Ficolin 3 promotes ferroptosis in HCC by downregulating IR/SREBP axis-mediated MUFA synthesis.

BACKGROUND: Targeting ferroptosis has been identified as a promising approach for the development of cancer therapies. Monounsaturated fatty acid (MUFA) is a type of lipid that plays a crucial role in inhibiting ferroptosis. Ficolin 3 (FCN3) is a component of the complement system, serving as a recognition molecule against pathogens in the lectin pathway. Recent studies have reported that FCN3 demonstrates inhibitory effects on the progression of certain tumors. However, whether FCN3 can modulate lipid metabolism and ferroptosis remains largely unknown. METHODS: Cell viability, BODIPY-C11 staining, and MDA assay were carried out to detect ferroptosis. Primary hepatocellular carcinoma (HCC) and xenograft models were utilized to investigate the effect of FCN3 on the development of HCC in vivo. A metabonomic analysis was conducted to assess alterations in intracellular and HCC intrahepatic lipid levels. RESULTS: Our study elucidates a substantial decrease in the expression of FCN3, a component of the complement system, leads to MUFA accumulation in human HCC specimens and thereby significantly promotes ferroptosis resistance. Overexpression of FCN3 efficiently sensitizes HCC cells to ferroptosis, resulting in the inhibition of the oncogenesis and progression of both primary HCC and subcutaneous HCC xenograft. Mechanistically, FCN3 directly binds to the insulin receptor ß (IR-ß) and its pro-form (pro-IR), inhibiting pro-IR cleavage and IR-ß phosphorylation, ultimately resulting in IR-ß inactivation. This inactivation of IR-ß suppresses the expression of sterol regulatory element binding protein-1c (SREBP1c), which subsequently suppresses the transcription of genes related to de novo lipogenesis (DNL) and lipid desaturation, and consequently downregulates intracellular MUFA levels. CONCLUSIONS: These findings uncover a novel regulatory mechanism by which FCN3 enhances the sensitivity of HCC cells to ferroptosis, indicating that targeting FCN3-induced ferroptosis is a promising strategy for HCC treatment.

trans-Palmitoleic acid promotes adipose thermogenesis to reduce obesity via hypothalamic FFAR1 signaling.

Diet-induced thermogenesis (DIT) is crucial for maintaining body weight homeostasis, and the role of dietary fatty acids in modulating DIT is essential. However, the underlying mechanism of fatty acid regulated diet-induced thermogenesis remains elusive. Utilizing the diet- and genetic ablation-induced obese mice models, we found that the C16 unsaturated fatty acids, trans-palmitoleic acid (TPA) and cis-palmitoleic acid (CPA), significantly increased the energy expenditure by promoting the thermogenesis of brown adipose tissues and the production of beige cells in white adipose. As a result, there is a significant reduction in the occurrence of obesity, associated hepatic steatosis and hyperglycemia. Notably, TPA exhibited more potent effects on promoting DIT and alleviating obesity than CPA did. Using inhibitor and gene deletion mice models, we unveiled that TPA acted as a signaling molecule to play a biological function, which could be sensed by the hypothalamic FFAR1 to activate the sympathetic nervous system in promoting adipose tissue thermogenesis. Together, these results demonstrate the underlying mechanism of free fatty acids associated-DIT and will provide fresh insights into the roles of trans-fatty acids in the development of obesity.

Scd1 and monounsaturated lipids are required for autophagy and survival of adipocytes.

OBJECTIVE: Exposure of adipocytes to 'cool' temperatures often found in the periphery of the body induces expression of Stearoyl-CoA Desaturase-1 (Scd1), an enzyme that converts saturated fatty acids to monounsaturated fatty acids. The goal of this study is to further investigate the roles of Scd in adipocytes. METHOD: In this study, we employed Scd1 knockout cells and mouse models, along with pharmacological Scd1 inhibition to dissect the enzyme's function in adipocyte physiology. RESULTS: Our study reveals that production of monounsaturated lipids by Scd1 is necessary for fusion of autophagosomes to lysosomes and that with a Scd1-deficiency, autophagosomes accumulate. In addition, Scd1-deficiency impairs lysosomal and autolysosomal acidification resulting in vacuole accumulation and eventual cell death. Blocking autophagosome formation or supplementation with monounsaturated fatty acids maintains vitality of Scd1-deficient adipocytes. CONCLUSION: This study demonstrates the indispensable role of Scd1 in adipocyte survival, with its inhibition in vivo triggering autophagy-dependent cell death and its depletion in vivo leading to the loss of bone marrow adipocytes.

Palmitoleic Acid Ameliorates Metabolic Disorders and Inflammation by Modulating Gut Microbiota and Serum Metabolites.

SCOPE: Palmitoleic acid (POA) is an omega-7 monounsaturated fatty acid that has been suggested to improve metabolic disorders. However, it remains unclear whether gut microbiota plays a role in the amelioration of metabolic disorders by POA. This study aims to investigate the regulation of POA on metabolism, as well as systemic inflammation in HFD-fed mice from the perspective of serum metabolome and gut microbiome. METHODS AND RESULTS: Thirty-six C57BL/6 male mice are randomly assigned to either a normal chow diet containing 1.9% w/w lard or an HFD containing 20.68% w/w lard or 20.68% w/w sea buckthorn pulp oil for 16 weeks. The study finds that POA significantly attenuated hyperlipidemia, insulin resistance, and inflammation in HFD-fed mice. POA supplementation significantly alters the composition of serum metabolites, particularly lipid metabolites in the glycerophospholipid metabolism pathway. POA obviously increases the abundance of Bifidobacterium and decreases the abundance of Allobaculum. Importantly, the study finds that glycerophosphocholine mediates the effect of Bifidobacterium on LDL-C, sphingomyelin mediates the effect of Bifidobacterium on IL-6, and maslinic acid mediates the effect of Allobaculum on IL-6. CONCLUSION: The results suggest that exogenous POA can improve metabolic disorders and inflammation in HFD-fed mice, potentially by modulating the serum metabolome and gut microbiome.

Female semiochemicals stimulate male courtship but dampen female sexual receptivity.

Chemical communication plays a vital role in mate attraction and discrimination among many insect species. Here, we document a unique example of semiochemical parsimony, where four chemicals act as both aphrodisiacs and anti-aphrodisiacs in different contexts in Bactrocera dorsalis. Specifically, we identified four female-specific semiochemicals, ethyl laurate, ethyl myristate, ethyl cis-9-hexadecenoate, and ethyl palmitate, which serve as aphrodisiacs to attract male flies and arouse male courtship. Interestingly, these semiochemicals, when sexually transferred to males during mating, can function as anti-aphrodisiacs, inhibiting the receptivity of subsequent female mates. We further showed that the expression of elongase11, a key enzyme involved in the biosynthesis of these semiochemicals, is under the control of doublesex, facilitating the exclusive biosynthesis of these four semiochemicals in females and guaranteeing effective chemical communication. The dual roles of these semiochemicals not only ensure the attractiveness of mature females but also provide a simple yet reliable mechanism for female mate discrimination. These findings provide insights into chemical communication in B. dorsalis and add elements for the design of pest control programs.

Metabolomic and Transcriptomic Analysis of Effects of Three MUFA-Rich Oils on Hepatic Glucose and Lipid Metabolism in Mice.

SCOPE: Olive oil, rapeseed oil, and lard are dietary fats rich in monounsaturated fatty acids, but the effects of dietary oils enriched in monounsaturated fatty acids on hepatic lipid deposition have seldom been compared. METHODS AND RESULTS: Ninety 8-week-old C57BL/6J male mice are randomly divided into six groups and fed diets containing lard, rapeseed oil, or olive oil with a 10% or 45% fat energy supply for 16 weeks. Under high-fat conditions, serum total cholesterol levels in the lard and olive oil groups are significantly higher than those in the rapeseed oil group. Hepatic lipid content in the olive oil group is higher than that in the other two groups. Compared with rapeseed oil, lard increases the liver levels of arachidonic, palmitic, and myristic acids and decreases the levels of eicosapentaenoic linolenic acid and linoleic acid. Olive oil increases the liver levels of docosatrienoic, arachidonic, oleic, and myristic acids; maltose; and fructose and decreases the levels of eicosapentaenoic, linolenic, and linoleic acids. CONCLUSION: Olive oil probably causes hepatic lipid deposition in mice, which may enhance hepatic lipid synthesis by activating the starch and sucrose metabolic pathways. By contrast, rapeseed oil shows a significant anti-lipid deposition effect on the liver.

Immediate-release niacin and a monounsaturated fatty acid-rich meal on postprandial inflammation and monocyte characteristics in men with metabolic syndrome.

BACKGROUND & AIM: When considered separately, long-term immediate-release niacin and fatty meals enriched in monounsaturated fatty acids (MUFA) decrease postprandial triglycerides, but their effects on postprandial inflammation, which is common in individuals with metabolic syndrome, are less known. Moreover, successful combination is lacking and its impact on acute disorders of the innate immune cells in the metabolic syndrome remains unclear. Here, we aimed to establish the effects from combination with niacin of different fats [butter, enriched in saturated fatty acids (SFA), olive oil, enriched in MUFA, and olive oil supplemented with eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids] on plasma inflammatory markers and circulating monocyte subsets, activation and priming at the postprandial period in individuals with metabolic syndrome. METHODS: A random-order within-subject crossover experiment was performed, in which 16 individuals with metabolic syndrome and 16 age-matched healthy volunteers took 2 g immediate-release niacin together with the corresponding fatty meal or a meal with no fat as control. In total, 128 postprandial curves were analysed. We sampled hourly over 6 h for plasma concentrations of soluble inflammatory markers and triglycerides. Circulating monocyte subsets (CD14/CD16 balance), activation (CCL2/CCR2 axis) and priming (M1/M2-like phenotype) at the time of postprandial hypertriglyceridemic peak were also addressed. RESULTS: Dietary SFA (combined with niacin) promote postprandial excursions of circulating IL-6, IL-1ß, TNF-α and CD14/CCR2-rich monocytes with a pro-inflammatory M1-like phenotype, particularly in individuals with metabolic syndrome. In contrast, dietary MUFA (combined with niacin) postprandially increased circulating CD16-rich monocytes with an anti-inflammatory M2-like phenotype. Omega-3 PUFA did not add to the effects of MUFA. CONCLUSION: The co-administration of a single-dose of immediate-release niacin with a fatty meal rich in MUFA, in contrast to SFA, suppresses postprandial inflammation at the levels of both secretory profile and monocyte response in individuals with metabolic syndrome. These findings highlight a potential role of combining niacin and dietary MUFA for the homeostatic control of inflammation and the innate immune system, identifying a new search direction for the management of disorders associated with the metabolic syndrome.

Cis-monounsaturated fatty acids inhibit ferroptosis through downregulation of transferrin receptor 1.

Ferroptosis, a form of cell death mediated by lipid peroxidation, is implicated in various pathological processes. Although monounsaturated fatty acids (MUFAs) can inhibit ferroptotic lipid peroxidation, the underlying structural mechanism of this antagonistic effect remains poorly understood. We hypothesized that MUFAs with different structures (including chain length, conformation, and double bond position) may affect their regulatory effect on ferroptosis. In this study, 11 MUFAs with varying structures were screened to identify those with an inhibitory effect on ferroptosis. Results from 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazoliumbromide assays indicated that only exogenous MUFAs with cis-conformation and centered double bond could inhibit ferroptosis. Meanwhile, it was found that suppressing the expression of SCD1 and SCD5 genes could sensitize cells to ferroptosis indicating the protective role of endogenous MUFA against ferroptosis. Additionally, western blot analysis revealed that cis-MUFAs with centered double bond downregulated the protein levels of transferrin receptor 1. Flow cytometry confirmed that these MUFAs led to decreases in intracellular iron, reactive oxygen species, and lipid peroxides. It was also found that SCD1 inhibitor could enhance ferroptosis inducer-mediated tumor suppression both in vivo and in vitro. Overall, these findings shed light on the particular structural features of MUFAs that contribute to their ferroptosis-resistant properties and suggest the potential therapeutic relevance of natural MUFAs in a range of ferroptosis-related diseases.

Comparison of the Effects of Monounsaturated Fatty Acids and Polyunsaturated Fatty Acids on Liver Lipid Disorders in Obese Mice.

Obesity is a recognized epidemic worldwide, and the accumulation of excess free saturated fatty acids (SFAs) in cells induces cellular lipotoxic damage and increases the risk of a wide spectrum of metabolic diseases including type 2 diabetes (T2D) and nonalcoholic fatty liver disease (NAFLD). Monounsaturated fatty acids (MUFAs) and polyunsaturated fatty acids (PUFAs) have been reported to combat SFA-induced cellular damage. However, the comparative studies of the two types of unsaturated fatty acids (UFAs) are still limited. We investigated the effects of different MUFAs and PUFAs in the human hepatocyte line L-02 cells in vitro, and in high-fat-diet (HFD)-induced obese C57BL/6 mice in vivo. The results of the in vitro study showed that SFAs induced significant cellular lipotoxic damage, but the combination of MUFAs/PUFAs with SFAs significantly improved the impaired cell viability. Particularly, oleic acid (OA) was superior to eicosapentaenoic acid (EPA), Docosahexaenoic acid (DHA), and arachidonic acid (AA) in terms of its anti-apoptotic effect and inhibition of endoplasmic reticulum (ER) stress. In vivo, both olive-oil-enriched (HFD + OO) and fish-oil-enriched high-fat diets (HFD + FO) reduced hepatic steatosis and improved insulin sensitivity in obese mice. However, FO induced an abnormal increase in serum aspartate aminotransferase (AST) and an increase in the oxidative stress indicator Malondialdehyde (MDA). Liver-targeted lipidomic analysis showed that liver lipid metabolites under the two types of UFA dietary interventions differed from the HFD group, modulating the abundance of some lipid metabolites such as triglycerides (TGs) and glycerophospholipids. Furthermore, the FO diet significantly increased the abundance of the associated FA 20:5 long-chain lipid metabolites, whereas the OO diet regulated the unsaturation of all fatty acids in general and increased the abundance of FA 18:1 in the overall lipid metabolites, especially TGs, which may primarily contribute to the FO, and OO drove protection in NAFLD.

Impact of saturated compared with unsaturated dietary fat on insulin sensitivity, pancreatic ß-cell function and glucose tolerance: a systematic review and meta-analysis of randomized, controlled trials.

BACKGROUND: The impact of the dietary fat type on type 2 diabetes (T2D) remains unclear. OBJECTIVES: We aimed to evaluate the effects of replacing dietary saturated fatty acids (SFA) with mono- or poly-unsaturated fatty acids (MUFA and PUFA, respectively) on insulin sensitivity, pancreatic ß-cell function, and glucose tolerance, as surrogate endpoints for T2D. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials that replaced ≥5% of total energy intake provided by SFA with MUFA or PUFA and reported indexes of insulin sensitivity, ß-cell function, and/or glucose tolerance. We searched MEDLINE, Scopus, and the Cochrane Library (CENTRAL) up to 9 January, 2023. Eligible interventions had to be isocaloric, with no significant difference in other macronutrients. Data were synthesized using random-effects model meta-analysis. RESULTS: Of 6355 records identified, 10 parallel and 20 crossover trials with 1586 participants were included. The mean age of the participants was 42 years, 47% were male, mean body mass index (BMI; in kg/m2) was 26.8, median baseline fasting glucose was 5.13 mmol/L, and the median duration of interventions was 5 weeks. Replacing SFA with MUFA or PUFA had no significant effects on insulin sensitivity [standardized mean difference (SMD) SFA compared with MUFA: 0.01, 95% confidence interval (CI): -0.06 to 0.09, I2 = 0% and SMD SFA compared with PUFA: 0, 95% CI: -0.15 to 0.14, I2 = 0%]. Replacing SFA with MUFA did not significantly impact the ß-cell function, evaluated by the disposition index (mean difference: -12, 95% CI: -158 to 133, I2=0%). Evidence on glucose tolerance (SFA compared with MUFA or PUFA) and on ß-cell function when SFA were replaced with PUFA was scant. CONCLUSIONS: Short-term substitution of saturated with unsaturated fat does not significantly affect insulin sensitivity nor ß-cell function (the latter in the SFA compared with MUFA comparison). Future studies are needed to elucidate longer term effects of dietary fat saturation on glucose homeostasis. This trial was registered at PROSPERO as CRD42020178382.

Dietary Saturated, Monounsaturated, or Polyunsaturated Fatty Acids and Estimated 10-Year Risk of a First Hard Cardiovascular Event.

BACKGROUND: The effects of dietary saturated, monounsaturated, or polyunsaturated fatty acids on the risk of cardiovascular events remain controversial. METHODS: This cross-sectional study was performed in 4211 patients, aged 40 to 79 years, from the National Health and Nutrition Examination Survey between 1999 and 2018. The independent variables were saturated fatty acids, monounsaturated fatty acids, and polyunsaturated fatty acids. The dependent variable was the 10-year risk of a first hard atherosclerotic cardiovascular event. The other variables were considered as the potential confounding factors. Multivariate linear regression models and smooth curve fittings were used to evaluate the association between saturated fatty acids, polyunsaturated fatty acids, or monounsaturated fatty acids and the 10-year risk. RESULTS: There was no association between dietary saturated fatty acids and 10-year risk after adjusting for all the potential confounding factors; 10-year risk decreased by 0.022% each 1-g increase in monounsaturated fatty acids intake from 0 to 153.772 g, and 0.025% each 1-g increase in polyunsaturated fatty acids intake from 0 to 98.323 g, respectively. Moreover, subgroup analysis showed that monounsaturated fatty acids and polyunsaturated fatty acids were both negatively correlated to 10-year risk in nondiabetes and non-high-low-density lipoprotein patients; monounsaturated fatty acids were also negatively associated with 10-year risk in hypertensive patients. CONCLUSIONS: There was no association between dietary saturated fatty acids and 10-year risk. Increased dietary intake of monounsaturated fatty acids or polyunsaturated fatty acids decreased 10-year risk, particularly in nondiabetes, non-high-low density lipoprotein patients.

Improved colonic inflammation by nervonic acid via inhibition of NF-κB signaling pathway of DSS-induced colitis mice.

BACKGROUND: Nervonic acid (C24:1∆15, 24:1 ω-9, cis-tetracos-15-enoic acid; NA), a long-chain monounsaturated fatty acid, plays an essential role in prevention of metabolic diseases, and immune regulation, and has anti-inflammatory properties. As a chronic, immune-mediated inflammatory disease, ulcerative colitis (UC) can affect the large intestine. The influences of NA on UC are largely unknown. PURPOSE: The present study aimed to decipher the anti-UC effect of NA in the mouse colitis model. Specifically, we wanted to explore whether NA can regulate the levels of inflammatory factors in RAW264.7 cells and mouse colitis model. METHODS: To address the above issues, the RAW264.7 cell inflammation model was established by lipopolysaccharide (LPS), then the inflammatory factors tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß), and Interleukin-10 (IL-10) were detected by Enzyme-linked immunosorbent assay (ELISA). The therapeutic effects of NA for UC were evaluated using C57BL/6 mice gavaged dextran sodium sulfate (DSS). Hematoxylin and eosin (H&E) staining, Myeloperoxidase (MPO) kit assay, ELISA, immunofluorescence assay, and LC-MS/MS were used to assess histological changes, MPO levels, inflammatory factors release, expression and distribution of intestinal tight junction (TJ) protein ZO-1, and metabolic pathways, respectively. The levels of proteins involved in the nuclear factor kappa-B (NF-κB) pathway in the UC were investigated by western blotting and RT-qPCR. RESULTS: In vitro experiments verified that NA could reduce inflammatory response and inhibit the activation of key signal pathways associated with inflammation in LPS-induced RAW264.7 cells. Further, results from the mouse colitis model suggested that NA could restore intestinal barrier function and suppress NF-κB signal pathways to ameliorate DSS-induced colitis. In addition, untargeted metabolomics analysis of NA protection against UC found that NA protected mice from colitis by regulating citrate cycle, amino acid metabolism, pyrimidine and purine metabolism. CONCLUSION: These results suggested that NA could ameliorate the secretion of inflammatory factors, suppress the NF-κB signaling pathway, and protect the integrity of colon tissue, thereby having a novel role in prevention or treatment therapy for UC. This work for the first time indicated that NA might be a potential functional food ingredient for preventing and treating inflammatory bowel disease (IBD).

Novel Formulation of Undecylenic Acid induces Tumor Cell Apoptosis.

Undecylenic acid, a monounsaturated fatty acid, is currently in clinical use as a topical antifungal agent, however the potential for therapeutic application in other disease settings has not been investigated. In this study, we describe a novel platform for the solubilization of fatty acids using amino acids and utilize this approach to define a tumoricidal activity and underlying mechanism for undecylenic acid. We examined a novel formulation of undecylenic acid compounded with L-Arginine, called GS-1, that induced concentration-dependent tumor cell death, with undecylenic acid being the cytotoxic component. Further investigation revealed that GS-1-mediated cell death was caspase-dependent with a reduction in mitochondrial membrane potential, suggesting a pro-apoptotic mechanism of action. Additionally, GS-1 was found to localize intracellularly to lipid droplets. In contrast to previous studies where lipid droplets have been shown to be protective against fatty acid-induced cell death, we showed that lipid droplets could not protect against GS-1-induced cytotoxicity. We also found a role for Fatty Acid Transport Protein 2 (FATP2) in the uptake of this compound. Collectively, this study demonstrates that GS-1 has effective pro-apoptotic antitumor activity in vitro and, together with the novel platform of fatty acid solubilization, contributes to the re-emerging field of fatty acids as potential anti-cancer therapeutics.

Hybrid nanoparticulate system of Fluvastatin loaded phospholipid, alpha lipoic acid and melittin for the management of colon cancer.

As a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, Fluvastatin (FLV) is used for reducing low-density lipoprotein (LDL) cholesterol as well as to prevent cardiovascular problems. FLV showed cell line cytotoxicity and antitumor effect. Melittin (MEL) exhibits antineoplastic activity and is known to be promising as a therapeutic option for cancer patients. The aim of this work was to investigate the combination of FLV with MEL loaded hybrid formula of phospholipid (PL) with alpha lipoic acid (ALA) nanoparticles to maximize anticancer tendencies. This study examines the optimization of the prepared formulation in order to minimize nanoparticles size and maximize zeta potential to potentiate cytotoxic potentialities in colon cancer cells (Caco2), cell viability, cell cycle analysis and annexin V were tested. In addition to biological markers as P53, Bax, bcl2 and Caspase 3 evaluation The combination involving FLV PL ALA MEL showed enhanced cytotoxic potentiality (IC50 = 9.242 ± 0.35 µg/mL), about twofold lower, compared to the raw FLV (IC50 = 21.74 ± 0.82 µg/mL). According to studies analyzing cell cycle, optimized FLV PL ALA MEL was found to inhibit Caco2 colon cancer cells more significantly than other therapeutic treatments, wherein a higher number of cells were found to accumulate over G2/M and pre-G1 phases, whereas G0/G1/S phases witnessed the accumulation of a lower number of cells. The optimized formulation may pave the way for a novel and more efficacious treatment for colon cancer.

Mediation analysis of erythrocyte lipophilic index on the association between BMI and risk of oral cancer.

AIMS: To explore the relationship between the fatty acid lipophilic index (LI) of the erythrocyte membrane and oral cancer risk, as well as to evaluate the possibility of LI acting as a mediator of the association between body mass index (BMI) and oral cancer. METHOD: Twenty-three fatty acids (FAs) of the erythrocyte membrane were measured using gas chromatography in 380 patients with oral cancer and 387 control subjects. The LI was calculated based on the FA proportion and FA melting points. The association of BMI and erythrocyte LI with oral cancer risk was analysed using logistic regression. The mediation effect of LI on the association between BMI and oral cancer risk was evaluated using mediation analysis. RESULTS: Among the control group, 46.0% were overweight or obese, which was significantly higher than that of oral cancer patients (29.5%). Significant differences in erythrocyte membrane saturated fatty acids (SFAs), monounsaturated fatty acids (MUFAs), and polyunsaturated fatty acids (PUFAs) were observed between the patient and control groups. The proportion of C18:1 n-9 from the MUFA family increased in oral cancer patients (12.67%) compared with controls (12.21%). While the total proportion of n-3 PUFAs decreased in oral cancer patients compared with controls, with C20:5 n-3 decreasing from 0.66 to 0.47%, and C22:6 n-3 decreasing from 5.82 to 4.86%. The LI was lower in the control participants (M = 27.6, IQR: 27.3-27.9) than in the oral cancer patients (M = 28.2, IQR: 27.9-28.5). BMI was inversely associated with oral cancer risk with a fully adjusted OR of 0.59 (95% CI: 0.43-0.83), while LI was positively associated with oral cancer risk with a fully adjusted OR of 1.99 (95% CI:1.36-2.94). LI explained 7% of the variance in the relationship between BMI and oral cancer risk. CONCLUSIONS: The distribution of the FA profile in erythrocyte membranes differed between the oral cancer patients and the control group. The LI derived from the profile of FAs was positively associated with the risk of oral cancer, and the associations between BMI and oral cancer risk can be explained, at least in part, by LI.

Overcoming chemoresistance in glioblastoma by fluvastatin via prenylation-dependent inhibition of Ras signaling.

The resistance of glioblastoma to chemotherapy remains a significant clinical problem. Targeting alternative pathways such as protein prenylation is known to be effective against many cancers. Fluvastatin is a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl- CoA (HMG-CoA) reductase, thereby inhibits prenylation. We demonstrate that fluvastatin alone effectively inhibits proliferation and induces apoptosis in multiple human glioblastoma cell lines. The combination index analysis shows that fluvastatin acts synergistically with common chemotherapy drugs for glioblastoma: temozolomide and irinotecan. We further show that fluvastatin acts on glioblastoma through inhibiting prenylation-dependent Ras activation. The combination of fluvastatin and low dose temozolomide resulted in remarkable inhibition of glioblastoma tumor in mice throughout the whole treatment duration without causing toxicity. Such combinatorial effects provide the basis for utilizing these FDA-approved drugs as a potential clinical approach in overcoming resistance and improving glioblastoma treatment.

The Different Insulin-Sensitising and Anti-Inflammatory Effects of Palmitoleic Acid and Oleic Acid in a Prediabetes Model.

Introduction: Monounsaturated fatty acids (MUFA) are understood to have therapeutic and preventive effects on chronic complications associated with type 2 diabetes mellitus (T2DM); however, there are differences between individual MUFAs. Although the effects of palmitoleic acid (POA) are still debated, POA can regulate glucose homeostasis, lipid metabolism, and cytokine production, thus improving metabolic disorders. In this study, we investigated and compared the metabolic effects of POA and oleic acid (OA) supplementation on glucose and lipid metabolism, insulin sensitivity, and inflammation in a prediabetic model, the hereditary hypertriglyceridemic rat (HHTg). HHTg rats exhibiting genetically determined hypertriglyceridemia, insulin resistance, and impaired glucose tolerance were fed a standard diet. POA and OA were each administered intragastrically at a dose of 100 mg/kg b.wt. for four weeks. Results: Supplementation with both MUFAs significantly elevated insulin and glucagon levels, but only POA decreased nonfasting glucose. POA-treated rats showed elevated circulating NEFA associated with increased lipolysis, lipoprotein lipase gene expression, and fatty acid reesterification in visceral adipose tissue (VAT). The mechanism of improved insulin sensitivity of peripheral tissues (measured as insulin-stimulated lipogenesis and glycogenesis) in POA-treated HHTg rats could contribute increased circulating adiponectin and omentin levels together with elevated FADS1 gene expression in VAT. POA-supplemented rats exhibited markedly decreased proinflammatory cytokine production by VAT, which can alleviate chronic inflammation. OA-supplemented rats exhibited decreased arachidonic acid (AA) profiles and decreased proinflammatory AA-derived metabolites (20-HETE) in membrane phospholipids of peripheral tissues. Slightly increased FADS1 gene expression after OA along with increased adiponectin production by VAT was reflected in slightly ameliorated adipose tissue insulin sensitivity (increased insulin-stimulated lipogenesis). Conclusions: Our results show that POA served as a lipokine, ameliorating insulin sensitivity in peripheral tissue and markedly modulating the metabolic activity of VAT including cytokine secretion. OA had a beneficial effect on lipid metabolism and improved inflammation by modulating AA metabolism.

Gondoic acid alleviates LPS­induced Kupffer cells inflammation by inhibiting ROS production and PKCθ/ERK/STAT3 signaling pathway.

Kupffer cells (KCs) is the main macrophage in liver, and its inflammation is related to liver diseases. It has been shown that inflammatory macrophages are accompanied by changes in monounsaturated fatty acid (MUFA) content. However, the effect of gondoic acid (GA) on inflammation and its underlying mechanism have not been described. In the current study, we demonstrated that GA significantly inhibited the expression of pro-inflammatory factors in LPS-exposed KCs. Further research found that GA reduced lipopolysaccharide (LPS)-stimulated reactive oxygen species (ROS) levels and enhanced the expression of antioxidant genes. Meanwhile, GA obviously blocked the LPS-stimulated PKCθ/ERK/STAT3 signaling pathways to alleviate the inflammatory responses. These results demonstrated for the first time that GA improves KCs inflammation through the inhibition of ROS production and PKCθ/ERK/STAT3 signaling pathway, the results assist in the potential development of functional foods or prodrugs based on the GA rich plant oils.

Lipidomics Analysis Reveals a Protective Effect of Myriocin on Cerebral Ischemia/Reperfusion Model Rats.

Ceramide accumulation has been associated with ischemic stroke. Myriocin is an effective serine palmitoyltransferase (SPT) inhibitor that reduces ceramide levels by inhibiting the de novo synthesis pathway. However, the role of myriocin in cerebral ischemia/reperfusion (I/R) injury and its underlying mechanism remain unknown. The present study established an experimental rat model of middle cerebral artery occlusion (MCAO). We employed ultra-performance liquid chromatograph quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS)-based lipidomic analysis to identify the disordered lipid metabolites and the effects of myriocin in cerebral cortical tissues of rats. In this study, we found 15 characterized lipid metabolites involved in sphingolipid and glycerophospholipid metabolism in cerebral I/R-injured rats, and these alterations were significantly alleviated by myriocin. Specifically, the mRNA expression of metabolism-related enzyme genes was detected by real-time quantitative polymerase chain reaction (RT-qPCR). We demonstrated that myriocin could regulate the mRNA expression of ASMase, NSMase, SGMS1, SGMS2, ASAH1, ACER2, and ACER3, which are involved in sphingolipid metabolism and PLA2, which is involved in glycerophospholipid metabolism. Moreover, TUNEL and Western blot assays showed that myriocin plays a key role in regulating neuronal cell apoptosis. In summary, the present work provides a new perspective for the systematic study of metabolic changes in ischemic stroke and the therapeutic applications of myriocin.

A label-free SPR biosensor for specific detection of TLR4 expression; introducing of 10-HDA as an antagonist.

Toll-like receptor 4 (TLR4) is actively involved in many health-related problems, including transplantation rejection and autoimmune diseases. Therefore, it is important to identify an antagonist to inhibit the TLR4-induced immune cell activation. In our previous study, 10-hydroxy-2-decanoic acid (10-HDA) was introduced as a potential antagonist for TLR4; however, possible interaction between 10-HDA and TLR4 needed to be detected. Due to the ability of surface plasmon resonance (SPR) biosensor to confirm the specific interactions between receptors and ligands, a new configuration of SPR biosensor proposed to detect the possible interaction between 10-HDA and TLR4. Hence, 10-HDA was immobilized using the (3-aminopropyl) triethoxysilane (APTES) polymer as a crosslinking agent on the Ag-MgF2 surface. Besides, genetically modified HEK293T cells with high TLR4 expression were used to study the possible interaction between 10-HDA and TLR4. Surprisingly, the SPR angle was significantly reduced in the presence of HEK cells expressing TLR4, while HEK cells without TLR4 did not affect the SPR angle. So, the proposed SPR biosensor successfully detected the interaction betweenTLR4 and 10-HDA. The sensitivity and detection limit of the biosensor were achieved at 0.05 and 0.5 million cells expressing TLR4, respectively, with a two-fold dynamic range.