A novel HIF2A mutation causes dyslipidemia and promotes hepatic lipid accumulation.

Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor responsible for regulating genes related to angiogenesis and metabolism. This study aims to explore the effect of a previously unreported mutation c.C2473T (p.R825S) in the C-terminal transactivation domain (CTAD) of HIF-2α that we detected in tissue of patients with liver disease. We sequenced available liver and matched blood samples obtained during partial liver resection or liver transplantation performed for clinical indications including hepatocellular carcinoma and liver failure. In tandem, we constructed cell lines and a transgenic mouse model bearing the corresponding identified mutation in HIF-2α from which we extracted primary hepatocytes. Lipid accumulation was evaluated in these cells and liver tissue from the mouse model using Oil Red O staining and biochemical measurements. We identified a mutation in the CTAD of HIF-2α (c.C2473T; p.R825S) in 5 of 356 liver samples obtained from patients with hepatopathy and dyslipidemia. We found that introduction of this mutation into the mouse model led to an elevated triglyceride level, lipid droplet accumulation in liver of the mutant mice and in their extracted primary hepatocytes, and increased transcription of genes related to hepatic fatty acid transport and synthesis in the mutant compared to the control groups. In mutant mice and cells, the protein levels of nuclear HIF-2α and its target perilipin-2 (PLIN2), a lipid droplet-related gene, were also elevated. Decreased lipophagy was observed in mutant groups. Our study defines a subpopulation of dyslipidemia that is caused by this HIF-2α mutation. This may have implications for personalized treatment.

Endoplasmic reticulum stress signaling in cancer and neurodegenerative disorders: Tools and strategies to understand its complexity.

The endoplasmic reticulum (ER) comprises a network of tubules and vesicles that constitutes the largest organelle of the eukaryotic cell. Being the location where most proteins are synthesized and folded, it is crucial for the upkeep of cellular homeostasis. Disturbed ER homeostasis triggers the activation of a conserved molecular machinery, termed the unfolded protein response (UPR), that comprises three major signaling branches, initiated by the protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1 (IRE1) and the activating transcription factor 6 (ATF6). Given the impact of this intricate signaling network upon an extensive list of cellular processes, including protein turnover and autophagy, ER stress is involved in the onset and progression of multiple diseases, including cancer and neurodegenerative disorders. There is, for this reason, an increasing number of publications focused on characterizing and/or modulating ER stress, which have resulted in a wide array of techniques employed to study ER-related molecular events. This review aims to sum up the essentials on the current knowledge of the molecular biology of endoplasmic reticulum stress, while highlighting the available tools used in studies of this nature.

Elafibranor restricts lipogenic and inflammatory responses in a human skin stem cell-derived model of NASH.

Non-alcoholic steatohepatitis (NASH) is characterized by hepatocellular steatosis with concomitant hepatic inflammation. Despite its pandemic proportions, no anti-NASH drugs have been approved yet. This is partially because drug development is decelerated due to the lack of adequate tools to assess the efficacy of potential new drug candidates. The present study describes the development and application of a new preclinical model for NASH using hepatic cells generated from human skin-derived precursors. Exposure of these cells to lipogenic (insulin, glucose, fatty acids) and pro-inflammatory factors (IL-1ß, TNF-α, TGF-ß) resulted in a characteristic NASH response, as indicated by intracellular lipid accumulation, modulation of NASH-specific gene expression, increased caspase-3/7 activity and the expression and/or secretion of inflammatory markers, including CCL2, CCL5, CCL7, CCL8, CXCL5, CXCL8, IL1a, IL6 and IL11. The human relevance of the proposed NASH model was verified by transcriptomics analyses that revealed commonly modulated genes and the identification of the same gene classes between the in vitro system and patients suffering from NASH. The application potential of this in vitro model was demonstrated by testing elafibranor, a promising anti-NASH compound currently under clinical phase III trial evaluation. Elafibranor attenuated in vitro key features of NASH, and dramatically lowered lipid load as well as the expression and secretion of inflammatory chemokines, which in vivo are responsible for the recruitment of immune cells. This reduction in inflammatory response was NFκB-mediated. In summary, this human-relevant, in vitro system proved to be a sensitive testing tool for the investigation of novel anti-NASH compounds.

Ilexgenin A inhibits endoplasmic reticulum stress and ameliorates endothelial dysfunction via suppression of TXNIP/NLRP3 inflammasome activation in an AMPK dependent manner.

Ilexgenin A is a natural triterpenoid with beneficial effects on lipid disorders. This study aimed to investigate the effects of ilexgenin A on endothelial homeostasis and its mechanisms. Palmitate (PA) stimulation induced endoplasmic reticulum stress (ER stress) and subsequent thioredoxin-interacting protein (TXNIP)/NLRP3 inflammasome activation in endothelial cells, leading to endothelial dysfunction. Ilexgenin A enhanced LKB1-dependent AMPK activity and improved ER stress by suppression of ROS-associated TXNIP induction. However, these effects were blocked by knockdown of AMPKα, indicating AMPK is essential for its action in suppression of ER stress. Meanwhile, ilexgenin A inhibited NLRP3 inflammasome activation by down-regulation of NLRP3 and cleaved caspase-1 induction, and thereby reduced IL-1ß secretion. It also inhibited inflammation and apoptosis exposed to PA insult. Consistent with these results in endothelial cells, ilexgenin A attenuated ER stress and restored the loss of eNOS activity in vascular endothelium, and thereby improved endothelium-dependent vasodilation in rat aorta. A further analysis in high-fat fed mice showed that oral administration of ilexgenin A blocked ER stress/NLRP3 activation with reduced ROS generation and increased NO production in vascular endothelium, well confirming the beneficial effect of ilexgenin A on endothelial homeostasis in vivo. Taken together, these results show ER stress-associated TXNIP/NLRP3 inflammasome activation was responsible for endothelial dysfunction and ilexgenin A ameliorated endothelial dysfunction by suppressing ER-stress and TXNIP/NLRP3 inflammasome activation with a regulation of AMPK. This finding suggests that the application of ilexgenin A is useful in the management of cardiovascular diseases in obesity.

Pharmacological activation of AMPK ameliorates perivascular adipose/endothelial dysfunction in a manner interdependent on AMPK and SIRT1.

Adipose and endothelial dysfunction is tightly associated with cardiovascular diseases in obesity and insulin resistance. Because perivascular adipose tissue (PVAT) surrounds vessels directly and influences vessel functions through paracrine effect, and AMP-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) show similarities in modulation of metabolic pathway, we hypothesized that activation of AMPK and SIRT1 in PVAT might regulate the endothelial function in pathological settings. Thus, in this study, we focused on the regulation of AMPK and SIRT1 activities implicated in adipocytokine expression and endothelial homeostasis under inflammatory conditions by using salicylate, metformin, AICA riboside (AICAR) and resveratrol as AMPK activating agents. We prepared conditioned medium (CM) by stimulating PVAT with palmitic acid (PA) and observed the effects of AMPK activating agents on adipocytokine expression and vessel vasodilation in rats. Moreover, we explored the effects of resveratrol and metformin in fructose-fed rats. We observed that PA stimulation induced inflammation and dysregulation of adipocytokine expression accompanied with reduced AMPK activity and SIRT1 abundance in PVAT. AMPK activating agents inhibited NF-κB p65 phosphorylation and suppressed gene expression of pro-inflammatory adipocytokines, and upregulated adiponectin and PPARγ expression in PVAT in an AMPK/SIRT1-interdependent manner. Meanwhile, CM stimulation impaired endothelium-dependent vasodilation in response to acetylcholine (ACh). Pretreatment of CM with AMPK-activating agents enhanced eNOS phosphorylation in the aorta and restored the loss of endothelium-dependent vasodilation, whereas this action was abolished by co-treatment with AMPK inhibitor compound C or SIRT1 inhibitor nicotinamide. Long-term fructose-feeding in rats induced dysregulation of adipocytokine expression in PVAT and the loss of endothelium-dependent vasodilation, whereas these alterations were reversed by oral administration of resveratrol and metformin. Altogether, pharmacological activation of AMPK beneficially regulated adipocytokine expression in PVAT and thus ameliorated endothelial dysfunction against inflammatory insult in an AMPK/SIRT1-interdependent manner.

Effects of isolated scenting on the taste quality of broken green tea based on metabolomics.

Liquid chromatography-mass spectrometry (LC-MS) combined with multivariate analysis were used to characterize the nonvolatile compounds of broken green tea and explore the effect of isolated scenting on metabolic profile and taste quality of broken green tea in this research. A total of 236 nonvolatile compounds were identified and 13 compounds were believed to be the key characteristic taste compounds of scented broken green tea. Meanwhile, the optimal isolated scenting time of broken green tea was determined to be 10 h based on the sensory evaluation and PLS results. The contents and types of flavonoids, organic acids and catechins lead to the difference of taste quality at different scenting times. Overall, these findings provided a theoretical basis for scenting to improve the taste of broken green tea, and provide a new idea for improving the taste of broken green tea.

Ethnobotany, phytochemistry, pharmacology and quality control of Peucedanum decursivum (Miq.) Maxim: A critical review.

ETHNOPHARMACOLOGICAL RELEVANCE: Dried roots of Peucedanum decursivum, a traditional Chinese medicine (TCM), has historically respiratory diseases such as cough, thick phlegm, headache, fever, and gynecological diseases, rheumatoid arthritis, and nasopharyngeal carcinoma. AIM OF THE STUDY: Made an endeavor to evaluate the research trajectory of P. decursivum, comprehensively discern its developmental status, and offer a guideline for future investigations. MATERIALS AND METHODS: A meticulous search of literatures and books from 1955 to 2024 via databases like PubMed, Web of Science and CNKI was conducted, including topics and keywords of " P. decursivum" "Angelica decursivum" and "Zihua Qianhu". RESULTS: P. decursivum and its prescriptions have traditionally been used for treating phlegm-heat cough, wind-heat cough, gastrointestinal diseases, pain relief and so on. It contains 234 identified compounds, encompassing coumarins, terpenes, volatile oils, phenolic acids, fatty acids and derivatives. It exhibits diverse pharmacological activities, including anti-asthmatic, anti-inflammatory, antioxidant effects, anti-hypertensive, anti-diabetic, anti-Alzheimer, and anti-cancer properties, primarily attributed to coumarins. Microscopic identification, HPLC fingerprinting, and bioinformatics identification are the primary methods currently used for the quality control. CONCLUSION: P. decursivum demonstrates anti-asthmatic, anti-inflammatory, and antioxidant effects, aligning with its traditional use. However, experimental validation of its efficacy against phlegm and viruses is needed. Additionally, analgesic effects mentioned in historical texts lack modern pharmacological studies. Numerous isolated compounds exhibit highly valuable medicinal properties. Future research can delve into exploring these substances further. Rigorous of heavy metal contamination, particularly Cd and Pb, is necessary. Simultaneously, investigating its pharmacokinetics and toxicity in humans is crucial for the safety.

The effect of data fusion on improving the accuracy of olive oil quality measurement.

Olive oil is one of the healthiest and most nutritious edible oils, and it has a great potential to be adulterated. In this research, fraud samples of olive oil were detected with six different classification models by fusion of two methods of E-nose and ultrasound. The samples were prepared in six categories of adulteration. The E-nose system included eight various sensors. 2 MHz probes were used in through transmission ultrasound system. Principal Component Analysis method was used to reduce features and six classification models were used for classification. Feature with the greatest influence in the classification was "percentage of ultrasonic amplitude loss." It was found that the ultrasound system's data had worked more effectively than the E-nose system. Results showed that the ANN method was recognized as the most effective classifier with the highest accuracy (95.51%). The accuracy of classification in all the classification models significantly increased with data fusion.

Nontargeted metabolomic and multigene expression analyses reveal the mechanism of oil biosynthesis in sea buckthorn berry pulp rich in palmitoleic acid.

Sea buckthorn berry pulp (SBP) oil is abundant in palmitoleic acid (C16:1). However, metabolic mechanisms of oil biosynthesis in SBP (non-seed tissues) are not clear. Thus, comparative nontargeted metabolomic analysis of the four developmental stages of berry pulp in two lines, Za56 and TF2-36, was performed. The results revealed that glycerol-3-phosphate (G3P) was critical for high oil accumulation in the mid-early developmental stages. In particular, the metabolism of phosphatidylcholine (PC) (16:0/16:0), PC (16:0/16:1), and PC (16:1/16:1) was also significantly altered. Sufficient supply of G3P and 16:1-CoA, coupled with upregulated expression of the glycerol-3-phosphate dehydrogenase (GPD1) and delta-9 desaturase (Δ9D) genes, were associated with high oil content enriched in C16:1 in SBP. Our results provide a scientific basis for the development of metabolic engineering strategies to increase the oil content in SBP with a high level of C16:1.

Thermal oxidation stability of different multi-element oleogels via 1H NMR spectroscopy.

In this study, 1H nuclear magnetic resonance was used to track the evolution of oxidation products of different multi-element oleogels (DMEOs) during temperature-accelerated oxidative degradation. The nutritional properties of the DMEOs were also indirectly explored. Oleogels prepared using sitosterol/lecithin oleogelator showed higher nutritional properties than those prepared using carnauba wax or ethyl cellulose oleogelators. Only a small amount of primary oxidation product hydroxide, (Z,E)-conjugated dienic systems, and (E,E)-conjugated dienic systems were produced from all oleogels upon accelerated oxidation. Furthermore, no 1H signal peaks of secondary oxidation products, such as aldehydes or ketones, were detected. However, very small amounts of primary alcohols (-CH2OH-), secondary alcohols (-CHOH-), and epoxides were identified. Moreover, resveratrol loading and surfactant addition effectively stabilized the internal structure and unsaturated fatty acid acyl content of the oleogels.

Changes in stability, tocopherols, fatty acids and antioxidant capacity of sacha inchi (Plukenetia volubilis) oil during French fries deep-frying.

Sacha inchi (Plukenetia volubilis) oil (SI) is appreciated for its nutritional and sensorial characteristics. The aim of this study was to evaluate SI changes during French fries deep-frying at 170 °C or 180 °C up to 119 and 50 min, respectively; commercial soybean oil (SO) was tested as control. SI had high α-linolenic acid (53.8%), linoleic acid (33.4%) and total tocopherols (2540.1 mg/kg). During frying tocopherol content, oil stability and antioxidant capacity (ABTS, DPPH) decreased following zero-order kinetics; γ-tocopherol showed the strongest decrease. Notwithstanding the high SI unsaturation and the commercial antioxidant (TBHQ) in SO, SI showed slightly higher or similar hydrolysis (free fatty acids and diacylglycerols), similar primary (K232, oxidized-triacylglycerols) and lower secondary (K268, triacylglycerol oligopolymers) oxidation. Because of the high tocopherol content, SI showed lower degradation than SO. Thus, SI is suitable for short-term deep-frying; additionally, it may enhance the nutritional value and the flavour of fried foods.

Integration of proteomics and metabolomics data of early and middle season Hass avocados under heat treatment.

Ripening heterogeneity of Hass avocados results in inconsistent quality fruit delivered to the triggered and ready to eat markets. This research aimed to understand the effect of a heat shock (HS) prior to controlled atmosphere (CA) storage on the reduction of ripening heterogeneity. HS prior to CA storage reduces more drastically the ripening heterogeneity in middle season fruit. Via correlation network analysis we show the different metabolomics networks between HS and CA. High throughput proteomics revealed 135 differentially expressed proteins unique to middle season fruit triggered by HS. Further integration of metabolomics and proteomics data revealed that HS reduced the glycolytic throughput and induced protein degradation to deliver energy for the alternative ripening pathways. l-isoleucine, l-valine, l-aspartic and ubiquitin carboxyl-terminal hydrolase involved in protein degradation were positively correlated to HS samples. Our study provides new insights into the effectiveness of HS in synchronizing ripening of Hass avocados.

Evaluation of anti-nociceptive and anti-inflammatory activities of the methanol extract of Holigarna caustica (Dennst.) Oken leaves.

ETHNOPHARMACOLOGICAL RELEVANCE: Holigarna caustica (Dennst.) is commonly used in traditional medicine to treat a variety of painful conditions such as eye irritation, inflammation, arthritis, skin diseases, cuts and wounds. AIM OF THE STUDY: The present study was undertaken to investigate the anti-nociceptive and anti-inflammatory activities of the methanol extract of H. caustica leaves and to elucidate its possible mechanism(s) of action. MATERIALS AND METHODS: Fresh leaves of H. caustica were collected, dried, and extracted with methanol (MEHC). MEHC was subjected to activity testing, using chemical-induced (acetic acid and formalin test) and heat-induced (hot plate and tail immersion test) pain models. To determine the possible mechanism behind the anti-nociceptive activity of MEHC, the opioid antagonist naltrexone was used to evaluate the involvement of opioid receptors in the case of formalin, hot plate and tail immersion tests, while the involvement of the cGMP and ATP-sensitive K+ channel pathways were assessed using methylene blue and glibenclamide respectively, in the acetic acid-induced writhing test. In parallel, the carrageenan-induced paw oedema model was used to determine the anti-inflammatory potential of the extract. Exploratory and motor behaviours were evaluated by the open-field test. Various bioactive compounds potentially responsible for the anti-nociceptive and anti-inflammatory activities were ascertained using GC-MS analysis. RESULTS: MEHC showed strong, significant and dose-dependent anti-nociceptive activity in all chemical-induced and heat-induced pain models at all experimental doses. The association of opioid receptors with the observed anti-nociceptive effects was confirmed by using naltrexone. The cGMP and ATP-sensitive K+ channel pathway was also shown to be involved in the anti-nociceptive activity of MEHC. In addition, MEHC exhibited a dose-dependent inhibition of inflammatory oedema induced by carrageenan. MEHC was not connected with changes in either the locomotor activity or motor responses of mice. In a GC-MS analysis, 40 compounds were identified, among which twelve are documented bioactive compounds with potent analgesic and anti-inflammatory properties. CONCLUSIONS: Our current study revealed that MEHC possesses strong central and peripheral anti-nociceptive as well as anti-inflammatory activity. It may also be concluded that both opioid receptors as well as the cGMP and ATP-sensitive K+ channel pathway are involved in the anti-nociceptive mechanism of MEHC. This study rationalizes the ethnomedicinal use of H. caustica leaves in various painful conditions.

A worldwide reliable indicator to differentiate wild vs. farmed Penaeid shrimps based on 207 fatty acid profiles.

Shrimps and prawns are especially subject to food fraud, which has consequences not only on the economy but also represents a potential risk for public health. Fatty acids (FA) of Penaeid shrimps have been largely explored in the literature, and although they are unable to discriminate shrimps geographical origin or species, they might provide an interesting tool to distinguish their production method (wild vs. farmed). The present study is based on a literature compilation of Penaeid shrimp FA profiles encompassing all continents and 28 species. It reveals that the ratio of FA 18:2ω6 + FA 18:3ω3 / FA 16:1ω7 can differentiate wild vs. farmed Penaeid shrimps with 100% accuracy within the 207 FA profiles of the dataset considered. Assuming a normal distribution of the dataset, 94.4% of the farmed shrimps population is expected to exhibit a ratio above 2.92, and 99.7% of the wild shrimps population is expected to fall below 2.92.

Effect of clones, year of harvest and geographical origin of fruits on quality and chemical composition of Argan oil.

Argan oil is precious oil with food and cosmetic uses. In recent years, this oil has been subject to an increasing national and international demand. The present work aims at studying the effect of clones and age, year of harvest and geographical origin on Argan oil quality and chemical composition. The results indicate that age does not affect Argan oil quality and fatty acids content. However, clones had a significant effect on fatty acids and tocopherol levels. Saturated and unsaturated fatty acids were highly influenced by the year of harvest and geographical origin, presumably due to climatic conditions. Unsaturated fatty acids varied from 78.28% to 81.77%. Depending on clones, total tocopherols varied from 687.40 mg/kg to 1068 mg/kg. This study is useful for the choice of clones with the aim of developing Argan trees orchards destined to oil production.

Chemical Composition and Antioxidant Activity of Monguba (Pachira aquatica) Seeds.

Monguba fruit has a seed with a chestnut-like flavor that can be consumed boiled, fried, and roasted. These nutritious seeds also have been used in popular medicine to treat several diseases. Nevertheless, the nutritional and functional potential of monguba seed is still underexploited. In this sense, we investigated the nutritional and functional components of monguba seeds. These seeds showed high total content of sugars, mainly sucrose, whereas the content of the raffinose family oligosaccharides was low. The mineral assay showed high amount of minerals, namely potassium, calcium, magnesium and zinc, which indicate that monguba seeds can be a new source of these minerals. UHPLC-ESI-MS/MS analysis showed caffeic, ferulic and 4-hydroxybenzoic acids as the main phenolic compounds, mainly in the esterified form, in these seeds. Monguba seed showed high lipid content, in which the main compounds were palmitic acid and γ-tocopherol. The soluble and insoluble phenolic fractions from monguba seeds showed high antioxidant activity measured by the oxygen radical absorption capacity (ORAC) and the trolox equivalent antioxidant capacity (TEAC) assays. Therefore, the monguba seeds have great potential to be explored by food, pharmaceutical and cosmetic industries due to their chemical composition.

Removal of phthalic acid esters from sea buckthorn (Hippophae rhamnoides L.) pulp oil by steam distillation and molecular distillation.

Sea buckthorn (Hippophae rhamnoides L.) pulp oils (SPOs) are rich in a variety of beneficial bioactive ingredients. Nevertheless, SPOs would be exposed to plastic equipment during processing, resulted in increasing phthalates contents and edible risk, as well as affecting oil quality. For these reasons, the effects of two stages steam distillation (SD2) and two stages molecular distillation (MD2) on phthalic acid esters (PAEs) content were investigated and compared in the present work. Compared with SD2, MD2 showed higher removal rates of seven selected PAEs from the SPO. Even if the initial concentration of DBP and DEHP in R-SPO were 1.626 and 10.933 mg/kg respectively, the concentration of DBP and DINP could be reduced below the limit set by China government after treated with MD2. Besides that, there was no trans-fatty acids generated in SPO during the distillation process.

Synthesis and characterization of lactose fatty acid ester biosurfactants using free and immobilized lipases in organic solvents.

In this work, lactose fatty acid esters were enzymatically synthesized from fatty acids and lactose using Candida antarctica B lipase (CALB) in organic solvents. Products were purified using a solvent extraction method and analyzed using ATR-FTIR and surface-active properties measurements. Results showed that hexanes and acetonitrile provide the highest conversions for both free and immobilized lipases, up to 77% and 93% respectively. The conversion rate of esterification is solvent-dependent for free lipase; the conversion rate of immobilized lipase still shows solvent dependency, but to a lesser degree. Surface tension, interfacial tension, critical micelle concentration (CMC), and contact angles were also measured for all of the samples, showing the potentials of these sugar esters as naturally derived surfactants for the food industry.

Nutritional value of the Tunisian mussel Mytilus galloprovincialis with a special emphasis on lipid quality.

This study reports, for the first time, data on nutritional quality parameters in Tunisian mussels, Mytilus galloprovincialis, with an especial emphasis on lipid compounds. Mussel condition index (CI), proximate composition and fatty acid profiles were investigated for a one year period in order to identify the best harvesting period. Analysis revealed that polyunsaturated fatty acids (PUFA) were the dominant fatty acids with a prevalence of n-3 over n-6 forms. Pearson's correlation indicated a strong relationship between CI and PUFA compound and Principal Components Analysis suggested that, from winter to summer, the product maintained a condition sufficiently good for marketing. The best CI and lipid quantity/quality occurred during summer and this may be used as criteria for product labelling. The study also included a thorough literature review that allowed data comparison on mussels from various Mediterranean sites and allowed the mussels from the Bizerte lagoon (North of Tunisia) to be differentiated.

Optimization of lipase-catalyzed synthesis of ß-sitostanol esters by response surface methodology.

The esters of ß-sitostanol and fatty acids are known for their effect as cholesterol-lowering agents. In this work, the efficiency of three lipases as biocatalysts of the esterification of ß-sitostanol and C16 and C18 fatty acids was compared. The sterol esterase of Ophiostoma piceae (OPEr) yielded the highest esterification rates and was selected for further optimization of the reaction. The effects of four parameters (temperature, enzymatic dosage, acyl donor concentration, and reaction time) on ester synthesis were investigated and the process conditions were optimized using response surface methodology (RSM). The best conditions for esterification for each fatty acid were predicted using a second-order model, and experimentally validated. Very high esterification efficiencies (86-97%) were observed using the predicted values for the four variables. This approach was shown to be suitable for optimizing the enzymatic production of ß-sitostanol esters, which represents a green alternative to the chemical synthesis of these dietary complements.