Biomarkers Of Lipid Metabolism Research Articles

#1613 Gadolinium and gadoteric acid's short-term impact on kidney function and lipid profile

Abstract Background and Aims Concerns regarding the safety of gadolinium-based contrast agents (GBCA), which are often employed in medical imaging, have been raised in light of reports of free gadolinium's [Gd (III)] cytotoxicity. It appears that GBCAs having macrocyclic structures, like gadoteric acid (Gd-DOTA), are more stable and less toxic. Previous work from our group found that Gd (III) promotes inflammation and fibrosis in proximal tubular cells cultures. A disturbance of lipid metabolism was also reported, accompanied by the build-up of lipid droplets, lipid peroxidation and the overexpression of genes linked to lipogenesis and lipolysis. The aim of this study was to evaluate the short-term effects of Gd (III) and of Gd-DOTA on renal function and lipid metabolism biomarkers, using an animal model. Method Male Wistar rats were exposed to a single dose of Gd (III) or Gd-DOTA (groups A and B, respectively); a control group was also included (C). Blood was collected after 48h of exposure to compounds. We evaluated circulating levels of renal function biomarkers—creatinine and cystatin—using a routine automated assay and ELISA, respectively. The lipid profile was also determined including triglycerides (TG), total cholesterol, HDL-cholesterol, LDL-cholesterol, and oxidized LDL (oxLDL) levels. Results Gd (III) group (A) presented significantly higher circulating cholesterol (P=0.006) and LDL-cholesterol (P<0.001) and lower TG (P<0.001) levels than the control group (C); a non-significant increment in cystatin was also observed for group A. The Gd-DOTA group (B) only presented lower TG levels (P=0.002) compared to the control group (C), being similar to those presented by group A. Both exposed groups (A and B) presented non-significantly higher oxLDL levels compared to the control group. Conclusion Single exposition to free Gd (III) induced prompt changes in lipid profile, with little short-term influence in traditional kidney biomarkers. The exposition to Gd-DOTA was associated with lower disturbance in lipids and lipoproteins (only lower TG levels) and imperceptible renal changes. Despite the significantly safer profile for Gd-DOTA, further studies are necessary, testing different biomarkers, to clarify the short-term, and even the long-term impacts, of these molecules. Acknowledgements This work was financed by FCT through the project 2022.08400.PTDC; FCT, in the scope of the project UIDP/04378/2020 and UIDB/04378/2020 of the Research Unit on Applied Molecular Biosciences—UCIBIO and the project LA/P/0140/2020 of the Associate Laboratory Institute for Health and Bioeconomy—i4HB.

The Influence of a High-Cholesterol Diet and Forced Training on Lipid Metabolism and Intestinal Microbiota in Male Wistar Rats.

Adequate experimental animal models play an important role in an objective assessment of the effectiveness of medicines and functional foods enriched with biologically active substances. The aim of our study was a comparative assessment of the effect of consumption of 1 or 2% cholesterol with and without regular (two times a week), moderate running exercise on the main biomarkers of lipid and cholesterol metabolism, as well as the intestinal microbiota of male Wistar rats. In experimental rats, a response of 39 indicators (body weight, food consumption, serum biomarkers, liver composition, and changes in intestinal microbiota) was revealed. Total serum cholesterol level increased 1.8 times in animals consuming cholesterol with a simultaneous increase in low-density lipoprotein cholesterol (2 times) and decrease in high-density lipoprotein cholesterol (1.3 times) levels compared to the control animals. These animals had 1.3 times increased liver weight, almost 5 times increased triglycerides level, and more than 6 times increased cholesterol content. There was a tendency towards a decrease in triglycerides levels against the background of running exercise. The consumption of cholesterol led to a predominance of the Bacteroides family, due to a decrease in F. prausnitzii (1.2 times) and bifidobacteria (1.3 times), as well as an increase in Escherichia family (1.2 times). The running exercise did not lead to the complete normalization of microbiota.

Abstract PO5-02-08: Prognostic value of serum lipid levels in breast cancer patients who received neoadjuvant chemotherapy: A retrospective exploratory analysis of the prospective cohort

Abstract 【Background】 Lipid metabolism is one of the most conspicuous metabolic changes in malignant tumors. Previous studies confirmed that higher levels of “adverse lipids” might lead to poor outcomes and lipid-lowering drugs could act as a protective role in improving the prognosis of breast cancer patients. Nevertheless, few studies have clarified the impact of serum lipid levels and their changes on the tumor prognosis. Particularly for breast cancer patients treated with neoadjuvant chemotherapy, little has been studied whether their lipid levels or changes during neoadjuvant chemotherapy can serve as a valid prognostic factor. 【Methods】This study enrolled patients who received surgical treatment after neoadjuvant chemotherapy in Renji Hospital from March 2016 to December 2020. Patients were included if they were female aged 18 years or older; had pathologically confirmed unilateral invasive breast cancer; had tumor of at least 2cm in size without distant metastasis (T1-4, N0-3, M0); and underwent radical surgery for breast cancer successfully after neoadjuvant chemotherapy. We retrospectively gathered the baseline clinicopathological information and lipid metabolism-related biomarkers from electronic medical records. The study endpoints were disease free survival (DFS), overall survival (OS), relapse free survival (RFS), distance recurrence free survival (DRFS), and local recurrence free survival (LRFS). The prognostic value of each lipid levels and their variation levels were systematically evaluated and the importance of lipid biomarkers were ranked by Random Forest. 【Results】 The baseline clinicopathological information and lipid metabolism biomarkers were available from 200 eligible patients. As of the last follow-up in March 2023, 11 patients died, 24 experienced DFS events and 20 underwent RFS events. It showed no significant correlations of lipid levels before (baseline) and after (preoperative) neoadjuvant chemotherapy with any survival outcome. However, we found that the relative increase of low-density lipoprotein (LDL) led to poorer DFS (P=0.003), RFS (P=0.01), DRFS (P=0.01), and LRFS (P=0.0039), meanwhile the relative increase of total cholesterol (TC) and non-high-density lipoprotein (NHDL) during neoadjuvant period was significantly related to the worse prognosis (TC, DFS P=0.0084; NHDL, DFS P=0.031, RFS P=0.009) as well. After adjusted by multiple factors, the adverse impacts of increasing TC (DFS P=0.005; RFS P=0.026), LDL (DFS P=0.004; RFS P=0.006) and NHDL (DFS P=0.032; RFS P=0.014) on DFS or RFS were still maintained. The results of Random Forest revealed that LDL changes and Body Mass Index (BMI) ranked higher in terms of predicting survival outcomes. Based on these data, BMI >25.4 kg/m2 or LDL elevation >0.54 mmol/L were defined as High-risk Lipid Metabolism (HLM), while BMI ≤ 25.4 kg/m2 and LDL elevation ≤ 0.54 mmol/L were regarded as Low-risk Lipid Metabolism (LLM). Compared to LLM, HLM had a worse OS (P=0.026), DFS (P=0.0011) and RFS (P=0.0011). 【Conclusion】Our study demonstrated that the relative elevation of LDL, TC and NHDL levels during neoadjuvant chemotherapy is an independent prognostic risk factor for breast cancer patients. It was also the first time to propose the concept of high-risk lipid metabolism (HLM). 【keywords】Breast cancer, Lipid metabolism, Low-density lipoprotein (LDL), Body Mass Index (BMI), Prognosis. Citation Format: Xinru Chen, Wenjin Yin, Yingying Zhao, Jinsong Lu. Prognostic value of serum lipid levels in breast cancer patients who received neoadjuvant chemotherapy: A retrospective exploratory analysis of the prospective cohort [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-08.

Association of Ultraprocessed Food Consumption with Risk of Cardiovascular Disease Among Individuals with Type 2 Diabetes: Findings from the UK Biobank.

Among patients with diabetes, who have modified nutritional behavior and a higher risk of cardiovascular disease (CVD), the influence of ultraprocessed foods (UPFs) on CVD remains unknown. The study aims to evaluate the association between UPF intake and the risk of CVD among individuals with type 2 diabetes (T2D) and further examine the potential biological pathways linking the association. This study includes 5405 participants with T2D who provided at least one 24-h dietary recall from the UK Biobank study. In the fully adjusted models, a 10% increase in the proportion of UPFs is associated with higher hazards of overall CVD (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.04, 1.15), coronary heart disease (HR: 1.10; 95% CI: 1.04, 1.16), heart failure (HR: 1.14; 95% CI: 1.05, 1.25), but not stroke (HR: 1.01; 95% CI: 0.90, 1.12). Cystatin C, high-density lipoprotein cholesterol (HDL-C), apolipoprotein A, C-reactive protein, and body mass index collectively explain 26.9% (12.8%, 48.5%) of the association between UPF intake and the risk of overall CVD. Higher UPF intakes are associated with increased hazards of CVD among individuals with T2D, and the association is partly mediated through worsening biomarkers of renal function, lipid metabolism, inflammation, and body weight.

Biomarkers of lipid metabolism in gastric cancer: a case control study

BackgroundThe aim of this study was to explore the correlation between biomarkers of lipid metabolism and gastric cancer.Methods1120 gastric cancer patients and 1134 health examiners enrolled in this study. The clinic data and serum lipid level, including Total cholesterol (TC), Triglyceride (TG), Low-density lipoprotein cholesterol (LDL-C) and High-density lipoprotein cholesterol (HDL-C), were collected.ResultsSerum TG and LDL-C levels in patients with gastric cancer were higher than those in the control group. HDL-C levels were lower than the control group (P < 0.05). HDL-C and LDL-C were significantly correlated with the risk of gastric cancer. Concentrating on clinicopathological features, increased TG was more frequently in male patients with distal gastric cancer, N0 stage and early TNM stage. Increased TC was more frequently in early T, N and TNM stage. Decreased HDL-C was more common in distal location and low-undifferentiated gastric cancer. LDL-C elevation was more common in distal gastric cancer and early T stage.ConclusionsThe serum lipid level of gastric cancer patients was higher than healthy controls. HDL-C and LDL-C abnormal correlated with gastric cancer risk. However, as the progresses of gastric cancer, poor patient intake, increased tumor consumption, and continuous declining in nutritional status, the levels of TC and TG gradually decreased in advanced gastric cancer.

Metabolic Profile and Long-Term Risk of Depression, Anxiety, and Stress-Related Disorders

Biomarkers of lipid, apolipoprotein, and carbohydrate metabolism have been previously suggested to be associated with the risk for depression, anxiety, and stress-related disorders, but results are inconsistent. To examine whether the biomarkers of carbohydrate, lipid, and apolipoprotein metabolism are associated with the risk of depression, anxiety, and stress-related disorders. This population-based cohort study with longitudinal data collection assessed 211 200 participants from the Apolipoprotein-Related Mortality Risk (AMORIS) cohort who underwent occupational health screening between January 1, 1985, and December 31, 1996, mainly in the Stockholm region in Sweden. Statistical analysis was performed during 2022 to 2023. Lipid, apolipoprotein, and carbohydrate biomarkers measured in blood. The associations between biomarker levels and the risk of developing depression, anxiety, and stress-related disorders through the end of 2020 were examined using Cox proportional hazards regression models. In addition, nested case-control analyses were conducted within the cohort, including all incident cases of depression, anxiety, and stress-related disorders, and up to 10 control individuals per case who were individually matched to the case by year of birth, sex, and year of enrollment to the AMORIS cohort, using incidence density sampling. Population trajectories were used to illustrate the temporal trends in biomarker levels for cases and controls. A total of 211 200 individuals (mean [SD] age at first biomarker measurement, 42.1 [12.6] years; 122 535 [58.0%] male; 188 895 [89.4%] born in Sweden) participated in the study. During a mean (SD) follow-up of 21.0 (6.7) years, a total of 16 256 individuals were diagnosed with depression, anxiety, or stress-related disorders. High levels of glucose (hazard ratio [HR], 1.30; 95% CI, 1.20-1.41) and triglycerides (HR, 1.15; 95% CI, 1.10-1.20) were associated with an increased subsequent risk of all tested psychiatric disorders, whereas high levels of high-density lipoprotein (HR, 0.88; 95% CI, 0.80-0.97) were associated with a reduced risk. These results were similar for male and female participants as well as for all tested disorders. The nested case-control analyses demonstrated that patients with depression, anxiety, or stress-related disorders had higher levels of glucose, triglycerides, and total cholesterol during the 20 years preceding diagnosis, as well as higher levels of apolipoprotein A-I and apolipoprotein B during the 10 years preceding diagnosis, compared with control participants. In this cohort study of more than 200 000 participants, high levels of glucose and triglycerides and low levels of high-density lipoprotein were associated with future risk of depression, anxiety, and stress-related disorders. These findings may support closer follow-up of individuals with metabolic dysregulations for the prevention and diagnosis of psychiatric disorders.

Combinatory data-independent acquisition and parallel reaction monitoring method for revealing the lipid metabolism biomarkers of coronary heart disease and its comorbidities.

Disorders of lipid metabolism are a common cause of coronary heart disease (CHD) and its comorbidities. In this study, ultra-performance liquid chromatography-high-resolution mass spectrometry in data-independent acquisition (DIA) mode was applied to collect abundant tandem mass spectrometry data, which provided valuable information for lipid annotation. For the lipid isomers that could not be completely separated by chromatography, parallel reaction monitoring (PRM) mode was used for quantification. A total of 223 plasma lipid metabolites were annotated, and 116 of them were identified for their fatty acyl chain composition and location. In addition, 152 plasma lipids in patients with CHD and its comorbidities were quantitatively analyzed. Multivariate statistical analysis and metabolic pathway analysis demonstrated that glycerophospholipid and sphingolipid metabolism deserved more attention for CHD. This study proposed a method combining DIA and PRM for high-throughput characterization of plasma lipids. The results also improved our understanding of metabolic disorders of CHD and its comorbidities, which can provide valuable suggestions for medical intervention.

Body mass index, lipid profile, and endothelial dysfunction gene polymorphism in women with early-onset and late-onset preeclampsia

The aim: to investigate and analyze clinical parameters, laboratory biomarkers of lipid metabolism and endothelial dysfunction gene polymorphisms in early-onset and late-onset preeclampsia and to identify potential risk factor(s) for the development of early-onset preeclampsia. Materials and methods: a prospective case-control study included 133 women in the second half of pregnancy, including 46 with early-onset (EOP) and 87 with late-onset preeclampsia (LOP) and 34 conditionally healthy pregnant women with an uncomplicated obstetric history and no risk factors for preeclampsia. Concentrations of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides in blood plasma were determined. Genetic polymorphisms of endothelial dysfunction (192 Q→R PON-1, 677 C→ T MTHFR) were studied using allele-specific polymerase chain reaction. Results: Early-onset preeclampsia is associated with an increased relative risk: preterm delivery by 2.08 times (95 % CI 1.48-2.93), operative delivery by 2.2 times (95 % CI 1.46-3.33), early operative delivery by 2.9 times (95 % CI 1.5-5.5), fetal distress during delivery by 3.78 times (95 % CI 1.2-11.9), a low score on the Apgar scale on the 1st minute, less than 6 points, by 2.59 times (95 % CI 1.84-3.66), on the 5th minute – 5.04 times (95 % CI 1.41-18.11), Grade III prematurity – 13.24 times (95 % CI 3.14-55.78) compared to women with late-onset preeclampsia. The study found that overweight was more often observed in patients with EOP (34.8 %) than in those with normal pregnancy (15.9 %) (p=0.02; OR=2.8; 95 % CI 1.03-7.7), obesity (BMI &gt; 30 kg/m2) was more often recorded in those with LOP (33.33 %) than in the control group (3 (6.8 %)) (p=0.02; OR=6.8; 95 % CI 1.9-23.9). Patients in both groups with preeclampsia showed signs of dyslipidemia, but its significance in the development of early-onset or late-onset preeclampsia has not been separately proven. The study found that the number of carriers of MTHFR 677 TT in the group with EOP prevailed over the indicator of C group where there were no carriers of the pathological homozygote 677TT (p&lt;0.05, OR= 20.73 95 % CI 1.16-371.28), and the T allele in the EOP group occurs 1.78 times more often than in the LOP group (p&lt;0.05, OR=2.22; 95 % CI 1.26-3.88) and 2.43 times more often than in the C group (P&lt;0.05, or= 3.15; 95 % CI 1.54-6.45). Conclusions: Factors of early onset of PE include pre-pregnancy, overweight, first pregnancy, a history of preeclampsia, and carrier of the 677T allele of the MTHFR gene

Effect of Combined Oral Contraceptive Pills on Established Biomarkers of Lipid Metabolism: Systematic Review and Meta-Analysis

Effect of Combined Oral Contraceptive Pills on Established Biomarkers of Lipid Metabolism: Systematic Review and Meta-Analysis

Integration of transcriptomics and metabolomics identify biomarkers of aberrant lipid metabolism in ulcerative colitis

BackgroundThe incidence of ulcerative colitis (UC) continues to rise globally, but effective therapeutic targets are still lacking. In recent years, numerous studies have indicated that lipid therapies could offer a novel perspective for UC treatment. Given the absence of prior research utilizing high-throughput data to identify target genes associated with lipid metabolism, we conducted this work. MethodsThe training set for this study was derived from four datasets within the Gene Expression Omnibus (GEO), encompassing a total of 357 UC patients. We employed four machine learning methods (LASSO, SVM, RF, and Boruta) to jointly identify core biomarkers in these patients, whose aberrant expression needed to be validated in independent datasets and in dextrose sulfate sodium salt (DSS)-induced UC mouse models. Regarding metabolomics, we detected abnormal oxidized lipids in the serum of UC mouse using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in conjunction with orthogonal partial least squares-discriminant analysis (OPLS-DA). ResultsPhospholipase A2 Group IIA (PLA2G2A) was first identified as a possible biomarker for UC, with AUC values of 0.810 and 1.000 in the two validation sets, while in animal models the gene showed similarly significant up-regulation in damaged intestinal mucosa. Further analysis of this gene showed that it was positively correlated with 17 immune cell types and histological severity. Additionally, we pioneered the development of a lipid metabolism score in UC research, which outperformed all individual genes in terms of disease diagnostic efficacy (AUC values of 0.980 and 1.000 for the two validation sets, respectively). Finally, the metabolomics study also identified 31 significantly abnormal oxidized lipids, including 12-HHT and DHA. ConclusionsPLA2G2A is a key therapeutic target for UC, and oxidized lipids such as 12-HHT can serve as potential serologic indicators for diagnosis.

Association between organophosphate flame retardant exposure and lipid metabolism: data from the 2013-2014 National Health and Nutrition Examination Survey.

Organophosphate flame retardants (OPFRs) are emerging environmental pollutants that can be detected in water, dust, and biological organisms. Certain OPFRs can disrupt lipid metabolism in animal models and cell lines. However, the effects of OPFRs on human lipid metabolism remain unclear. We included 1,580 participants (≥20 years) from the 2013-2014 National Health and Nutrition Examination Survey (NHANES) to explore the relationship between OPFR exposure and lipid metabolism biomarkers. After adjusting for confounding factors, results showed that one-unit increases in the log levels of diphenyl phosphate (DPhP) (regression coefficient = -5.755; S.E. = 2.289; p = 0.023) and log bis-(1-chloro-2-propyl) phosphate (BCPP) (regression coefficient = -4.637; S.E. = 2.019; p = 0.036) were negatively associated with the levels of total cholesterol (TC) in all participants. One-unit increases in the levels of DPhP (regression coefficient = -2.292; S.E. = 0.802; p = 0.012), log bis (1,3-dichloro-2-propyl) phosphate (BDCPP) (regression coefficient = -2.046; S.E. = 0.825; p = 0.026), and log bis-2-chloroethyl phosphate (BCEP) (regression coefficient = -2.604; S.E. = 0.704; p = 0.002) were negatively associated with the levels of high-density lipoprotein cholesterol (HDL-C). With increasing quartiles of urine BDCPP levels, the mean TC levels significantly decreased in all participants (p value for trend = 0.028), and quartile increases in the levels of DPhP (p value for trend = 0.01), BDCPP (p value for trend = 0.001), and BCEP (p value for trend<0.001) were negatively corelated with HDL-C, with approximately 5.9, 9.9, and 12.5% differences between the upper and lower quartiles. In conclusion, DPhP, BDCPP, and BCEP were negatively related to HDL-C concentration, whereas DPhP and BCPP levels were negatively associated with TC level. Thus, exposure to OPFRs may interfere with lipid metabolism.

Diet with different concentrations of lychee peel flour modulates oxidative stress parameters and antioxidant activity in zebrafish

The agri-food industry generates substantial waste, leading to significant environmental impacts. Lychee (Litchi chinensis Sonnerat), which is rich in bioactive compounds in its peel, pulp, and seeds, offers an opportunity for waste use. This study aimed to evaluate the effects of supplementing a high-carbohydrate diet with varying levels of lychee peel flour on lipid metabolism biomarkers and oxidative stress in a zebrafish (Danio rerio) model. A total of 225 zebrafish, approximately four months old, were divided into five groups: control, high-carbohydrate (HC), HC2%, HC4%, and HC6%. The study did not find significant differences in the growth performance of zebrafish in any group. However, the HC6% group exhibited a significant decrease in glucose and triglyceride levels compared with the HC group. Furthermore, this group showed enhanced activities of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD), along with reduced levels of malondialdehyde (MDA). Increased antioxidant activity was also evidenced by DPPH−, ABTS+, and β-carotene/Linoleic acid assays in the HC6% group. A positive correlation was identified between SOD/CAT activity and in vitro antioxidant assays. These findings suggest that dietary supplementation with 6% lychee peel flour can significantly modulate glucose homeostasis, lipid metabolism, and antioxidant activity in zebrafish.

Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIVRNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF.

Reversal of High Fat Diet-Induced Obesity, Systemic Inflammation, and Astrogliosis by the NLRP3 Inflammasome Inhibitors NT-0249 and NT-0796.

Systemic and cerebral inflammatory responses are implicated in the pathogenesis of obesity and associated metabolic impairment. While the NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome has been linked to obesity-associated inflammation, whether it contributes to the development or maintenance of obesity is unknown. We provide support for a direct role of saturated fatty acids, such as palmitic acid, as NLRP3 activating stimuli in obese states. To investigate whether NLRP3 activation contributes to the pathogenesis of diet-induced obesity (DIO) in mice, we tested two different clinical-stage NLRP3 inflammasome inhibitors. We demonstrate a contributory role of this key inflammasome to established obesity and associated systemic and cerebral inflammation. By comparing their effects to calorie restriction, we aimed to identify specific NLRP3-sensitive mechanisms contributing to obesity-induced inflammation (as opposed to be those regulated by weight loss per se). In addition, a direct comparison of an NLRP3 inhibitor to a glucagon like peptide-1 receptor agonist, semaglutide (Wegovy), in the DIO model allowed an appreciation of the relative efficacy of these two therapeutic strategies on obesity, its associated systemic inflammatory response, and cerebral gliosis. We show that two structurally distinct, NLRP3 inhibitors, NT-0249 and NT-0796, reverse obesity in the DIO mouse model and that brain exposure appears necessary for efficacy. In support of this, we show that DIO-driven hypothalamic glial fibrillary acidic protein expression is blocked by dosing with NT-0249/NT-0796. While matching weight loss driven by semaglutide or calorie restriction, remarkably, NLRP3 inhibition provided enhanced improvements in disease-relevant biomarkers of acute phase response, cardiovascular inflammation, and lipid metabolism. SIGNIFICANCE STATEMENT: Obesity is a global health concern that predisposes individuals to chronic disease such as diabetes and cardiovascular disease at least in part by promoting systemic inflammation. We report that in mice fed a high-fat, obesogenic diet, obesity is reversed by either of two inhibitors of the intracellular inflammatory mediator NLRP3. Furthermore, NLRP3 inhibition reduces both hypothalamic gliosis and circulating biomarkers of cardiovascular disease risk beyond what can be achieved by either the glucagon like peptide-1 agonist semaglutide or calorie restriction alone.

PuRenDan alleviates type 2 diabetes mellitus symptoms by modulating the gut microbiota and its metabolites

Ethnopharmacological relevancePuRenDan (PRD) is a traditional Chinese medicine formula comprising five herbs that have been traditionally used to treat type 2 diabetes mellitus (T2DM). While PRD has been shown to be effective in treating T2DM in clinical and animal studies, the mechanisms by which it works on the gut microbiome and metabolites related to T2DM are not well understood. Aim of the studyThe objective of this study was to partially elucidate the mechanism of PRD in treating T2DM through analyses of the gut microbiota metagenome and metabolome. Materials and methodsSprague-Dawley rats were fed high-fat diets (HFDs) and injected with low-dose streptozotocin (STZ) to replicate T2DM models. Then the therapeutic effects of PRD were evaluated by measuring clinical markers such as blood glucose, insulin resistance (IR), lipid metabolism biomarkers (total cholesterol, low-density lipoprotein, non-esterified fatty acids, and triglycerides), and inflammatory factors (tumor necrosis factor alpha, interleukin-6 [IL-6], interferon gamma, and IL-1β). Colon contents were collected, and metagenomics, combined with ultra-high-performance liquid chromatography quadrupole time-of-flight mass spectrometry metabolic profiling, was performed to evaluate the effects of T2DM and PRD on gut microbiota and its metabolites in rats. Spearman analysis was used to calculate the correlation coefficient among different microbiota, clinical indices, and metabolites. ResultsPRD exhibited significant improvement in blood glucose and IR, and reduced serum levels of lipid metabolism biomarkers and inflammatory factors. Moreover, the diversity and abundance of gut microbiota undergo significant changes in rats with T2DM that PRD was able to reverse. The gut microbiota associated with T2DM including Rickettsiaceae bacterium 4572_127, Psychrobacter pasteurii, Parabacteroides sp. CAG409, and Paludibacter propionicigenes were identified. The gut microbiota most closely related to PRD were Prevotella sp. 10(H), Parabacteroides sp. SN4, Flavobacteriales bacterium, Bacteroides massiliensis, Alistipes indistinctus, and Ruminococcus flavefaciens. Additionally, PRD regulated the levels of gut microbiota metabolites including pantothenic acid, 1-Methylhistamine, and 1-Methylhistidine; these affected metabolites were involved in pantothenate and coenzyme A biosynthesis, histidine metabolism, and secondary bile acid biosynthesis. Correlation analysis illustrated a close relationship among gut microbiota, its metabolites, and T2DM-related indexes. ConclusionOur study provides insights into the gut microbiota and its metabolites of PRD therapy for T2DM. It clarifies the role of gut microbiota and the metabolites in the pathogenesis of T2DM, highlighting the potential of PRD for the treatment of this disease.

Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-β/δ Polymorphisms.

To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-β/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-β/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-β/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. PPAR-γ2 rs1801282 and PPAR-β/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved.

Lipid metabolism-related gene expression in the immune microenvironment predicts prognostic outcomes in renal cell carcinoma.

Rates of renal cell carcinoma (RCC) occurrence and mortality are steadily rising. In an effort to address this issue, the present bioinformatics study was developed with the goal of identifying major lipid metabolism biomarkers and immune infiltration characteristics associated with RCC cases. The Cancer Genome Atlas (TCGA) and E-MTAB-1980 were used to obtain matched clinical and RNA expression data from patients diagnosed with RCC. A LASSO algorithm and multivariate Cox regression analyses were employed to design a prognostic risk model for these patients. The tumor immune microenvironment (TIME) in RCC patients was further interrogated through ESTIMATE, TIMER, and single-cell gene set enrichment analysis (ssGSEA) analyses. Gene Ontology (GO), KEGG, and GSEA enrichment approaches were further employed to gauge the mechanistic basis for the observed results. Differences in gene expression and associated functional changes were then validated through appropriate molecular biology assays. Through the approach detailed above, a risk model based on 8 genes associated with RCC patient overall survival and lipid metabolism was ultimately identified that was capable of aiding in the diagnosis of this cancer type. Poorer prognostic outcomes in the analyzed RCC patients were associated with higher immune scores, lower levels of tumor purity, greater immune cell infiltration, and higher relative immune status. In GO and KEGG enrichment analyses, genes that were differentially expressed between risk groups were primarily related to the immune response and substance metabolism. GSEA analyses additionally revealed that the most enriched factors in the high-risk group included the stable internal environment, peroxisomes, and fatty acid metabolism. Subsequent experimental validation in vitro and in vivo revealed that the most significantly differentially expressed gene identified herein, ALOX5, was capable of suppressing RCC tumor cell proliferation, invasivity, and migration. In summary, a risk model was successfully established that was significantly related to RCC patient prognosis and TIME composition, offering a robust foundation for the development of novel targeted therapeutic agents and individualized treatment regimens. In both immunoassays and functional analyses, dysregulated lipid metabolism was associated with aberrant immunological activity and the reprogramming of fatty acid metabolic activity, contributing to poorer outcomes.

Physical Activity and Cardiovascular Risk Factors in Children from 4 to 9 Years of Age

BackgroundPhysical activity guidelines for children encourage moderate-to-vigorous intensity activities (MVPA); however, some studies have found that only vigorous intensity activities (VPA) might promote health benefits in young children. Thus, the aim of this study is to investigate cross-sectional and 5-year longitudinal associations of VPA and MVPA with cardiovascular disease (CVD) risk factors in childhood using compositional data analysis.ResultsThis study utilized data from the SPINACH study (n = 411). Physical activity was measured with accelerometers at 4- and 9-years of age. CVD risk factors were measured at 9-years of age, and included blood pressure (BP), lipid metabolism, and glucose metabolism biomarkers, as well as a continuous metabolic syndrome risk score (MetS). Cross-sectional and longitudinal linear regression models were built using compositional data analysis standards. Cross-sectionally, reallocating time to VPA from lower-intensity behaviours at 9-years was associated with lower waist circumference (B = − 3.219, P = 0.002), diastolic BP (B = − 1.836, P = 0.036), triglycerides (B = − 0.214, P < 0.001), glucose (B = − 0.189, P = 0.033), insulin (B = − 2.997, P < 0.001), and HOMA-IR (B = − 0.778, P < 0.001). Similarly, reallocating time to VPA at 4-years was associated with lower MetS (B = − 0.831, P = 0.049), waist circumference (B = − 4.211, P = 0.015), systolic BP (B = − 5.572, P = 0.015), diastolic BP (B = − 2.931, P = 0.044), triglycerides (B = − 0.229, P = 0.034), glucose (B = − 0.325, P = 0.032), insulin (B = − 5.114, P = 0.001), and HOMA-IR (B = − 0.673, P = 0.001) at 9-years. Reallocations of time to MVPA at 4- or 9-years were not associated with CVD risk factors at 9-years.ConclusionsVPA was associated with CVD risk factors in children both cross-sectionally (9-years) and longitudinally (at 4- and 9-years). MVPA seemed not to be a stimulus of enough intensity to trigger these potential cardiometabolic benefits in healthy children. Thus, these findings suggest the importance of higher intensity activities, i.e., VPA already in early childhood for cardiometabolic health.

A cross-sectional study of nutritional status in healthy, young, physically-active German omnivores, vegetarians and vegans reveals adequate vitamin B12 status in supplemented vegans

Background/Objective Plant-based diets reduce the risk of cardiovascular disease but also increase the risk of certain micronutrient deficiencies, particularly, of vitamin B12 (B12). The extent to which the unsupervised use of oral nutrient supplements is sufficient to prevent these deficiencies is not well established. We analyzed nutrient intake, laboratory biomarkers, supplementation behavior, and B12 status adequacy amongst young, healthy, physically active omnivores, lacto-ovo-vegetarians and vegans from Germany. Methods We recruited 115 participants (n = 40 omnivores; n = 37 lacto-ovo-vegetarians, and n = 38 vegans) with comparable age, sex, marital status, physical activity and educational levels through online advertisements and local newspapers in Freiburg, Germany. Results Energy intake and macronutrient distribution were comparable across diets. Major differences included intake of fiber, cholesterol, and several vitamins. Vegans had the lowest intake of B12 from foods (0.43 (0.58) µg/d), compared to omnivores (2.14 (2.29) µg/d) and lacto-ovo-vegetarians (0.98 (1.34) µg/day). Multivariate analysis of 36 blood biomarkers revealed that three major classes of biomarkers contributed the most to the clustering of individuals by dietary group, namely, biomarkers of B12 status (B12, holoTC, Hcy), iron (iron, ferritin, transferrin) and lipid metabolism (vitamin A, HDL, LDL, total cholesterol, TAG). This suggests that nutrients that modify the metabolic pathways represented by these biomarkers have the most penetrating effect on health status across diets. Analysis of B12 status (including 4cB12) revealed adequacy in omnivores and vegans, and a poorer B12 status amongst lacto-ovo-vegetarians. Fewer lacto-ovo-vegetarians used B12 supplements compared to vegans (51% versus 92%). Conclusions Even amongst homogeneously healthy Germans, each diet manifested with measurable differences in dietary intakes and biomarkers of health. Plant-based diets, in particular the vegan diet, exhibited the most favorable patterns of lipid metabolism and glycemic control, but the lowest food intake of B12. Supplementation of healthy vegans with B12 (median 250 µg B12/day, over 1 year) secured an adequate B12 status that was comparable to that of healthy omnivores. Clinical Trial Registry: German Clinical Trial register number: DRKS00027425

Derangement of metabolic homeostasis, detoxifying ability and CA 15-3 in young adult female rats by fructose (15%) drinking is akin to known carcinogens: A missed fiend?

Objectives: Breast cancer (BC) has been the bane of peri-and post-menopausal women, but is now increasingly incident in adolescent/young adult (AYA) females. Pari-passu, there has been a &gt;1000% increase in consumption of fructose as a caloric sweetener in soft drinks, whose top consumers are AYAs. The link between fructose consumption and mammary gland (MG) carcinogenesis is not well-established and the same is investigated and compared against known carcinogens such as 7,12-dimethylbenz(a)anthracene (DMBA) and electromagnetic radiations from mobile phone (EMF-MP). Materials and Methods: Weaned female Wistar rats were randomly grouped as normal control (NOR), fructose control (FRC), DMBA control (DMC), and exposure control (EXC). For 8 weeks, the NOR was provided chow and water, ad libitum, while FRC, DMC, and EXC additionally received 15% fructose drinking solution, ad libitum, DMBA (20 mg/Kg, p.o; at weaning) and EMF-MP (Global System for Mobile Communications [GSM]), 2 h/day daily), respectively. At the end of the study, the groups were compared for the biomarkers of insulin resistance (IR), carbohydrate and lipid metabolism, liver function, cardiometabolic function, oxidative stress, and MG carcinogenesis. Results: The serum markers of MG carcinogenesis (CA 15–3), IR (homeostasis model assessment-IR, area under the curve – oral glucose tolerance test), and liver and cardiometabolic function (serum glutamicoxaloacetic transaminase and homocysteine) were significantly raised (P &lt; 0.05) in FRC versus NOR. The metabolic homeostasis (leptin, ghrelin, triglyceride-Glucose index, glucose-6-phosphatase, triglyceride, high-density lipoprotein, serum glutamic pyruvic transaminase, alkaline phosphatase, and glycogen) and detoxifying ability (free-radical scavenging activity [%] and superoxide dismutase) in FRC were not different from DMC, or EXC. Conclusion: The development of early indicators of MG carcinogenesis due to unhindered fructose drinking by AYA female rats is akin to exposure to DMBA or EMF-MPs that evidence the propensity of the former.