Sodium silicate accelerates suberin accumulation at wounds of potato tuber by inducing phenylpropanoid pathway and fatty acid metabolism during healing.

Although soluble silicate was reported to accelerate wound healing in muskmelon fruit through encouraging the deposition of lignin or free fatty acids, whether sodium silicate affects the biosynthesis, cross-linking and transport of suberin monomers during potato wound healing remains unknown. In this study, sodium silicate upregulated the expression and activity of 4-coumarate: coenzyme A ligase (4CL), phenylalanine ammonia lyase (PAL), and promoted the synthesis of phenolic acids (caffeic acid, p-coumaric acid, cinnamic acid, sinapic acid, and ferulic acid) in tuber wounds. Meanwhile, sodium silicate upregulated the expression of glycerol-3-phosphate acyltransferase (StGPAT), fatty acyl reductase (StFAR), long-chain acyl-CoA synthetase (StLACS), ß-ketoacyl-CoA synthase (StKCS), and cytochrome P450 (StCYP86A33), and thus increased the levels of α, ω-diacids, ω-hydroxy acids, and primary alcohols in wounds. Sodium silicate also induced the expression of ω-hydroxy acid/fatty alcohol hydroxycinnamoyl transferase (StFHT), ABC transporter (StABCG), and promoted the deposition of suberin in wound surface, hence reducing tuber disease index and weight loss during healing. Taken together, sodium silicate may accelerate suberin accumulation at potato tubers wound through inducing the phenylpropanoid pathway and fatty acid metabolism.

Fatty acid metabolism affects hepatocellular carcinoma progression via the PPAR-γ signaling pathway and fatty acid ß-oxidation.

PURPOSE: This study aimed to explore novel targets for hepatocellular carcinoma (HCC) treatment by investigating the role of fatty acid metabolism. METHODS: RNA-seq and clinical data of HCC were obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Bioinformatic analyses were employed to identify differentially expressed genes (DEGs) related to prognosis. A signature was then constructed using the Least Absolute Shrinkage and Selection Operator (LASSO) Cox regression to classify HCC patients from the TCGA database into low-risk and high-risk groups. The predictive performance of the signature was evaluated through principal components analysis (PCA), Kaplan Meier (KM) survival analysis, receiver operating characteristics (ROC) curves, nomogram, genetic mutations, drug sensitivity analysis, immunological correlation analysis, and enrichment analysis. Single-cell maps were constructed to illustrate the distribution of core genes. Immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR), and western blot were employed to verify the expression of core genes. The function of one core gene was validated through a series of in vitro assays, including cell viability, colony formation, wound healing, trans-well migration, and invasion assays. The results were analyzed in the context of relevant signaling pathways. RESULTS: Bioinformatic analyses identified 15 FAMGs that were related to prognosis. A 4-gene signature was constructed, and patients were divided into high- and low-risk groups according to the signature. The high-risk group exhibited a poorer prognosis compared to the low-risk group in both the training (P < 0.001) and validation (P = 0.020) sets. Furthermore, the risk score was identified as an independent predictor of OS (P < 0.001, HR = 8.005). The incorporation of the risk score and clinicopathologic features into a nomogram enabled the effective prediction of patient prognosis. The model was able to effectively predict the immune microenvironment, drug sensitivity to chemotherapy, and gene mutation for each group. Single-cell maps demonstrated that FAMGs in the model were distributed in tumor cells. Enrichment analyses revealed that the cell cycle, fatty acid ß oxidation and PPAR signaling pathways were the most significant pathways. Among the four key prognostically related FAMGs, Spermine Synthase (SMS) was selected and validated as a potential oncogene affecting cell cycle, PPAR-γ signaling pathway and fatty acid ß oxidation in HCC. CONCLUSIONS: The risk characteristics based on FAMGs could serve as independent prognostic indicators for predicting HCC prognosis and could also serve as evaluation criteria for gene mutations, immunity, and chemotherapy drug therapy in HCC patients. Meanwhile, targeted fatty acid metabolism could be used to treat HCC through related signaling pathways.

The Role of Adipose Tissue and Nutrition in the Regulation of Adiponectin.

Adipose tissue (AT), composed mainly of adipocytes, plays a critical role in lipid control, metabolism, and energy storage. Once considered metabolically inert, AT is now recognized as a dynamic endocrine organ that regulates food intake, energy homeostasis, insulin sensitivity, thermoregulation, and immune responses. This review examines the multifaceted role of adiponectin, a predominant adipokine released by AT, in glucose and fatty acid metabolism. We explore the regulatory mechanisms of adiponectin, its physiological effects and its potential as a therapeutic target for metabolic diseases such as type 2 diabetes, cardiovascular disease and fatty liver disease. Furthermore, we analyze the impact of various dietary patterns, specific nutrients, and physical activities on adiponectin levels, highlighting strategies to improve metabolic health. Our comprehensive review provides insights into the critical functions of adiponectin and its importance in maintaining systemic metabolic homeostasis.

The role of DGAT1 and DGAT2 in tumor progression via fatty acid metabolism: A comprehensive review.

Fatty acid metabolism is a complex biochemical process, including the production, breakdown and application of fatty acids. Not only is it an important component of lipid metabolism, fatty acid metabolism is also connected to the energy metabolism pathways of cells and plays a vital role in maintaining the energy balance of organisms. Diacylglycerol-O-acyltransferase 1 (DGAT1) and Diacylglycerol-O-acyltransferase 2 (DGAT2) are key components in regulating lipid metabolism, which provide energy for cell proliferation and growth. Recent studies have shown that DGAT1 and DGAT2 influence tumor progression through fatty acid metabolism in cancer. Although DGAT1 and DGAT2 have similar names, they differ significantly in various aspects and play distinct roles in individual tumors. A comparative analysis of the physiological roles of these enzymes and their differential expressions in different types of tumors will enhance our understanding of their unique characteristics. This article summarizes the characteristics of tumor fatty acid metabolism and explains how DGAT1 and DGAT2 specifically promote tumor progression. In addition, this review discusses the potential of lipid-lowering drugs in tumor treatment, providing a new perspective on targeting fatty acid metabolism to inhibit tumor progression in the future, while emphasizing the importance of DGAT1 and DGAT2 as potential targets for tumor treatment.

ARHGEF39 targeted by E2F1 fosters hepatocellular carcinoma metastasis by mediating fatty acid metabolism.

BACKGROUND: Hepatocellular carcinoma (HCC) stands as the prevailing manifestation of primary liver cancer. Previous studies have implicated ARHGEF39 in various cancer progression processes, but its impact on HCC metastasis remains unclear. METHODS: Bioinformatics analysis and qRT-PCR were employed to test ARHGEF39 expression in HCC tissues and cells, identified enriched pathways associated with ARHGEF39, and investigated its regulatory relationship with E2F1. The impact of ARHGEF39 overexpression or knockdown on cellular phenotypes in HCC was assessed through the implementation of CCK-8 and Transwell assays. Accumulation of neutral lipids was determined by BODIPY 493/503 staining, while levels of triglycerides and phospholipids were measured using specific assay kits. Expression of E-cadherin, Vimentin, MMP-2, MMP-9, and FASN were analyzed by Western blot. The interaction between ARHGEF39 and E2F1 was validated through ChIP and dual-luciferase reporter assays. RESULTS: Our study demonstrated upregulated expression of both ARHGEF39 and E2F1 in HCC, with ARHGEF39 being associated with fatty acid metabolism (FAM) pathways. Additionally, ARHGEF39 was identified as a downstream target gene of E2F1. Cell-based experiments unmasked that high expression of ARHGEF39 mediated the promotion of HCC cell viability, migration, and invasion via enhanced FAM. Moreover, rescue assays demonstrated that the promotion of HCC cell metastasis by high ARHGEF39 expression was attenuated upon treatment with Orlistat. Conversely, the knockdown of E2F1 suppressed HCC cell metastasis and FAM, while the upregulation of ARHGEF39 counteracted the repressive effects of E2F1 downregulation on the metastatic potential of HCC cells. CONCLUSION: Our findings confirmed the critical role of ARHGEF39 in HCC metastasis and unmasked potential molecular mechanisms through which ARHGEF39 fostered HCC metastasis via FAM, providing a theoretical basis for exploring novel molecular markers and preventive strategies for HCC metastasis.

Effects of Dietary Oxidized Phytosterol on Lipid Metabolism in Rats.

Many in vitro studies have revealed the toxic effects of oxidized phytosterols (OPSs); however, their effects on lipid metabolism are not well understood in vivo. Therefore, we examined the bioavailability of OPS and compared the effects of dietary phytosterols (PSs) or OPS on lipid metabolism in rats. OPS was detected in the plasma and liver of rats administered 50 mg of OPS for 3 days. Rats were fed the AIN76 diet (C group), basal diet plus 0.25% PS (P group), or 0.25% OPS (O group) for 4 weeks. Dietary OPS but not PS reduced hepatic fatty acid synthase activity. Liver triacylglycerol (TG) levels tended to be lower in the P group than in the C group and were significantly lower in the O group. The mRNA expression level of HMG-CoA reductase in the liver was the lowest in the O group, whereas that of CYP27A1 was the highest in the O group. The mRNA expression levels of NPC1L1 in the intestinal mucosa were significantly lower in the P and O groups than in the C group. Consistent with these modulations, plasma total cholesterol (TC) and HDL-C levels were similar between the C and P groups but tended to be higher or significantly higher in the O group. Liver TC levels were significantly lower in the P and O groups than in the C group. Moreover, fecal neutral and acidic steroid levels were the highest in the O group. The mRNA expression level of Δ6 desaturase in the liver was significantly higher in both the P and the O groups than in the C group. The Δ6 desaturation indices of fatty acids in the total liver lipids were the highest in the O group. Thus, dietary OPS may modulate lipid metabolism in the liver.

Periodic protein-restricted diets extend the lifespan of high-fat diet-induced Drosophila melanogaster males.

Research has shown that sustained protein restriction can improve the effects of a high-fat diet on health and extend lifespan. However, long-term adherence to a protein-restricted diet is challenging. Therefore, we used a fly model to investigate whether periodic protein restriction (PPR) could also mitigate the potential adverse effects of a high-fat diet and extend healthy lifespan. Our study results showed that PPR reduced body weight, lipid levels, and oxidative stress induced by a high-fat diet in flies and significantly extended the healthy lifespan of male flies. Lipid metabolism and transcriptome results revealed that the common differences between the PPR group and the control group and high-fat group showed a significant decrease in palmitic acid in the PPR group; the enriched common differential pathways Toll and Imd were significantly inhibited in the PPR group. Further analysis indicated a significant positive correlation between palmitic acid levels and gene expression in the Toll and Imd pathways. This suggests that PPR effectively improves fruit fly lipid metabolism, reduces palmitic acid levels, and thereby suppresses the Toll and Imd pathways to extend the healthy lifespan of flies. Our study provides a theoretical basis for the long-term effects of PPR on health and offers a new dietary adjustment option for maintaining health in the long term.

SsCyp86 modulates sporisorium scitamineum mating/filamentation and pathogenicity through regulating fatty acid metabolism.

BACKGROUND: Fatty acid metabolism constitutes a significant and intricate biochemical process within microorganisms. Cytochrome P450 (CYP450) enzymes are found in most organisms and occupy a pivotal position in the metabolism of fatty acids. However, the role of CYP450 enzyme mediated fatty acid metabolism in the pathogenicity of pathogenic fungi remains unclear. METHODS: In this study, a CYP450 enzyme-encoding gene, SsCYP86, was identified in the sugarcane smut fungus Sporisorium scitamineum and its functions were characterized using a target gene homologous recombination strategy and metabonomics. RESULTS: We found that the expression of SsCYP86 was induced by or sugarcane wax or under the condition of mating/filamentation. Sexual reproduction assay demonstrated that the SsCYP86 deletion mutant was defective in mating/filamentation and significantly reduced its pathogenicity. Further fatty acid metabolomic analysis unravelled the levels of fatty acid metabolites were reduced in the SsCYP86 deletion mutant. Exogenous addition of fatty acid metabolites cis-11-eicosenoic acid (C20:1N9), pentadecanoic acid (C15:0), and linolenic acid (C18:3N3) partially restored the mating/filamentation ability of the SsCYP86 deletion mutant and restored the transcriptional level of the SsPRF1, a pheromone response transcription factor that is typically down-regulated in the absence of SsCYP86. Moreover, the constitutive expression of SsPRF1 in the SsCYP86 deletion mutant restored its mating/filamentation. CONCLUSION: Our results indicated that SsCyp86 modulates the SsPRF1 transcription by fatty acid metabolism, and thereby regulate the sexual reproduction of S. scitamineum. These findings provide insights into how CYPs regulate sexual reproduction in S. scitamineum.

Cinnamaldehyde activates AMPK/PGC-1α pathway via targeting GRK2 to ameliorate heart failure.

BACKGROUND: According to recent research, treating heart failure (HF) by inhibiting G protein-coupled receptor kinase 2 (GRK2) to improve myocardial energy metabolism has been identified as a potential approach. Cinnamaldehyde (CIN), a phenylpropyl aldehyde compound, has been demonstrated to exhibit beneficial effects in cardiovascular diseases. However, whether CIN inhibits GRK2 to ameliorate myocardial energy metabolism in HF is still unclear. PURPOSE: This study examines the effects of CIN on GRK2 and myocardial energy metabolism to elucidate its underlying mechanism to treat HF. METHODS: The isoproterenol (ISO) induced HF model in vivo and in vitro were constructed using Sprague-Dawley (SD) rats and primary neonatal rat cardiomyocytes (NRCMs). Based on this, the effects of CIN on myocardial energy metabolism and GRK2 were investigated. Additionally, validation experiments were conducted after interfering and over-expressing GRK2 in ISO-induced NRCMs to verify the regulatory effect of CIN on GRK2. Furthermore, binding capacity between GRK2 and CIN was explored by Cellular Thermal Shift Assay (CETSA) and Microscale Thermophoresis (MST). RESULTS: In vivo and in vitro, CIN significantly improved HF as demonstrated by reversing abnormal changes in myocardial injury markers, inhibiting myocardial hypertrophy and decreasing myocardial fibrosis. Additionally, CIN promoted myocardial fatty acid metabolism to ameliorate myocardial energy metabolism disorder by activating AMPK/PGC-1α signaling pathway. Moreover, CIN reversed the inhibition of myocardial fatty acid metabolism and AMPK/PGC-1α signaling pathway by GRK2 over-expression in ISO-induced NRCMs. Meanwhile, CIN had no better impact on the stimulation of cardiac fatty acid metabolism and the AMPK/PGC-1α signaling pathway in ISO-induced NRCMs when GRK2 was disrupted. Noticeably, CETSA and MST confirmed that CIN binds to GRK2 directly. The binding of CIN and GRK2 promoted the ubiquitination degradation of GRK2 mediated by murine double mimute 2. CONCLUSION: This study demonstrates that CIN exerts a protective intervention in HF by targeting GRK2 and promoting its ubiquitination degradation to activate AMPK/PGC-1α signaling pathway, ultimately improving myocardial fatty acid metabolism.

Circulating miRNA Signaling for Fatty Acid Metabolism in Response to a Maximum Endurance Test in Elite Long-Distance Runners.

Maximal oxygen uptake (VO2max) is a determining indicator for cardiorespiratory capacity in endurance athletes, and epigenetics is crucial in its levels and variability. This initial study examined a broad plasma miRNA profile of twenty-three trained elite endurance athletes with similar training volumes but different VO2max in response to an acute maximal graded endurance test. Six were clustered as higher/lower levels based on their VO2max (75.4 ± 0.9 and 60.1 ± 5.0 mL.kg-1.min-1). Plasma was obtained from athletes before and after the test and 15 ng of total RNA was extracted and detected using an SYBR-based 1113 miRNA RT-qPCR panel. A total of 51 miRNAs were differentially expressed among group comparisons. Relative amounts of miRNA showed a clustering behavior among groups regarding distinct performance/time points. Significantly expressed miRNAs were used to perform functional bioinformatic analysis (DIANA tools). Fatty acid metabolism pathways were strongly targeted for the significantly different miRNAs in all performance groups and time points (p < 0.001). Although this pathway does not solely determine endurance performance, their significant contribution is certainly achieved through the involvement of miRNAs. A highly genetically dependent gold standard variable for performance evaluation in a homogeneous group of elite athletes allowed genetic/epigenetic aspects related to fatty acid pathways to emerge.

Tissue-specific sex-dependent difference in the metabolism of fatty acid esters of hydroxy fatty acids.

Fatty acid esters of hydroxy fatty acids (FAHFAs) are endogenous bioactive lipids known for their anti-inflammatory and anti-diabetic properties. Despite their therapeutic potential, little is known about the sex-specific variations in FAHFA metabolism. This study investigated the role of sex and Androgen Dependent TFPI Regulating Protein (ADTRP), a FAHFA hydrolase. Additionally, tissue-specific differences in FAHFA levels, focusing on the perigonadal white adipose tissue (pgWAT), subcutaneous white adipose tissue (scWAT), brown adipose tissue (BAT), plasma, and liver, were evaluated using metabolomics and lipidomics. We found that female mice exhibited higher FAHFA levels in pgWAT, scWAT, and BAT compared to males. FAHFA levels were inversely related to testosterone and Adtrp mRNA, which showed significantly lower expression in females compared with males in pgWAT and scWAT. However, no significant differences between the sexes were observed in plasma and liver FAHFA levels. Adtrp deletion had minimal impact on both sexes' metabolome and lipidome of pgWAT. However, we discovered higher endogenous levels of triacylglycerol estolides containing FAHFAs, a FAHFA metabolic reservoir, in the pgWAT of female mice. These findings suggest that sex-dependent differences in FAHFA levels occur primarily in specific WAT depots and may modulate local insulin sensitivity in adipocytes, and the role of ADTRP is limited to adipose depots. However, further investigations are warranted to fully comprehend the underlying mechanisms and implications of sex-dependent regulation of human FAHFA metabolism.

Exposure to different cobalt chloride levels produces oxidative stress and lipidomic changes and affects the liver structure of Cyprinus carpio juveniles.

The present investigation was undertaken to evaluate the toxic effects of CoCl2-induced hepatotoxicity and fatty acid changes in juvenile Cyprinus carpio. Fish were divided into six experimental groups in duplicate. The first group served as controls. The second group received the lowest exposure dose at 2.5 µg/L. In the third group, fish were exposed to 25 µg/L of CoCl2. The fourth group was exposed to 50 µg/L of CoCl2. The last two groups were exposed to the highest doses, 100 and 500 µg/L of CoCl2. Total antioxidant activities were estimated using a colorimetric method. Liver fatty acid compositions were analyzed by high-performance gas chromatography (GC). Hepatopathy was identified through microscopic analysis. Exposure of C. carpio to CoCl2 resulted in hepatotoxicity, indicated by increased levels of malondialdehyde (MDA), hydrogen peroxide (H2O2), protein carbonyls (PCO), and alterations in the ferric reducing antioxidant power system (FRAP). Superoxide dismutase (SOD), glutathione-S-transferase (GST), glutathione peroxidase (GPx), reduced glutathione (GSH), metallothioneins (MTs), and low thiol levels (L-SH) significantly increased, particularly under exposure to the highest CoCl2 doses (100 and 500 µg/L). Acetylcholinesterase activity decreased significantly in C. carpio exposed to graded CoCl2 doses. Additionally, there was a decrease in polyunsaturated fatty acids (PUFA), primarily n-3 PUFA, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA), while an increase in monounsaturated (MUFA) and saturated fatty acids (SFA), including palmitic (C16:0), stearic (C18:0), palmitoleic (C16:1), and oleic (C18:1) acids, was observed. Histopathological examination of the liver confirmed hepatopathy revealing characteristic tissue changes such as leucocyte infiltration, hepatic cell membrane degradation, vacuolization, and lipid inclusions. The study provided ethnophysiology insights into the responses of C. carpio to CoCl2-induced oxidative stress and lipidomic alteration, underscoring its potential as a bioindicator for assessing environmental impacts and metal contamination.

Targeting CSF1R in myeloid-derived suppressor cells: insights into its immunomodulatory functions in colorectal cancer and therapeutic implications.

OBJECTIVE: This study aimed to investigate the critical role of MDSCs in CRC immune suppression, focusing on the CSF1R and JAK/STAT3 signaling axis. Additionally, it assessed the therapeutic efficacy of LNCs@CSF1R siRNA and anti-PD-1 in combination. METHODS: Single-cell transcriptome sequencing data from CRC and adjacent normal tissues identified MDSC-related differentially expressed genes. RNA-seq analysis comprehensively profiled MDSC gene expression in murine CRC tumors. LNCs@CSF1R siRNA nanocarriers effectively targeted and inhibited CSF1R. Flow cytometry quantified changes in MDSC surface markers post-CSF1R inhibition. RNA-seq and pathway enrichment analyses revealed the impact of CSF1R on MDSC metabolism and signaling. The effect of CSF1R inhibition on the JAK/STAT3 signaling axis was validated using Colivelin and metabolic assessments. Glucose and fatty acid uptake were measured via fluorescence-based flow cytometry. The efficacy of LNCs@CSF1R siRNA and anti-PD-1, alone and in combination, was evaluated in a murine CRC model with extensive tumor section analyses. RESULTS: CSF1R played a significant role in MDSC-mediated immune suppression. LNCs@CSF1R siRNA nanocarriers effectively targeted MDSCs and inhibited CSF1R. CSF1R regulated MDSC fatty acid metabolism and immune suppression through the JAK/STAT3 signaling axis. Inhibition of CSF1R reduced STAT3 activation and target gene expression, which was rescued by Colivelin. Combined treatment with LNCs@CSF1R siRNA and anti-PD-1 significantly slowed tumor growth and reduced MDSC abundance within CRC tumors. CONCLUSION: CSF1R via the JAK/STAT3 axis critically regulates MDSCs, particularly in fatty acid metabolism and immune suppression. Combined therapy with LNCs@CSF1R siRNA and anti-PD-1 enhances therapeutic efficacy in a murine CRC model, providing a strong foundation for future clinical applications.

Secondary carnitine deficiency during refeeding in severely malnourished patients with eating disorders: a retrospective cohort study.

BACKGROUND: Secondary carnitine deficiency in patients with anorexia nervosa has been rarely reported. This study aimed to investigate the occurrence of carnitine deficiency in severely malnourished patients with eating disorders during refeeding and assess its potential adverse effects on treatment outcomes. METHOD: In a cohort study of 56 female inpatients with eating disorders at a single hospital from March 2010 to December 2020, we measured plasma free carnitine (FC) levels and compared to those of a healthy control group (n = 35). The patients were categorized into three groups based on FC levels: FC deficiency (FC< 20 µmol/L), FC pre-deficiency (20 µmol/L ≤ FC< 36 µmol/L), and FC normal (36 µmol/L ≤ FC). RESULTS: Upon admission, the patients had a median age of 26 years (interquartile range [IQR]: 21-35) and a median body mass index (BMI) of 13.8 kg/m2 (IQR: 12.8-14.8). Carnitine deficiency or pre-deficiency was identified in 57% of the patients. Hypocarnitinemia was associated with a decline in hemoglobin levels during refeeding (odds ratio [OR]: 0.445; 95% confidence interval [CI]: 0.214-0.926, p = 0.03), BMI at admission (OR: 0.478; 95% CI: 0.217-0.874, p = 0.014), and moderate or greater hepatic impairment at admission (OR: 6.385; 95% CI: 1.170-40.833, p = 0.032). CONCLUSIONS: Hypocarnitinemia, particularly in cases of severe undernutrition (BMI< 13 kg/m2 at admission) was observed in severely malnourished patients with eating disorders during refeeding, a critical metabolic transition phase. Moderate or severe hepatic impairment at admission was considered a potential indicator of hypocarnitinemia. Although hypocarnitinemia was not associated with any apparent adverse events other than anemia during refeeding, the possibility that carnitine deficiency may be a risk factor for more serious complications during sudden increases in energy requirements associated with changes in physical status cannot be denied. Further research on the clinical significance of hypocarnitinemia in severely malnourished patients with eating disorders is warranted.

Carnitine is an amino acid derivative that plays an important role in the promotion and regulation of fatty acid metabolism, and carnitine deficiency is assumed in patients with anorexia nervosa associated with chronic starvation, but there are few reports on this issue. This study represents the inaugural documentation of hypocarnitinemia in severely malnourished patients with eating disorders, including anorexia nervosa. Hypocarnitinemia, particularly in cases of severe undernutrition (BMI < 13 kg/m²) was observed during refeeding, a critical metabolic transition phase. Moderate or severe hepatic impairment was considered a potential indicator of hypocarnitinemia. Although no apparent association with adverse events other than anemia during refeeding was identified, clinical manifestations of hypocarnitinemia may occur when a sudden increase in energy demand is added to a change in the physical condition of the patient group. Further investigation is required to determine the clinical significance of hypocarnitinemia.

Leveraging FAM features to predict the prognosis of LGG patients and immunotherapy outcome.

Heterogeneity at biological and transcriptomic levels poses a challenge in defining and typing low-grade glioma (LGG), leading to a critical need for specific molecular signatures to enhance diagnosis, therapy, and prognostic evaluation of LGG. This study focused on fatty acid metabolism (FAM) related genes and prognostic features to investigate the mechanisms and treatment strategies for LGG cell metastasis and invasion. By screening 158 FAM-related genes and clustering 512 LGG samples into two subtypes (C1 and C2), differential gene expression analysis and functional enrichment were performed. The immune cell scores and prognosis were compared between the two subtypes, with C1 showing poorer outcomes and higher immune scores. A four-gene signature (PHEX, SHANK2, HOPX, and LGALS1) was identified and validated across different datasets, demonstrating a stable predictive effect. Cellular experiments confirmed the roles of LGALS1 and HOPX in promoting tumor cell proliferation, migration, and invasion, while SHANK2 exhibited a suppressive effect. This four-gene signature based on FAM-related genes offers valuable insights for understanding the pathogenesis and clinical management of LGG.

Discovering predisposing genes for hereditary breast cancer using deep learning.

Breast cancer (BC) is the most common malignancy affecting Western women today. It is estimated that as many as 10% of BC cases can be attributed to germline variants. However, the genetic basis of the majority of familial BC cases has yet to be identified. Discovering predisposing genes contributing to familial BC is challenging due to their presumed rarity, low penetrance, and complex biological mechanisms. Here, we focused on an analysis of rare missense variants in a cohort of 12 families of Middle Eastern origins characterized by a high incidence of BC cases. We devised a novel, high-throughput, variant analysis pipeline adapted for family studies, which aims to analyze variants at the protein level by employing state-of-the-art machine learning models and three-dimensional protein structural analysis. Using our pipeline, we analyzed 1218 rare missense variants that are shared between affected family members and classified 80 genes as candidate pathogenic. Among these genes, we found significant functional enrichment in peroxisomal and mitochondrial biological pathways which segregated across seven families in the study and covered diverse ethnic groups. We present multiple evidence that peroxisomal and mitochondrial pathways play an important, yet underappreciated, role in both germline BC predisposition and BC survival.

An optimal combination of four active components in Huangqin decoction for the synergistic sensitization of irinotecan against colorectal cancer.

BACKGROUND: Irinotecan (CPT-11) is a first-line treatment for advanced colorectal cancer (CRC). Four components (baicalin, baicalein, wogonin, and glycyrrhizic acid) derived from Huangqin Decoction (HQD) have been proven to enhance the anticancer activity of CPT-11 in our previous study. OBJECTIVE: This study aimed to determine the optimal combination of the four components for sensitizing CPT-11 as well as to explore the underlying mechanism. METHODS: The orthogonal design method was applied to obtain candidate combinations (Cmb1-9) of the four components. The influence of different combinations on the anticancer effect of CPT-11 was first evaluated in vitro by cell viability, wound healing ability, cloning formation, apoptosis, and cell cycle arrest. Then, a CRC xenograft mice model was constructed to evaluate the anticancer effect of the optimal combination in vivo. Potential mechanisms of the optimal combination exerting a sensitization effect combined with CPT-11 against CRC were analyzed by targeted metabolomics. RESULTS: In vitro experiments determined that Cmb8 comprised of baicalin, baicalein, wogonin, and glycyrrhizic acid at the concentrations of 17 µM, 47 µM, 46.5 µM and 9.8 µM respectively was the most effective combination. Importantly, the cell viability assay showed that Cmb8 exhibited synergistic anticancer activity in combination with CPT-11. In in vivo experiments, this combination (15 mg/kg of baicalin, 24 mg/kg of baicalein, 24 mg/kg of wogonin, and 15 mg/kg of glycyrrhizic acid) also showed a synergistic anticancer effect. Meanwhile, inflammatory factors and pathological examination of the colon showed that Cmb8 could alleviate the gastrointestinal damage induced by CPT-11. Metabolic profiling of the tumors suggested that the synergistic anticancer effect of Cmb8 might be related to the regulation of fatty acid metabolism. CONCLUSION: The optimal combination of four components derived from HQD for the synergistic sensitization of CPT-11 against CRC was identified.

miR-218-5p promotes hepatic lipogenesis through targeting Elovl5 in non-alcoholic fatty liver disease.

Investigating and identifying pathogenic molecules of non-alcoholic fatty liver disease (NAFLD) has become imperative, which would serve as effective targets in the future. We established high-fat diet (HFD)-induced NAFLD model in mice and palmitic acid (PA)-induced model in mouse AML12 cells. The level of miR-218-5p was examined by qRT-PCR, and Elovl5 was identified as the potential target gene of miR-218-5p. The binding relationship between miR-218-5p and Elovl5 was validated by double luciferase reporter gene assay, and inhibition/overexpression of miR-218-5p in vitro. The functional mechanisms of miR-218-5p/Elovl5 in regulating lipogenesis in NAFLD were investigated in vivo and in vitro through gain- and loss-of-function studies. MiR-218-5p was significantly increased, and Elovl5 was decreased in model group. According to the double luciferase reporter and gene interference experiments in AML12 cells, Elovl5 was a target gene of miR-218-5p and its expression was regulated by miR-218-5p. The SREBP1-mediated lipogenesis signaling pathway regulated by Elovl5 was upregulated in model group. Moreover, silencing of miR-218-5p significantly upregulated Elovl5 expression, and suppressed SREBP1 signaling pathway in PA-induced AML-12 cells. Correspondingly, the cell injury, elevated TC, TG contents and lipid droplet accumulation were ameliorated. Furthermore, the effect of miR-218-5p on lipogenesis in vitro and in vivo was obstructed by si-Elovl5, implicating that miR-218-5p promotes lipogenesis by targeting ELOVL5 in NAFLD. miR-218-5p could promote fatty acid synthesis by targeting Elovl5, thereby accelerating the development of NAFLD, which is one of the key pathogenic mechanisms of NAFLD and provides a new molecular target for the management of NAFLD.

Pro-survival signaling regulates lipophagy essential for multiple myeloma resistance to stress-induced death.

Pro-survival metabolic adaptations to stress in tumorigenesis remain less well defined. We find that multiple myeloma (MM) is unexpectedly dependent on beta-oxidation of long-chain fatty acids (FAs) for survival under both basal and stress conditions. However, under stress conditions, a second pro-survival signal is required to sustain FA oxidation (FAO). We previously found that CD28 is expressed on MM cells and transduces a significant pro-survival/chemotherapy resistance signal. We now find that CD28 signaling regulates autophagy/lipophagy that involves activation of the Ca2+→AMPK→ULK1 axis and regulates the translation of ATG5 through HuR, resulting in sustained lipophagy, increased FAO, and enhanced MM survival. Conversely, blocking autophagy/lipophagy sensitizes MM to chemotherapy in vivo. Our findings link a pro-survival signal to FA availability needed to sustain the FAO required for cancer cell survival under stress conditions and identify lipophagy as a therapeutic target to overcome treatment resistance in MM.

Alleviation effects of dexmedetomidine on myocardial ischemia/reperfusion injury through fatty acid metabolism pathway via Elovl6.

Dexmedetomidine (Dex) is widely used in the sedation in intensive care units and as an anesthetic adjunct. Considering the anti-inflammatory and antioxidant properties of Dex, we applied in vivo rat model as well as in vitro cardiomyocyte models (embryonic rat cardiomyocytes H9c2 cells and neonatal rat cardiomyocytes, NRCMs) to evaluate the effects of Dex against myocardial ischemia reperfusion (I/R) injury. Transcriptomic sequencing for gene expression in heart tissues from control rats and Dex-treated rats identified that genes related to fatty acid metabolism were significantly regulated by Dex. Among these genes, the elongation of long-chain fatty acids (ELOVL) family member 6 (Elovl6) was most increased upon Dex-treatment. By comparing the effects of Dex on both wild type and Elovl6-knockdown H9c2 cells and NRCMs under oxygen-glucose deprivation/reoxygenation (OGD/R) challenge, we found that Elovl6 knockdown attenuated the protection efficiency of Dex, which was supported by the cytotoxicity endpoints (cell viability and lactate dehydrogenase release) and apoptosis as well as key gene expressions. These results indicate that Dex exhibited the protective function against myocardial I/R injury via fatty acid metabolism pathways and Elovl6 plays a key role in the process, which was further confirmed using palmitate exposure in both cells, as well as in an in vivo rat model. Overall, this study systematically evaluates the protective effects of Dex on the myocardial I/R injury and provides better understanding on the fatty acid metabolism underlying the beneficial effects of Dex.