterized by central adiposity, deteriorating metabolic profiles, and altered fatty acid composition, especially in women. Full article

Ischemic stroke remains a leading cause of mortality and disability, with proinflammatory, metabolic, and oxidative stress-related factors contributing to outcome variability. We conducted a retrospective cross-sectional study of 124 consecutive patients (53 women, 71 men; median age 71 [62–76]) discharged with ICD-10 code I69.3 from the Neurology Department of the Clinical Rehabilitation Hospital in Cluj-Napoca (January 2023–September 2024). Men were younger (median age of 69 vs. 73 years, p-value = 0.010), more frequently smokers (42% vs. 9%, p < 0.001), and alcohol consumers (21% vs. 4%, p-value = 0.007) than women. In contrast, women were more frequently sedentary (68% vs. 49%, p-value = 0.038) and had higher LDL cholesterol (89 vs. 74 mg/dL, p = 0.026) than men. Patients with at least moderate disability (n = 84) presented higher levels of C-Reactive Protein (CRP), 1.4 vs. 1.1 mg/L, p-value = 0.027) and more frequently low HDL cholesterol serum levels (29.8% vs. 7.5%, p-value = 0.006) compared to those with minor disability. In multivariable regression, low HDL was the sole independent predictor of disability severity (OR = 4.58, 95% CI 1.21–17.41; AUC = 0.78, sensitivity = 88%, specificity = 42%), while CRP and age did not retain the significance obtained in univariable regression. Our findings highlight sex-specific risk profiles and underline the contribution of proinflammatory, metabolic, and oxidative pathways to ischemic stroke severity, underscoring the need for prospective validation in larger cohorts. Full article

Salinity is a pivotal environmental factor that significantly influences the survival, growth, development, and reproduction of aquatic organisms. However, the characteristics of serum metabolites and their mechanistic roles in mediating the response of grass carp (Ctenopharyngodon idellus) to long-term salinity stress remain incompletely understood. Therefore, the present study exposed grass carp to different salinity levels (0, 4, and 8 g/L) for 60 days to evaluate the associated physiological alterations and metabolic responses. The results revealed that high salinity (8 g/L) significantly suppressed growth performance (p < 0.05), whereas low salinity (4 g/L) caused no significant reduction in growth or survival. Physiological analyses indicated that fish in the 8 g/L group exhibited markedly reduced levels of lactic acid and total protein, along with elevated concentrations of total cholesterol, triglycerides, glucose, and glutamic-oxaloacetic transaminase (p < 0.05). Serum ion homeostasis was also disrupted under high salinity, characterized by increased Ca²⁺, Na⁺, and Cl⁻ levels and decreased Mg²⁺ (p < 0.05). Furthermore, oxidative stress was evident in the high-salinity group through heightened activities of antioxidant enzymes (SOD, CAT, GPx), accumulation of oxidative damage markers (protein carbonyl, 8-OHdG) (p < 0.05). Metabolomic profiling identified 367 and 403 significantly altered metabolites in the 4 g/L and 8 g/L groups, respectively, primarily belonging to lipids and lipid-like molecules along with organic acids and derivatives. KEGG enrichment analysis revealed that these differential metabolites were chiefly involved in amino acid biosynthesis, glycerophospholipid metabolism, biosynthesis of unsaturated fatty acids, and glycine, serine, and threonine metabolism. Trend analysis further uncovered eight distinct expression patterns of metabolites across salinity gradients. These results provide novel insights into the metabolic adaptations of grass carp to salinity stress, demonstrating that high salinity induces oxidative stress, disrupts ion regulation, and drives extensive metabolic reprogramming. The study offers valuable theoretical support for improving salinity tolerance management in aquaculture and informs the selective breeding of salt-tolerant fish strains. Full article

Grape pomace, a polyphenol-rich byproduct of wine production, represents a promising source of bioactive compounds for managing diabetes and its complications. This study evaluates the effect of a novel grape pomace extract on carbohydrate and lipid metabolism, and oxidative stress in type 1 diabetes mellitus. Diabetes was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin. Starting on day 14 post-induction, rats received oral grape pomace extract at a dose of 45 mg of polyphenols/kg body weight daily for 14 days. On day 28 of the experiment, blood plasma was collected. One-way ANOVA with post hoc testing revealed a hypoglycemic effect of grape pomace extract, as evidenced by reduced fasting blood glucose and improved postprandial glycemic responses. The extract also ameliorated dyslipidemia, lowering total cholesterol and triglycerides while increasing high-density lipoprotein levels and paraoxonase activity in plasma of diabetic rats. Antioxidant defenses were enhanced, as indicated by elevated superoxide dismutase, catalase, and glutathione peroxidase activities, along with reduced protein carbonyls, TBA-reactive products, and lipofuscin in blood plasma following extract administration. These findings demonstrate the metabolic and antioxidant potential of grape pomace polyphenols, although further investigations are needed to elucidate the underlying molecular mechanisms. Full article

People living with the human immunodeficiency virus (PLWH) are continually subjected to challenges involving the development of non-acquired immunodeficiency syndrome (AIDS)-related comorbidities despite the effectiveness of highly active antiretroviral therapy (HAART). Exacerbated oxidative stress, which is intrinsically linked to chronic inflammation, is implicated in non-AIDS comorbidities, including the increased risk of cardiovascular disease (CVD) observed in PLWH. Here, we review evidence on the potential pathological implications of myeloperoxidase (MPO), a leukocyte-derived enzyme and a key mediator of oxidative stress and inflammation, in driving CVD-related complications in PLWH. A systematic review approach was taken to identify relevant clinical studies through searches of Cochrane Libraries, PubMed, Web of Science, ScienceDirect, and Google Scholar, up to the 30 June 2025. The summarized data appraised clinical studies (n = 14) on adults (n = 1445) with a mean age of 45 years reporting on the association between MPO and enhanced lipid peroxidation marked by elevated concentrations of oxidized low-density lipoprotein cholesterol (oxLDL-C) in PLWH. Such results were consistent with elevated inflammatory markers, including high sensitivity C-reactive protein (hsCRP), which was also linked with endothelial dysfunction. There is a lack of evidence linking the duration of HAART to MPO levels or an increased risk of CVD. However, there is room to explore whether enhanced levels of oxLDL-C, in association with sustained MPO activation, could drive CVD risk in PLWH. The present review provides essential information on the pathological relevance of MPO in endothelial dysfunction and CVD risk in PLWH. Full article

The increasing demand for sustainable and cost-effective animal feed alternatives has stimulated the use of agro-industrial by-products in poultry diets. This study evaluated the effects of tambaqui (Colossoma macropomum) residual oil (TRO), derived from aquaculture waste, on productive performance, physiological responses, and egg quality in commercial laying hens. A total of 144 Hisex Brown hens were assigned to diets containing 0%, 1.5%, 3.0%, or 4.5% TRO for 63 days. While TRO inclusion did not affect overall productivity, moderate levels (1.5% and 3.0%) improved egg weight, yolk pigmentation, and internal quality (Haugh unit). Hematological and biochemical parameters indicated metabolic adaptations, with increased cholesterol and decreased triglycerides in treated groups. The yolk fatty acid profile revealed higher omega-3 content with TRO inclusion, but lipid oxidation (TBARS) also increased, especially at higher levels. Sensory evaluation showed reduced aroma and flavor acceptability in eggs from hens fed 3.0% and 4.5% TRO. These findings suggest that moderate TRO inclusion can enhance egg nutritional value and support sustainable aquaculture waste reuse, though excessive levels may compromise product acceptability. Optimal inclusion levels should be further explored to balance metabolic benefits, oxidative stability, and consumer preferences. Full article