Lipids in Health and Disease最新文献

Background: Bladder cancer is one of the most common malignancies of the urinary system. Despite significant advances in diagnosis and treatment, the compromised therapeutic effect of chemotherapeutic agents, such as Oxaliplatin (OXA), remains a major clinical challenge. Thus, a combination therapy is required to enhance the OXA's therapeutic effectiveness and improve patient outcomes.

Methods: The thin film hydration method was used to prepare the liposomes. Drug encapsulation efficiency and loading capacity were determined to investigate the advantages of the SRT3025-loaded cell membrane hybrid liposomes (3025@ML). Bladder cancer cell lines T24 and 5637 were cultured in McCoy's 5 A and RPMI 1640 medium, respectively. The Cell Counting Kit-8 assay was used to determine the cell viability by treating cells with a medium containing either the vehicle solution (control), the cell membrane hybrid liposomes (ML), 3025@ML, or compound 3 K. The antiproliferative activities were investigated after treating cells with OXA + 3025@ML and compound 3 K + OXA. Cell death and apoptosis were quantified by trypan blue and Annexin V-APC/PI apoptosis assay after treating cells with control, OXA, OXA + 3025@ML, and 3025@ML. Western blot analysis was performed after treating cells with 3025@ML, OXA, 3 K, 3025@ML + OXA, and 3 K + OXA to determine the protein levels of pyruvate kinase M2 (PKM2) and fatty acid synthase (FASN), etc. RESULTS: The present study demonstrated that 3025@ML enhances the chemotherapeutic effect of OXA. 3025@ML + OXA treated T24 and 5637 cells showed that combination therapy significantly reduced cell viability and increased cell death rate. Flow cytometry analysis showed that the combination of 3025@ML and OXA significantly increased the percentage of apoptotic cells in T24 cells. 3025@ML and compound 3 K reduced the levels of FASN in T24 and 5637 cells and increased the anti-tumor activity of OXA. Mechanistic studies showed that 3025@ML inhibited the PI3K/AKT/mTOR signaling pathway and reduced the expression of key metabolic regulators PKM2 and FASN. Furthermore, this study demonstrated that targeting lipid metabolism and inhibiting FASN can effectively overcome the compromised therapeutic effect of OXA.

Conclusion: The study demonstrated that 3025@ML significantly enhances the anti-tumor activity of OXA. This novel drug delivery system inhibits key metabolic pathways, which increase DNA damage and tumor cell apoptosis. The results indicate that 3025@ML is a promising therapeutic strategy for overcoming OXA's compromised therapeutic effect and potentially improving cancer treatment outcomes.

Background: This study aimed to investigate the association between relative fat mass (RFM) and asthma, as well as to explore the mediating role of Systemic Immune-Inflammation Index (SII) and Systemic Inflammation Response Index (SIRI).

Methods: This cross-sectional study utilized data from the National Health and Nutrition Examination Survey from 2007 to 2018. Associations between RFM and asthma were tested using multivariable logistic regressions, restricted cubic splines, subgroup analyses, and interaction tests, with mediation analysis for SII and SIRI. The inflection point was determined by the two-piecewise linear regression. Sensitivity analysis and propensity score matching (PSM) was applied to validate the stability of the associations.

Results: Higher RFM was positively associated with asthma, with an inflection point at 34.08. Below this threshold, each unit increase in RFM was positively associated with a 2% increase in the odds of asthma (Odds ratio (OR) 1.02, 95% Confidence interval (CI): 1.00-1.03), while above it, the association strengthened, with a 5% increase in the odds per unit (OR 1.05, 95% CI: 1.04-1.07). The association was consistent across subgroups. The association between RFM and asthma is stronger in current asthma patients than in ever had asthma ones. Mediation analyses showed that SII and SIRI partially mediated 7.48% and 3.88% of the RFM-asthma association, respectively. The findings remained robust after sensitivity analyses and adjusting for confounding bias using PSM.

Conclusions: RFM is positively associated with the prevalence of asthma in the U.S., particularly among individuals with current asthma, with systemic inflammation partially mediating this relationship.

Lipid metabolism in cancer is characterized by dysregulated lipid regulation and utilization, critical for promoting tumor growth, survival, and resistance to therapy. Pancreatic cancer (PC) is a highly aggressive malignancy of the gastrointestinal tract that has a dismal 5-year survival rate of less than 10%. Given the essential function of the pancreas in digestion, cancer progression severely disrupts its function. Standard treatments for PC such as surgical resection, chemotherapy, and radiotherapy. However, these therapies often face significant challenges, including biochemical recurrence and drug resistance.Given these limitations, new therapeutic approaches are being developed to target tumor metabolism. Dysregulation of cholesterol biosynthesis and alterations in fatty acids (FAs), such as palmitate, stearate, omega-3, and omega-6, have been observed in pancreatic cancer. These lipids serve as energy sources, signaling molecules, and essential components of cell membranes. Their accumulation fosters an immunosuppressive tumor microenvironment that supports cancer cell proliferation and metastasis.Moreover, lipid metabolism dysregulation within immune cells, particularly T cells, impairs immune surveillance and weakens the body's defenses against cancer. Abnormal lipid metabolism also contributes to drug resistance in PC. Despite these challenges, targeting lipid metabolism may offer a promising therapeutic strategy. By enhancing lipid peroxidation, the induction of ferroptosis-a form of regulated cell death-could impair the survival of PC cells and hinder disease progression.

Background: The connection between lipid-related obesity indices and severe headache or migraine in young and middle-aged people aged 20-60 remains ambiguous, and there are gaps in the discriminative ability of different indicators for severe headaches or migraines. Consequently, we set out to look into this association utilizing National Health and Nutrition Examination Survey (NHANES) data from 1999 to 2004.

Methods: After the values of waist-to-height ratio (WHtR), body-mass index (BMI), body roundness index (BRI), visceral adiposity index (VAI), lipid accumulation product (LAP), triglyceride glucose index (TyG), cardiac metabolism index (CMI), waist triglyceride Index (WTI), conicity index (CI) and weight-adjusted waist index (WWI) were estimated, with minimal sufficient adjustment for confounders determined by directed acyclic graph (DAG), weighted univariable and multivariable logistic regression analyses were carried out to ascertain the relationship between them and migraine. Stratified analysis and cross-effect analysis were implemented to examine the variability of intergroup correlations. Restricted cubic splines (RCS) and receiver operating characteristic (ROC) were then employed to examine nonliner relationships and its discriminatory ability for severe headache or migraine, respectively.

Results: 3354 United States adults were involved in our study, of whom 839 (25.01%) had severe headache or migraine. After adjusting for relevant covariables, WHtR, BRI, BMI, LAP, WTI and VAI were all associated with migraine and WHtR (OR = 6.38, 95% CI: 2.25,18.09, P < 0.01) showed the best predictive ability. Additionally, WHtR, BMI, and BRI demonstrated linear dose-response relationships with the prevalence of migraine (all P_overall < 0.05, P_{non-linearity} > 0.05).

Conclusions: Among those ten lipid-related obesity indicators evaluated in the study, WHtR, BMI and BRI demonstrated linear positive dose-response relationships with the prevalence of migraine in young and middle-aged individuals within the United States and WHtR showed the best predictive ability. Our study can provide important insight into epidemiological research and comprehensive management of obese patients with migraine.

Background: Insulin resistance (IR) and metabolic syndrome (MetS) are significant global health challenges that increase the risk of various chronic diseases. The lymphocyte-to-high-density lipoprotein cholesterol ratio (LHR) has emerged as a novel inflammatory metabolic marker. The present study focused on evaluating the association between the LHR and both IR and MetS.

Methods: We analyzed data from 14,779 adults aged ≥ 20 years from the National Health and Nutrition Examination Survey (2007-2018). To investigate the relationship between LHR and both IR and MetS, we conducted multivariable logistic regression analyses. The reliability of the results was validated through both stratified and sensitivity analyses. Furthermore, we thoroughly examined possible nonlinear associations by implementing a restricted cubic spline in conjunction with a threshold effect analysis.

Results: Compared to the lowest LHR quartile, individuals in the highest quartile indicated significantly increased prevalence of IR (odds ratio = 3.72, 95% confidence intervals: 3.01-4.59) and MetS (odds ratio = 11.38, 95% confidence intervals: 8.85-14.63) in fully adjusted models. Subgroup analyses demonstrated that the association between the LHR and IR remained consistent across all subgroups, with no significant interaction effect observed. However, the association between LHR and MetS was more pronounced in female participants. Restricted cubic spline analyses revealed nonlinear associations between LHR and both IR and MetS. The threshold effect analyses identified inflection points at 0.055 for these non-linear relationships.

Conclusions: An elevated LHR was positively associated with the prevalence of IR and MetS, indicating its promising role in early screening and disease prevention through biological monitoring.

Clinical studies have suggested that tirzepatide may also possess hepatoprotective effects; however, the molecular mechanisms underlying this association remain unclear. In our study, we performed biochemical analyses of serum and histopathological examinations of liver tissue in mice. To preliminarily explore the molecular mechanisms of tirzepatide on metabolic dysfunction-associated fatty liver disease (MAFLD), liquid chromatography-mass spectrometry (LC-MS) was employed for comprehensive metabolomic, lipidomic, and proteomic analyses in MAFLD mice fed a high-fat diet (HFD). The results demonstrated that tirzepatide significantly reduced serum levels of alanine transaminase (ALT) and aspartate transaminase (AST), as well as hepatic triglycerides (TG) and total cholesterol (TC), indicating its efficacy in treating MAFLD. Further findings revealed that tirzepatide reduced fatty acid uptake by downregulating Cd36 and Fabp2/4, as well as enhance the mitochondrial-lysosomal function by upregulating Lamp1/2. In addition, tirzepatide promoted cholesterol efflux and reduced cholesterol reabsorption by upregulating the expression of Hnf4a, Abcg5, and Abcg8. These results suggest that tirzepatide exerts its therapeutic effects on MAFLD by reducing fatty acid uptake, promoting cholesterol excretion, and enhancing mitochondrial-lysosomal function, providing a theoretical basis for a comprehensive understanding of tirzepatide.

Background: The Cardiometabolic Index (CMI) represents a novel anthropometric measurement, which combines characteristics of adiposity and lipids. Since obesity, lipid metabolism, and inflammation may collectively facilitate the occurrence of stroke, we hypothesize that a combination of elevated levels of the CMI and high-sensitivity C-reactive protein (hs-CRP) increases the risk of future stroke among middle-aged and older Chinese adults.

Methods: This study included 8,973 participants aged 45 years or older from the China Longitudinal Study on Health and Retirement (CHARLS), who were stroke-free and underwent baseline evaluations between 2011 and 2012, with followed-up at 2013, 2015 and 2018. The exposures were CMI and hs-CRP, with CMI calculated using the formula [waist circumference (cm)/height (cm)] × [triglycerides (mmol/L)/HDL-C (mmol/L)]. The primary outcome was the occurrence of new-onset stroke events. Cox proportional hazards models and restricted cubic spline (RCS) analyses were conducted to examine the associations between CMI, hs-CRP, and their combined effects on stroke risk. Sensitivity analysis was further implemented to verify the robustness of the results.

Results: A total of 629 participants (7.01%) suffered new-onset stroke during follow-up. The risk for stroke increased with each elevating quartile of baseline CMI levels, with adjusted HRs and 95% CIs being 1.27 (0.98-1.66), 1.41 (1.08-1.83), and 1.46 (1.09-1.96) for Q2, Q3, and Q4, respectively. Moreover, participants with levels of hs-CRP ≥ 2 mg/L also had significantly higher stroke incidence compared to those with CRP levels < 2 mg/L (adjusted HR 1.24, 95% CI 1.05-1.47, p = 0.012). Specifically, those concurrently with the highest CMI quartile and levels of hs-CRP ≥ 2 mg/L had the highest risk of stroke (adjusted HR 1.90, 95% CI 1.32-2.74). The subsequent sensitivity analyses yielded consistent results, further corroborating the initial findings.

Conclusions: The combination of CMI and hs-CRP exhibited a significant association with stroke risk among middle-aged and older Chinese adults, highlighting the importance of joint assessments of these biomarkers for refining risk stratification and enhancing primary prevention strategies for stroke.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is an asymptomatic, multifaceted condition often associated with various risk factors, including fatigue, obesity, insulin resistance, metabolic syndrome, and sleep apnea. The increasing burden of MASLD underscores the critical need for early diagnosis and effective therapies. Owing to the lack of efficient therapies for MASLD, early diagnosis is crucial. Consequently, noninvasive biomarkers and imaging techniques are essential for analyzing disease risk and play a pivotal role in the global diagnostic process. The use of extracellular vesicles has emerged as promising for early diagnosis and therapy of various liver ailments. Herein, a comprehensive summary of the current diagnostic modalities for MASLD is presented, highlighting their advantages and limitations while exploring the potential of extracellular vesicles (EVs) as innovative diagnostic and therapeutic tools for MASLD. With this aim, this review emphasizes an in-depth understanding of the origin of EVs and the pathophysiological alterations of these ectosomes and exosomes in various liver diseases. This review also explores the therapeutic potential of EVs as key components in the future management of liver disease. The dual role of EVs as biomarkers and their therapeutic utility in MASLD essentially highlights their clinical integration to improve MASLD diagnosis and treatment. While EV-based therapies are still in their early stages of development and require substantial research to increase their therapeutic value before they can be used clinically, the diagnostic application of EVs has been extensively explored. Moving forward, developing diagnostic devices leveraging EVs will be crucial in advancing MASLD diagnosis. Thus, the literature summarized provides suitable grounds for clinicians and researchers to explore EVs for devising diagnostic and treatment strategies for MASLD.

Fatty acid metabolism, exercise, and insulin action play critical roles in maintaining vascular health, especially relevant in metabolic disorders such as obesity, type 2 diabetes, and cardiovascular disease. Insulin, a vasoactive hormone, induces arterial vasodilation throughout the arterial tree, increasing arterial compliance and enhancing tissue perfusion. These effects, however, are impaired in individuals with obesity and type 2 diabetes, and evidence suggests that vascular insulin resistance contributes to the pathogenesis of type 2 diabetes and its cardiovascular complications. Elevated plasma levels of free fatty acids in people with insulin resistance engender vascular inflammation, endothelial dysfunction, and vascular insulin resistance. Importantly, these effects are both functionally and structurally dependent, with saturated fatty acids as the primary culprits, while polyunsaturated fatty acids may support insulin sensitivity and endothelial function. Exercise enhances fatty acid oxidation, reduces circulating free fatty acids, and improves insulin sensitivity, thereby mitigating lipotoxicity and promoting endothelial function. Additionally, exercise induces beneficial vascular adaptations. This review examines the complex interplay among fatty acid metabolism, exercise training-induced vascular adaptations, and insulin-mediated vascular changes, highlighting their collective impact on vascular health and underlying mechanisms in both healthy and insulin-resistant states. It also explores the therapeutic potential of targeted exercise prescriptions and fatty acid-focused dietary strategies for enhancing vascular health, emphasizing tailored interventions to maximize metabolic benefits. Future research should investigate the pathways linking fatty acid metabolism to vascular insulin resistance, with a focus on how exercise and dietary modifications can be personalized to enhance vascular insulin sensitivity, optimize vascular health, and reduce the risks of type 2 diabetes and associated cardiovascular complications.