L-Carnitine

Abstract

Thoracic aortic aneurysm (TAA) is a life-threatening condition characterized by pathological dilation of the aorta. While inflammatory responses have been implicated in TAA pathogenesis, the causal relationships remain elusive. This study aimed to elucidate potential causal associations between inflammatory cytokines, plasma metabolites, and TAA risk using Mendelian randomization (MR) analysis. We conducted bidirectional two-sample MR analysis utilizing genome-wide association study data from 91 inflammatory cytokines (n = 14,824), 1400 plasma metabolites (n = 8299), and TAA (n = 385,857). The inverse-variance weighted method served as the primary analytical approach, with comprehensive sensitivity analyses performed to assess pleiotropy and heterogeneity. Two-step MR analysis was employed to explore potential mediating roles of plasma metabolites. Single-cell sequencing analysis was utilized to detect cell type enrichment and elucidate cellular functions of identified cytokines. Additionally, we conducted an analysis to identify druggable proteins as potential therapeutic targets for TAA. MR analysis revealed that genetically-determined increases in C-X-C motif chemokine 10 (CXCL10) (odds ratios [OR] = 1.149, 95% confidence interval [CI]: 1.009-1.309, P = .037) and fibroblast growth factor 5 (OR = 1.101, 95% CI: 1.013-1.196, P = .024) were associated with elevated TAA risk. Conversely, C-C motif chemokine 20 (CCL20) (OR = 0.870, 95% CI: 0.759-0.996, P = .043) and CD40L receptor (CD40) (OR = 0.906, 95% CI: 0.827-0.992, P = .033) demonstrated inverse associations with TAA risk. Two-step MR analysis identified potential mediating metabolites: the phosphate to linoleoyl-arachidonoyl-glycerol ratio for CXCL10, thyroxine and X-24585 for FGF-5, and the creatine to carnitine ratio for CCL20. Single-cell sequencing analysis revealed enrichment of these cytokines in specific cell types and pathways relevant to TAA pathogenesis. Drug-gene interaction analysis identified CXCL10, CCL20, and CD40 as potential targets for treatment of TAA. This study provides robust genetic evidence supporting causal relationships between specific inflammatory cytokines and TAA risk, with plasma metabolites potentially mediating these effects. CXCL10 and FGF-5 were identified as potential risk factors, while CCL20 and CD40 may confer protective effects. These findings offer novel insights into TAA pathogenesis and suggest potential targets for intervention. Further research is warranted to elucidate the underlying mechanisms and validate these results across diverse populations.

Abstract

This study investigated the effects of ageing period (5 vs. 90 days) and meat status (raw vs. cooked) in a 2 × 2 factorial design on the concentration of bioactive compounds, intramuscular fat content and fatty acid composition of the longissimus lumborum muscle in beef. Samples were collected from 20 Angus steers finished on pasture. Significant (P < 0.05) interactions between ageing period and meat status were found for l-carnitine, glutathione, and taurine. Taurine and glutathione concentrations were greater (P < 0.05) in raw beef aged for 90 days, while L- carnitine content was lower in cooked meat aged for 5 days than the other treatments. Concentrations of coenzyme Q10, glutathione, l-carnitine, and taurine were higher (P < 0.05), and carnosine and anserine content were lower (P < 0.05) in meat aged for 90 days compared to 5 days. All bioactive compounds presented greater (P < 0.05) concentrations in raw than cooked meat. Beef aged for 90 days presented a greater (P < 0.05) proportion of intramuscular fat (IMF), and concentrations of saturated fatty acids (SFA), monounsaturated (MUFA), n-6 polyunsaturated fatty acids (PUFA)/n-3 PUFA ratio, atherogenic and thrombogenic indices. Cooking increased (P < 0.05) the concentrations of all fatty acids, however the PUFA/SFA ratio was greater (P < 0.05) in raw meat. Our findings show that ageing and cooking affect the bioactive compounds concentrations and fatty acids present in beef, and both factors should be considered to really know what meat provides under the conditions in which it is consumed.

Abstract

This study aimed to evaluate the efficacy of Morinda officinalis oligosaccharides (MOS) in improving sperm motility and quality in a gossypol-induced asthenozoospermia mouse model, and to explore the potential underlying mechanisms.

Abstract

Tibetan sheep from different altitudes exhibit unique meat quality attributes, whereas the molecular mechanisms remain unelucidated. Such meat quality attributes are associated with underlying metabolic processes, which are influenced by high-altitude conditions. Herein, meat quality and muscle metabolism in Tibetan sheep from Oula (2900 m), Huoerba (4000 m), and Duoma (5100 m) were compared. Oula sheep showed higher moisture and lighter color, while Duoma sheep had the lowest fat content. A total of 419 differential metabolites were identified based on metabolomics. Among them, peptide contents decreased with increasing altitude of Tibetan sheep's residence, while carnitine derivatives increased. Bioinformatics analysis indicated that high altitude regulates HIF-1α signaling through hypoxic conditions and oxidative stress mediates glutathione oxidation, thus affecting meat L* value. This study reveals meat quality and the metabolic basis in Tibetan sheep at different altitudes, establishing a scientific foundation for resource utilization and development of Tibetan sheep at specific altitudes.

Abstract

Acyl-CoA binding protein plays a vital role in lipid metabolism by mediating the intracellular flux and utilization of long-chain acyl-CoAs. We generated an adipocyte-wide ACBP knockout mouse and a brown adipose tissue-specific ACBP knockout mouse to investigate ACBP function in adipose tissue.

Abstract

Environmental adaptation often involves a shift in energy utilization toward mitochondrial fatty acid oxidation, which requires carnitine. Besides dietary sources of animal origin, carnitine biosynthesis from trimethyllysine (TML) is essential, particularly for those who consume plant-based diets; however, its molecular regulation and physiological role remain elusive. Here, we identify SLC25A45 as a mitochondrial TML carrier that controls carnitine biosynthesis and fuel switching. SLC25A45 deficiency decreased the carnitine pool and impaired mitochondrial fatty acid oxidation, shifting reliance to carbohydrate metabolism. Slc25a45-deficient mice were cold-intolerant and resistant to lipid mobilization by glucagon-like peptide-1 receptor agonist (GLP-1RA), rendering them resistant to adipose tissue loss. Our study suggests that mitochondria serve as a regulatory checkpoint in fuel switching, with implications for metabolic adaptation and the efficacy of GLP-1RA-based anti-obesity therapy.

Abstract

The ketogenic diet (KD), initially developed for the treatment of neurological disorders, has gained increasing attention for its potential role in the management of various metabolic diseases. Alongside its expanding clinical use, concerns have emerged regarding its safety, tolerability, and suitability in specific patient populations. This review summarises key contraindications, clinical situations requiring caution, relevant drug interactions, and commonly reported adverse effects associated with KD.

Abstract

Triple-negative breast cancer (TNBC) is highly aggressive tumor with limited therapeutic options. Studying the molecular mechanisms underlying TNBC is necessary to address the unmet need in novel therapeutic targets. TNBC is demonstrated to have robust fatty acid (FA) metabolism activity, and recent studies proposed the linkage of FA metabolism with ferroptosis sensitivity. Hence, this study aimed to explore the targets that may regulate FA metabolism to sensitize TNBC cells to ferroptosis.

Abstract

Trimethylamine-N-oxide (TMAO), a gut microbiota-derived dietary metabolite, is linked to progression of chronic kidney disease (CKD). Megalin, a renal proximal tubule receptor crucial for albumin reabsorption, also plays a role in CKD. However, the relationship between them is not well explored. The aim of this study was to investigate if there are any correlations between the levels of TMAO, megalin, lysine and markers of tubular damage in CKD. Urinary metabolites (TMAO, choline, L-carnitine, betaine, lysine) and tubular markers (megalin, albumin, EGF, MCP-1) were quantified by LC-MS/MS and ELISA. Associations were evaluated using analysis of covariance (ANCOVA) adjusted for age and diabetes, with false discovery rate correction. Compared with controls, CKD patients showed higher urinary choline (FDR < 0.001), betaine (FDR = 0.007), lysine (FDR = 0.005), and soluble megalin (FDR < 0.001) but lower EGF and EGF/MCP-1 ratio (both FDR < 0.001). Correlation analyses revealed that serum TMAO was positively associated with soluble megalin and negatively with EGF/MCP-1 ratio. Choline, L-carnitine, and betaine were positively correlated with megalin. This cross-sectional study identifies associations between urinary metabolites, megalin, and tubular injury markers in advanced CKD. Although causality cannot be inferred, the results point to a potential metabolic-tubular link that should be explored in future longitudinal and mechanistic studies.

Abstract

In deep eutectic solvent (DES)-H2O systems, protein stability is not determined solely by chemical composition but by a general colloid-interface mechanism: there exists a moisture-dependent hydrogen-bonding network reorganization point at which interfacial hydration forces and bulk DES structure are co-optimized. At this "critical point", protein-solvent interfacial properties-wettability, hydration layer structure, and interfacial tension-are tuned to form stable colloid systems.

Abstract

EPDR1 has been shown to play critical regulatory roles in development of several types of cancer. Nevertheless, the role of EPDR1, a family of glycoproteins involved in cell-cell contact, to gastric cancer (GC) remain unknown. Here, we determined that EPDR1 is significantly upregulated in GC tissues and cell lines, and is associated with poor prognosis. In vitro and in vivo functional assays demonstrate that EPDR1 promotes the proliferation, migration, and invasion of GC cells. Mechanistically, EPDR1 regulates the expression level of CPT1A, thereby mediating metabolic reprogramming of the fatty acid oxidation pathway. Our RNA immunoprecipitation (RIP) experiments show that CPT1A interacts with STAT3 in GC cell lines, and that EPDR1 mediates the phosphorylation of STAT3 via CPT1A. Overall, our work elucidates that EPDR1 activates the JAK-STAT pathway through the regulation of CPT1A, leading to enhanced phosphorylation of STAT3 and promoting fatty acid oxidation levels in GC, thus facilitating the progression of gastric cancer and providing a potential therapeutic target for its treatment.

Abstract

Food allergy has become a global public health problem. This study established a BALB/c mouse food allergy model to investigate the possible therapeutic effects of two widely studied polyphenols: chlorogenic acid (CA) and quercetin (QR).

Abstract

Cirrhotic cardiomyopathy (CCM) is a significant complication of cirrhosis, but its progression and underlying mechanisms remain incompletely understood. This study aimed to investigate dynamic changes in cardiac function, pathology, inflammation, and mitochondrial damage in a mouse model of CCM, and to compare echocardiographic characteristics in patients with cirrhosis.

Abstract

This study investigated the year-round metabolomic variation in Fucus serratus (FS) and F. vesiculosus (FV) collected monthly from Danish coastal water around Aarhus Bay. Untargeted high-resolution liquid chromatography-mass spectrometry profiling (LC-HRMS), combined with multivariate data analysis and temporal clustering analysis, revealed that species identity was the primary driver of metabolic separation, followed by seasonal variation. FS showed higher levels of hydrolyzable tannins, flavonoid derivatives, aromatic amino acids, and glutamine-rich peptides, whereas FV was enriched in complex phlorotannins, tricarboxylic acid cycle intermediates, and carnitine derivatives. Temporal analysis identified recurring seasonal patterns across both species, including spring increases in amino acids, purine metabolites, and osmolytes; mid-summer peaks in mannitol and sulfated derivatives; and late-autumn elevations in phenolic compounds and betaine-type osmolytes. Despite apparent interspecific differences, several metabolite groups exhibited similar seasonal dynamics, suggesting shared physiological strategies associated with growth activation in spring, metabolic adjustment during summer to possible increased grazing pressure, and nutrient reallocation prior to winter. These findings provide a comprehensive, high-resolution view of seasonal metabolomic patterns in Fucus spp., offering new insights into their biochemical ecology and supporting the targeted utilization of these species for applications requiring specific metabolite profiles. Finally, this study contributes to the creation or expansion of metabolomic libraries for HRMS specific to Fucus seaweeds.

Abstract

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) confer cardio-renal protection, and recent work implicates enhanced branched-chain amino acid (BCAA) catabolism as a potential mechanism in the heart. Whether SGLT2i also promotes renal BCAA catabolism is largely unknown. We hypothesized that SGLT2i enhances renal BCAA catabolism independently of glycemic effects.

Abstract

Cognitive dysfunction (CD) is a clinical syndrome that affects individual cognitive ability seriously. Liensinine could significantly alleviate cognitive impairments in dementia, however, the underlying mechanisms are still unclear. This study investigated the mechanism of liensinine on intervention of CD by metabolomics and 16S rRNA. After administration of liensinine, the CD mice showed a significant decrease in the escape latency and increase in the numbers of crossing the target quadrant and residence times. The levels of Aβ and Tau proteins were decreased, while neurotransmitters were increased. Metabolomics results showed that fecal metabolites were altered significantly, especially increasing the content of carnitine compounds and reducing the levels of 4-hydroxyquinoline, dihydroceramide, and indole-3-carboxaldehyde. Furthermore, liensinine also improved the proliferation of beneficial bacteria (including Bifidobacterium and Akkermansia) and reduced the abundance of harmful bacteria (Helicobacter and Enterorhabdus). The critical mechanism of Liensinine ameliorates cognitive dysfunction may be through the modulation of intestinal flora and metabolic function.

Abstract

Tacrolimus-induced chronic nephrotoxicity (TACN) represents a major barrier to long-term graft survival in kidney transplantation, yet its molecular pathogenesis remains incompletely understood. We have previously reported metabolic abnormalities, including carnitine deficiency, nicotinamide adenine dinucleotide depletion, and elevated asymmetric dimethyl arginine (ADMA), in TACN. To identify upstream regulators associated with these metabolic disturbances, we conducted a comprehensive trans-omic analysis, integrating transcriptomics and proteomics of kidney tissues from male ICR mice with TACN (n = 5/group). Differentially expressed genes and proteins were subjected to functional enrichment and transcription factor binding motif analyses, followed by upstream master regulator identification using the Genome Enhancer platform. A total of 785 genes and 2472 proteins were differentially expressed, with partially discordant regulation between transcriptomic and proteomic profiles, underscoring the limitations of single-omic approaches. Upstream analysis identified protein arginine methyltransferase-1 (PRMT1) and integrins, particularly αVβ6, as potential master regulators and therapeutic targets. PRMT1 is implicated in ADMA-mediated nitric oxide inhibition and fibrosis, whereas integrin αVβ6 is associated with tubular injury and renal fibrogenesis. Notably, PRMT1 may activate STAT3, which in turn regulates integrin β6 expression, suggesting a novel PRMT1-STAT3-integrin αVβ6 axis in TACN pathogenesis. This study represents the first trans-omic approach to TACN, providing a foundation for mechanistic validation and therapeutic exploration of PRMT1 and integrins in both preclinical and clinical settings.

Abstract

Fetal growth restriction (FGR) may impair early postnatal cardiopulmonary function by limiting the heart's ability to shift from glycolytic to fatty acid metabolism. We investigated whether the cardiac metabolic milieu is altered in newborn FGR lambs compared with control lambs 24 h after birth. Twin-bearing ewes at 89 days of gestation (term = 148 days) underwent single umbilical artery ligation to induce FGR or sham surgery (control). Lambs were delivered late preterm at 136 days (∼0.92 gestation) and monitored for 24 h before postmortem tissue collection. Left ventricles were snap-frozen for untargeted metabolomics analysis via liquid chromatography/mass spectroscopy (LC-MS) and reverse transcriptase quantitative PCR (RT-qPCR) or fixed for immunohistochemical analysis. FGR lambs had lower body weights at birth (2.7 ± 0.3 vs. 4.3 ± 0.2; P = 0.0002) and at 24 h (2.7 ± 0.2 vs. 4.4 ± 0.2; P < 0.0001) compared with controls. LC-MS identified 14 significantly altered metabolites in FGR hearts, with upregulated peptide and uric acid metabolism and downregulated lipid, carnitine, and serotonin metabolism (fold change from control >1.5; P < 0.05). RT-qPCR identified higher gene expression of long-chain fatty acid transport proteins SLC27A6 and ACADL and lower gene expression of serotonin receptor HTR4. No differences in the gene expression of carnitine metabolism (CPT1A and CPT1B) or uric acid metabolism (XDH, HPRT1, GDA, and PNP) were observed. Serotonin (5-hydroxytryptamine) density was reduced in FGR hearts (P = 0.048). These findings suggest early shifts in postnatal cardiac metabolic adaptations in FGR lambs, particularly in lipid and serotonin pathways, and provide a foundation for future studies exploring the functional consequences of these changes.NEW & NOTEWORTHY Within 24 h of birth, growth-restricted (FGR) newborn lambs exhibited altered lipid and serotonin metabolites, suggesting disrupted postnatal cardiac metabolic adaptation. Despite upregulation of the fatty acid transporter gene SLC27A6, with other fatty acid oxidation genes remaining largely unchanged, reductions in lipid and carnitine metabolites indicate potential impairments in fatty acid utilization. Decreased serotonin bioavailability further suggests metabolic reprogramming in FGR hearts, highlighting the need for future studies on the implications for postnatal cardiac function.

Abstract

IgA vasculitis (IgAV) is an autoimmune disorder characterized by inflammation of the small blood vessels. The pathogenesis of IgAV is believed to involve a complex interplay between immune cells, metabolites, and inflammatory cytokines (ICs).

Abstract

Non-alcoholic fatty liver disease (NAFLD), recently reclassified as metabolic dysfunction-associated fatty liver disease (MAFLD), is closely linked to mitochondrial dysfunction and impaired lipid metabolism. Bifidobacterium bifidum has emerged as a promising probiotic candidate for restoring metabolic balance, yet its mitochondrial-targeted mechanisms remain underexplored. This study investigates the role of B. bifidum in modulating hepatic mitochondrial β-oxidation pathways and key transcriptional regulators involved in fatty acid metabolism. MAFLD was induced in male Sprague-Dawley rats using a high-fat diet and streptozotocin (STZ). Following disease induction, B. bifidum was administered over two treatment durations (6 and 14 weeks). Liver function tests, lipid profiles, and stereological analyses were performed, and hepatic gene expression of UCP2, CPT1A, PGC-1α, PPAR-α, and PPAR-γ was evaluated using quantitative RT-PCR. B. bifidum treatment significantly reduced serum triglycerides, total cholesterol, and LDL-C levels, while showing a non-significant upward trend in HDL-C levels. Gene expression analysis revealed that B. bifidum restored downregulated PGC-1α, CPT1A, and PPAR-α expression and normalized elevated UCP2 and PPAR-γ levels, suggesting enhanced mitochondrial fatty acid oxidation. Histological and stereological assessments confirmed structural improvements in liver tissue, including reduced steatosis and improved hepatocyte morphology. These findings provide new mechanistic evidence that B. bifidum exerts hepatoprotective effects by reprogramming mitochondrial lipid metabolism through the PPAR-α/PGC-1α/CPT1A axis. This probiotic may offer a novel, mitochondria-targeted therapeutic strategy for managing MAFLD and related metabolic disorders. Further studies are warranted to evaluate strain-specific effects and long-term outcomes in clinical settings.

Abstract

Coconut oil has gained popularity for its potential health benefits, particularly regarding energy metabolism. One of its key components, lauric acid (LA), has been reported to reduce body fat and improve insulin sensitivity, making it beneficial for individuals with obesity and type 2 diabetes. However, its full metabolic effects remain unclear, and further research is needed. This study investigated how LA influences fat cells (adipocytes) metabolism. Mice fed a diet containing 40% coconut oil showed elevated blood levels of glycerol and free fatty acids (FAs), indicating enhanced lipolysis. Gene expression analysis showed upregulation of pathways involved in FA uptake and metabolism. Concurrently, leptin expression in white adipose tissue (WAT), and circulating leptin levels, were reduced. Protein analysis revealed increased activation of lipid turnover regulators, including hormone-sensitive lipase (HSL) and perilipin 1 (PLIN1). In vitro, rat adipocytes treated with LA showed enhanced activity of metabolic processes that support fat oxidation, such as citrate synthase and carnitine palmitoyltransferase, along with a higher rate of oxygen consumption. Leptin production was likewise reduced by LA in vitro. The reduction in leptin levels and increased lipolysis appear to be partly mediated by the modulation of peroxisome proliferator-activated receptor gamma (PPARγ), a key regulator of lipid metabolism. While these effects support fat mobilization, the concurrent reduction in leptin expression may influence energy homeostasis, potentially counteracting the metabolic benefits of LA. These findings underscore the complex role of lauric acid in adipose tissue metabolism and raise questions about potential trade-offs.

Abstract

Hedgehog inhibitors (HHIs) are approved for the treatment of locally advanced BCCs in patients who are not surgical candidates or have had recurrence following surgical treatment. This expert consensus panel further characterizes the efficacy and safety of HHIs while also providing clinical guidance on their appropriate dosing, laboratory monitoring, and supplementation.

Abstract

Diabetic kidney disease (DKD) is a major complication of diabetes, characterized by progressive renal dysfunction and mitochondrial impairment. Mitophagy, a selective form of macroautophagy/autophagy that maintains mitochondrial quality, is essential for kidney homeostasis. However, the molecular mechanisms by which mitophagy links these pathways to DKD remain poorly understood. This study investigated the role of XIAP-ULK1-mediated mitophagy in regulating carnitine metabolism and its therapeutic potential in alleviating DKD. Through a combination of renal biopsy analysis from DKD patients, diabetic mouse models, high-glucose-treated tubular epithelial cells, and molecular docking, we determined that XIAP upregulation led to ULK1 degradation via K48-linked polyubiquitination, impairing mitophagy and disrupting carnitine metabolism. Restoring ULK1 expression through the ULK1 agonist echinacoside and L-carnitine supplementation improved mitophagy and carnitine homeostasis, reducing kidney injury and enhancing mitochondrial function in diabetic mouse models. These findings suggested that targeting the XIAP-ULK1 axis to restore mitophagy and stabilize carnitine metabolism hold significant promise as a therapeutic strategy for DKD, highlighting the importance of metabolic regulation in kidney disease management.Abbreviations: ACR: ALB (albumin):creatinine ratio; AAV: adeno-associated virus; BUN: blood urea nitrogen; CETSA: cellular thermal shift assay; DARTS: drug affinity responsive target stability; DMEM/F12: Dulbecco's modified Eagle medium/nutrient mixture F-12; FBS: fetal bovine serum; HG: high glucose; IHC: immunohistochemistry; IF: immunofluorescence; LC-MS: liquid chromatography-mass spectrometry; MitoQ: Mitoquinone; PCT: proximal convoluted tubule; PPI: protein-protein interaction; PAS: periodic acid-Schiff; RMSD: root mean square deviation; RMSF: root mean square fluctuation; RNA-seq: RNA sequencing; RT-qPCR: reverse transcription quantitative polymerase chain reaction; Scr: serum creatinine; SDH: succinate dehydrogenase; STZ: streptozotocin; TMLHE: trimethyllysine hydroxylase, epsilon; TEM: transmission electron microscopy; TECs: tubular epithelial cells; scRNA-seq: single-cell RNA sequencing; ULK1: unc-51 like autophagy activating kinase 1; XIAP: X-linked inhibitor of apoptosis.

Abstract

Obesity is a multifactorial condition projected to affect over half of the global population by 2035, posing significant clinical and socioeconomic challenges. Traditional metrics such as body mass index lack precision in predicting individual risk, disease progression, and therapeutic response due to the heterogeneous nature of obesity. Advances in omics technologies such as genomics, epigenomics, transcriptomics, proteomics, and metabolomics have enabled the identification of molecular subtypes and candidate biomarkers that offer deeper insights into obesity pathophysiology. Genomic studies have revealed hundreds of loci associated with obesity related traits, while polygenic risk scores offer modest improvements in early risk prediction. Epigenomic profiling, particularly deoxy ribose nucleic acid (DNA) methylation signatures such as those at carnitine palmitoyl transferase 1A (CPT1A) and hypoxia inducible factor 3 subunit alpha (HIF3A), has uncovered modifiable pathways linked to adiposity and metabolic dysfunction. These findings are increasingly being integrated with other omics layers to improve stratification and therapeutic targeting. Metabolomic subtypes, including ceramide driven insulin resistance and branched chain amino acid (BCAA) dominant dysregulation, have shown potential in guiding treatment selection, such as sodium glucose cotransporter 2 (SGLT2) inhibitors or glucagon like peptide-1 (GLP-1) agonists. Proteomic markers like proprotein convertase subtilisin/kexin type 9 (PCSK9) and retinol binding protein 4 (RBP4) are being evaluated for cardiovascular risk stratification independent of body mass index (BMI). Integrative multiomics frameworks and AI driven models are beginning to bridge molecular data with clinical phenotypes, enabling patient stratification and risk modeling. However, most findings remain in research grade environments, and clinical translation is limited by cohort diversity, data harmonization challenges, and the lack of standardized validation protocols. This review synthesizes evidence from single and multiomics studies, highlights emerging biomarkers and molecular subtypes, and discusses the potential of omics guided frameworks to inform precision obesity care.

Abstract

Lipopeptides are bioactive molecules typically produced via nonribosomal pathways. Only four types of lipidated ribosomally synthesized and post-translationally modified peptides (RiPPs) are known, all modified on amine groups by GNAT enzymes. We report an unprecedented biosynthetic gene cluster combining lasso peptide biosynthesis and acyl-CoA metabolism that produces a novel family of lipolasso peptides. A crotonobetainyl-CoA:carnitine CoA-transferase lipidates the Tyr hydroxy group within precursor peptides, revealing a distinct RiPP lipidation strategy. This work expands the paradigm of ribosomal lipopeptide biosynthesis.

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths. Most patients present at advanced stages, and the effectiveness of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors is constrained by limited patient response. A subset of HCC shows elevated expression of the promoter 2 ("P2")-driven hepatocyte nuclear factor 4 alpha (HNF4α) isoform, which directly transcriptionally represses the circadian brain and muscle ARNT-like protein 1 (BMAL1) transcription factor. This subtype of HCC is robustly inhibited by the plant-based flavonoid nobiletin (NOB), a circadian-fortifying compound. Using patient-matched human HCC and serum, we show that BMAL1-deficient HCC shows exaggerated carnitine palmitoyl transferase expression and related metabolite abundance and that P2-HNF4α regulates the carnitine palmitoyl transferase I gene. Finally, using different preclinical models, we show that the anti-tumor activity of TKIs, when they are co-administered with NOB, is maximal. Our results suggest that chronotherapy and combination therapy might provide improved clinical outcomes for individuals with BMAL1-deficient HCC.

Abstract

Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease and is closely linked to type 2 diabetes mellitus (T2DM). The pathogenesis of MAFLD involves complex metabolic imbalances, including impaired fatty acid β-oxidation and chronic inflammation. GLP-1 receptor agonists (GLP-1 RAs) have shown promise in improving metabolic outcomes, but their specific effects on MAFLD remain unclear. This study aims to investigate the molecular mechanisms underlying the hepatic benefits of semaglutide, a GLP-1 RA, in T2DM patients with MAFLD using serum proteomics and metabolomics.

Abstract

Bergenin, the main active ingredient of Bergenia purpurascens, was previously reported to alleviate dextran sulfate sodium (DSS)-induced colitis in mice. Cytokine IL-17 plays a pivotal role in the development of ulcerative colitis (UC), and γδT17 cells are the primary producers of IL-17 in gut. Whether bergenin functions through inhibiting γδT17 cell activation remains to be identified.

Abstract

Disturbances within the cerebrovascular system substantially contribute to the pathogenesis of age-related cognitive impairment and Alzheimer's disease (AD). Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid-β (Aβ) in the leptomeningeal and cortical arteries and is highly prevalent in AD, affecting over 90% of cases. While the ε4 allele of apolipoprotein E (APOE) represents the strongest genetic risk factor for AD, it is also associated with cerebrovascular dysregulations. APOE plays a crucial role in brain lipid transport, particularly in the trafficking of cholesterol and phospholipids. Lipid metabolism is increasingly recognized as a critical factor in AD pathogenesis. However, the precise mechanism by which APOE influences cerebrovascular lipid signatures in AD brains remains unclear. In this study, we conducted non-targeted lipidomics on cerebral vessels isolated from the middle temporal cortex of 89 postmortem human AD brains, representing varying degrees of CAA and different APOE genotypes: APOE ε2/ε3 (N = 9), APOE ε2/ε4 (N = 14), APOE ε3/ε3 (N = 21), APOE ε3/ε4 (N = 23), and APOE ε4/ε4 (N = 22). Lipidomics detected 10 major lipid classes with phosphatidylcholine (PC) and phosphatidylethanolamine (PE) being the most abundant lipid species. While we observed a positive association between age and total acyl-carnitine (CAR) levels (p = 0.0008), the levels of specific CAR subclasses were influenced by the APOE ε4 allele. Notably, APOE ε4 was associated with increased PE (p = 0.049) and decreased sphingomyelin (SM) levels (p = 0.028) in the cerebrovasculature. Furthermore, cerebrovascular Aβ40 and Aβ42 levels showed associations with sphingolipid levels including SM (p = 0.0079) and ceramide (CER) (p = 0.024). Weighted correlation network analysis revealed correlations between total tau and phosphorylated tau and lipid clusters enriched for PE plasmalogen and lysoglycerophospholipids. Taken together, our results suggest that cerebrovascular lipidomic profiles offer novel insights into the pathogenic mechanisms of AD, with specific lipid alterations potentially serving as biomarkers or therapeutic targets for AD.

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by joint inflammation, largely mediated by pro-inflammatory cytokines. Considering the established involvement of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway and transforming growth factor-beta1 (TGF-β1) in RA, this research aimed to assess efficacy and safety of L-carnitine as an adjunct therapy targeting these pathways. Forty-six patients with active RA were randomly divided into two equal groups. Group1 (control group) received disease-modifying antirheumatic drugs (DMARDs), including methotrexate, leflunomide, and hydroxychloroquine. Group2 (L-carnitine group) received, DMARDs plus L-carnitine 500 mg twice daily for 12 weeks. A clinical evaluation was conducted, which included tender joint count (TJC), swollen joint count (SJC), pain intensity quantified via the visual analogue scale (VAS), and morning stiffness duration. Additionally, the Disease Activity Score in 28 joints (DAS28) and functional capability as measured by a modified health assessment questionnaire (MHAQ) were assessed. Laboratory evaluation included C-reactive protein (CRP), STAT3, and TGF-β1 measurement. All evaluations were executed both at baseline and following a 12-week treatment period. After 12 weeks, the L-carnitine group showed significant improvement in morning stiffness, VAS, TJC, CRP, DAS28, and MHAQ compared to baseline. While no significant within-group changes were observed in STAT3, TGF-β1 in the L-carnitine group, STAT3 levels increased significantly in the control group compared to baseline. In conclusion, L-carnitine in combination with DMARDs may enhance clinical outcomes in RA by mitigating systemic inflammation. Nevertheless, its impact on STAT3 and TGF-β1 remains unclear and warrants further research.