Towards consolidated bioprocessing of biomass and plastic substrates for semi-synthetic production of bio-poly(ethylene furanoate) (PEF) polymer using omics-guided construction of artificial microbial consortia.

Poly(ethylene furanoate) (PEF) plastic is a 100% renewable polyester that is currently being pursued for commercialization as the next-generation bio-based plastic. This is in line with growing demand for circular bioeconomy and new plastics economy that is aimed at minimizing plastic waste mismanagement and lowering carbon footprint of plastics. However, the current catalytic route for the synthesis of PEF is impeded with technical challenges including high cost of pretreatment and catalyst refurbishment. On the other hand, the semi-biosynthetic route of PEF plastic production is of increased biotechnological interest. In particular, the PEF monomers (Furan dicarboxylic acid and ethylene glycol) can be synthesized via microbial-based biorefinery and purified for subsequent catalyst-mediated polycondensation into PEF. Several bioengineering and bioprocessing issues such as efficient substrate utilization and pathway optimization need to be addressed prior to establishing industrial-scale production of the monomers. This review highlights current advances in semi-biosynthetic production of PEF monomers using consolidated waste biorefinery strategies, with an emphasis on the employment of omics-driven systems biology approaches in enzyme discovery and pathway construction. The roles of microbial protein transporters will be discussed, especially in terms of improving substrate uptake and utilization from lignocellulosic biomass, as well as from depolymerized plastic waste as potential bio-feedstock. The employment of artificial bioengineered microbial consortia will also be highlighted to provide streamlined systems and synthetic biology strategies for bio-based PEF monomer production using both plant biomass and plastic-derived substrates, which are important for circular and new plastics economy advances.

Volatile communication in plants relies on a KAI2-mediated signaling pathway.

Plants are constantly exposed to volatile organic compounds (VOCs) that are released during plant-plant communication, within-plant self-signaling, and plant-microbe interactions. Therefore, understanding VOC perception and downstream signaling is vital for unraveling the mechanisms behind information exchange in plants, which remain largely unexplored. Using the hormone-like function of volatile terpenoids in reproductive organ development as a system with a visual marker for communication, we demonstrate that a petunia karrikin-insensitive receptor, PhKAI2ia, stereospecifically perceives the (-)-germacrene D signal, triggering a KAI2-mediated signaling cascade and affecting plant fitness. This study uncovers the role(s) of the intermediate clade of KAI2 receptors, illuminates the involvement of a KAI2ia-dependent signaling pathway in volatile communication, and provides new insights into plant olfaction and the long-standing question about the nature of potential endogenous KAI2 ligand(s).

Genotoxic mode of action and threshold exploration of 2-methyl furan under 120-day sub-chronic exposure in male Sprague-Dawley rats.

2-Methylfuran (2-MF) is an important member of the furan family generated during food thermal processing. An in-vivo multiple endpoint genotoxicity assessment system was applied to explore the genotoxic mode of action and threshold of 2-MF. Male Sprague-Dawley rats received 2-MF by oral gavage at doses of 0.16, 0.625, 2.5, and 10 mg/kg.bw/day for 120 days. An additional 15 days were granted for recovery. The Pig-a gene mutation frequency of RET and RBC showed significant increases among the 2-MF groups on day 120. After a 15-day recovery period, the Pig-a gene mutation frequency returned to levels similar to those in the vehicle control. The tail intensity (TI) values of peripheral blood cells at a dose of 10 mg/kg.bw/day significantly increased from day 4 and remained at a high level after the recovery period. No statistical difference was found in the micronucleus frequency of peripheral blood between any 2-MF dose group and the corn oil group at any timepoint. 2-MF may not induce the production of micronuclei, but it could cause DNA breakage. It could not be ruled out that 2-MF may accumulate in vivo and cause gene mutations. Hence, DNA, other than the spindle, may be directly targeted. The mode of action of 2-MF may be that it was metabolized by EPHX1 to more DNA-active metabolites, thus leading to oxidative and direct DNA damage. The point of departure (PoD) of 2-MF-induced genotoxicity was derived as 0.506 mg/kg bw/day.

Relevance of flounder caging and proteomics to explore the impact of a major industrial accident caused by fire on the Seine estuarine water quality.

On September 26th 2019, a major fire occurred in the Lubrizol factory located near the Seine estuary, in Rouen-France. Juvenile flounders were captured in the Canche estuary (a reference system) and caged one month in the Canche and in the Seine downstream the accident site. No significant increases of PAHs, PCBs and PFAS was detected in Seine vs Canche sediments after the accident, but a significant increase of dioxins and furans was observed in water and sewage sludge in the Rouen wastewater treatment plant. The proteomics approach highlighted a dysregulation of proteins associated with cholesterol synthesis and lipid metabolism, in fish caged in the Seine. The overall results suggested that the fire produced air borne dioxins and furans that got deposited on soil and subsequently entered in the Seine estuarine waters via runoff; thus contaminating fish preys and caged flounders in the Seine estuary.

Monaspin B, a Novel Cyclohexyl-furan from Cocultivation of Monascus purpureus and Aspergillus oryzae, Exhibits Potent Antileukemic Activity.

Natural products are a rich resource for the discovery of innovative drugs. Microbial cocultivation enables discovery of novel natural products through tandem enzymatic catalysis between different fungi. In this study, Monascus purpureus, as a food fermentation strain capable of producing abundant natural products, was chosen as an example of a cocultivation pair strain. Cocultivation screening revealed that M. purpureus and Aspergillus oryzae led to the production of two novel cyclohexyl-furans, Monaspins A and B. Optimization of the cocultivation mode and media enhanced the production of Monaspins A and B to 1.2 and 0.8 mg/L, respectively. Monaspins A and B were structurally elucidated by HR-ESI-MS and NMR. Furthermore, Monaspin B displayed potent antiproliferative activity against the leukemic HL-60 cell line by inducing apoptosis, with a half-maximal inhibitory concentration (IC50) of 160 nM. Moreover, in a mouse leukemia model, Monaspin B exhibited a promising in vivo antileukemic effect by reducing white blood cell, lymphocyte, and neutrophil counts. Collectively, these results indicate that Monaspin B is a promising candidate agent for leukemia therapy.

Karrikin signalling: impacts on plant development and abiotic stress tolerance.

Plants rely upon a diverse range of metabolites to control growth and development, and to overcome stress that results from suboptimal conditions. Karrikins (KARs) are a class of butenolide compounds found in smoke that stimulate seed germination and regulate various developmental processes in plants. KARs are perceived via a plant α/ß-hydrolase called KARRIKIN INSENSITIVE2 (KAI2), which also functions as a receptor for a postulated phytohormone, provisionally termed KAI2 ligand (KL). Considered natural analogues of KL, KARs have been extensively studied for their effects on plant growth and their crosstalk with plant hormones. The perception and response pathway for KAR-KL signalling is closely related to that of strigolactones, another class of butenolides with numerous functions in regulating plant growth. KAR-KL signalling influences seed germination, seedling photomorphogenesis, root system architecture, abiotic stress responses, and arbuscular mycorrhizal symbiosis. Here, we summarize current knowledge of KAR-KL signalling, focusing on its role in plant development, its effects on stress tolerance, and its interaction with other signalling mechanisms.

Mutations in the genes responsible for the synthesis of furan fatty acids resolve the light-induced off-odor in soybean oil.

Soybean oil is the second most produced edible vegetable oil and is used for many edible and industrial materials. Unfortunately, it has the disadvantage of 'reversion flavor' under photooxidative conditions, which produces an off-odor and decreases the quality of edible oil. Reversion flavor and off-odor are caused by minor fatty acids in the triacylglycerol of soybean oil known as furan fatty acids, which produce 3-methyl-2,4-nonanedione (3-MND) upon photooxidation. As a solution to this problem, a reduction in furan fatty acids leads to a decrease in 3-MND, resulting in a reduction in the off-odor induced by light exposure. However, there are no reports on the genes related to the biosynthesis of furan fatty acids in soybean oil. In this study, four mutant lines showing low or no furan fatty acid levels in soybean seeds were isolated from a soybean mutant library. Positional cloning experiments and homology search analysis identified two genes responsible for furan fatty acid biosynthesis in soybean: Glyma.20G201400 and Glyma.04G054100. Ectopic expression of both genes produced furan fatty acids in transgenic soybean hairy roots. The structure of these genes is different from that of the furan fatty acid biosynthetic genes in photosynthetic bacteria. Homologs of these two group of genes are widely conserved in the plant kingdom. The purified oil from the furan fatty acid mutant lines had lower amounts of 3-MND and reduced off-odor after light exposure, compared with oil from the wild-type.

Role of covalent modification by hepatic aldehydes in dictamnine-induced liver injury.

Dictamnine is a representative furan-containing hepatotoxic compound. Administration of dictamnine caused acute liver injury in mice and the metabolic activation of furan to reactive epoxy intermediate was responsible for the hepatotoxicity. This study aimed to characterize the protein adduction by endogenous hepatic aldehydes and investigate its role in dictamnine-induced hepatotoxicity. In the liver sample of dictamnine-treated mice, the protein adduction by five aldehydes was characterized as lysine residue-aldehyde adducts using high-resolution UPLC-Q/Orbitrap MS after exhaustive proteolytic digestion. The levels of protein adduct were increased at 2-3 h after the treatment with dictamnine. The formation of protein adduction increased with increasing doses of dictamnine. Inhibition of the bioactivation by CYP3A inhibitor ketoconazole prevented the protein adduction. Treatment with 2,3-dihydro-dictamnine, an analog of dictamnine that was unable to form the epoxy intermediate, did not lead to an increase in protein adduction. Application of aldehyde dehydrogenase-2 activator ALDA-1 or nucleophilic trapping reagent N-acetyl-L-lysine significantly reduced the protein adduction and attenuated dictamnine-induced liver injury without affecting the bioactivation. In conclusion, the metabolic activation of the furan ring of dictamnine resulted in the protein adduction by multiple hepatic aldehydes and the protein modification played a crucial role in dictamnine-induced liver injury.

Identification and characterization of the karrikins signaling gene SsSMAX1 in Sapium sebiferum.

SUPPRESSOR OF MAX2 LIKE 1 (SMAX1) is a member of the SUPPRESSOR of MAX2 1­LIKE family of genes and is known as a target protein of KARRIKIN INSENSITIVE2 (KAI2)-MORE AXILLARY BRANCHES2 (MAX2), which mediates karrikin signaling in Arabidopsis. SMAX1 plays a significant role in seed germination, hypocotyl elongation, and root hair development in Arabidopsis. SMAX1 has not yet been identified and characterized in woody plants. This study identified and characterized SsSMAX1 in Sapium sebiferum and found that SsSMAX1 was highly expressed in the seed, hypocotyl, and root tips of S. sebiferum. SsSMAX1 was functionally characterized by ectopic expression in Arabidopsis. SsSMAX1 overexpression lines of Arabidopsis showed significantly delayed seed germination and produced seedlings with longer hypocotyl and roots than wild-type and Atsmax1 functional mutants. SsSMAX1 overexpression lines of Arabidopsis also had broader and longer leaves and petioles than wild-type and Atsmax1, suggesting that SsSMAX1 is functionally conserved. This study characterizes the SMAX1 gene in a woody and commercially valuable bioenergy plant, Sapium sebiferum. The results of this study are beneficial to future research on the molecular biology of woody plants.

Novel Strigolactone Mimics That Modulate Photosynthesis and Biomass Accumulation in Chlorella sorokiniana.

In terrestrial plants, strigolactones act as multifunctional endo- and exo-signals. On microalgae, the strigolactones determine akin effects: induce symbiosis formation with fungi and bacteria and enhance photosynthesis efficiency and accumulation of biomass. This work aims to synthesize and identify strigolactone mimics that promote photosynthesis and biomass accumulation in microalgae with biotechnological potential. Novel strigolactone mimics easily accessible in significant amounts were prepared and fully characterized. The first two novel compounds contain 3,5-disubstituted aryloxy moieties connected to the bioactive furan-2-one ring. In the second group of compounds, a benzothiazole ring is connected directly through the cyclic nitrogen atom to the bioactive furan-2-one ring. The novel strigolactone mimics were tested on Chlorella sorokiniana NIVA-CHL 176. All tested strigolactones increased the accumulation of chlorophyll b in microalgae biomass. The SL-F3 mimic, 3-(4-methyl-5-oxo-2,5-dihydrofuran-2-yl)-3H-benzothiazol-2-one (7), proved the most efficient. This compound, applied at a concentration of 10-7 M, determined a significant biomass accumulation, higher by more than 15% compared to untreated control, and improved the quantum yield efficiency of photosystem II. SL-F2 mimic, 5-(3,5-dibromophenoxy)-3-methyl-5H-furan-2-one (4), applied at a concentration of 10-9 M, improved protein production and slightly stimulated biomass accumulation. Potential utilization of the new strigolactone mimics as microalgae biostimulants is discussed.

Adverse outcome pathway exploration of furan-induced liver fibrosis in rats: Genotoxicity pathway or oxidative stress pathway through CYP2E1 activation?

Furan is a widespread endogenous contaminant in heat-processed foods that can accumulate rapidly in the food chain and has been widely detected in foods, such as wheat, bread, coffee, canned meat products, and baby food. Dietary exposure to this chemical may bring health risk. Furan is classified as a possible category 2B human carcinogen by the International Agency for Research on Cancer, with the liver as its primary target organ. Hepatic fibrosis is the most important nontumoral harmful effect of furan and also an important event in the carcinogenesis of furan. Although the specific mechanism of furan-induced liver fibrosis is still unclear, it may involve oxidative stress and genetic toxicity, in which the activation of cytochrome P450 2E1 (CYP2E1) may be the key event. Thus, we conducted a study using an integrating multi-endpoint genotoxicity platform in 120-day in vivo subchronic toxicity test in rats. Results showed that the rats with activated CYP2E1 exhibited DNA double-strand breaks in D4, gene mutations in D60, and increased expression of reactive oxygen species and nuclear factor erythroid 2-related factor 2 in D120. Necrosis, apoptosis, hepatic stellate cell activation, and fibrosis also occurred in the liver, suggesting that furan can independently affect liver fibrosis through oxidative stress and genotoxicity pathways. Point of Departure (PoD) was obtained by benchmark-dose (BMD) method to establish health-based guidance values. The human equivalent dose of PoD derived from BMDL05 was 2.26 µg/kg bw/d. The findings laid a foundation for the safety evaluation and risk assessment of furan and provided data for the further construction and improvement of the adverse outcome pathway network in liver fibrosis.

Lestaurtinib (CEP-701) reduces the duration of limbic status epilepticus in periadolescent rats.

BACKGROUND: The timely abortion of status epilepticus (SE) is essential to avoid brain damage and long-term neurodevelopmental sequalae. However, available anti-seizure treatments fail to abort SE in 30% of children. Given the role of the tropomyosin-related kinase B (TrkB) receptor in hyperexcitability, we investigated if TrkB blockade with lestaurtinib (CEP-701) enhances the response of SE to a standard treatment protocol and reduces SE-related brain injury. METHODS: SE was induced with intra-amygdalar kainic acid in postnatal day 45 rats under continuous electroencephalogram (EEG). Fifteen min post-SE onset, rats received intraperitoneal (i.p.) CEP-701 (KCEP group) or its vehicle (KV group). Controls received CEP-701 or its vehicle following intra-amygdalar saline. All groups received two i.p. doses of diazepam, followed by i.p. levetiracetam at 15 min intervals post-SE onset. Hippocampal TrkB dimer to monomer ratios were assessed by immunoblot 24 hr post-SE, along with neuronal densities and glial fibrillary acid protein (GFAP) levels. RESULTS: SE duration was 50% shorter in the KCEP group compared to KV (p < 0.05). Compared to controls, SE induced a 1.5-fold increase in TrkB dimerization in KV rats (p < 0.05), but not in KCEP rats which were comparable to controls (p > 0.05). The KCEP group had lower GFAP levels than KV (p < 0.05), and both were higher than controls (p < 0.05). KCEP and KV rats had comparable hippocampal neuronal densities (p > 0.05), and both were lower than controls (p < 0.05). CONCLUSIONS: Given its established human safety, CEP-701 is a promising adjuvant drug for the timely abortion of SE and the attenuation of SE-related brain injury.

Early microRNA responses in rodent liver mediated by furan exposure establish dose thresholds for later adverse outcomes.

To reduce reliance on long-term in vivo studies, short-term data linking early molecular-based measurements to later adverse health effects is needed. Although transcriptional-based benchmark dose (BMDT) modeling has been used to estimate potencies and stratify chemicals based on potential to induce later-life effects, dose-responsive epigenetic alterations have not been routinely considered. Here, we evaluated the utility of microRNA (miRNA) profiling in mouse liver and blood, as well as in mouse primary hepatocytes in vitro, to indicate mechanisms of liver perturbation due to short-term exposure of the known rodent liver hepatotoxicant and carcinogen, furan. Benchmark dose modeling of miRNA measurements (BMDmiR) were compared to the referent transcriptional (BMDT) and apical (BMDA) estimates. These analyses indicate a robust dose response for 34 miRNAs to furan and involvement of p53-linked pathways in furan-mediated hepatotoxicity, supporting mRNA and apical measurements. Liver-sourced miRNAs were also altered in the blood and primary hepatocytes. Overall, these results indicate mechanistic involvement of miRNA in furan carcinogenicity and provide evidence of their potential utility as accessible biomarkers of exposure and disease.

Structural insights into a bacterial ß-glucosidase capable of degrading sesaminol triglucoside to produce sesaminol: toward the understanding of the aglycone recognition mechanism by the C-terminal lid domain.

The sesaminol triglucoside (STG)-hydrolyzing ß-glucosidase from Paenibacillus sp. (PSTG1), which belongs to glycoside hydrolase family 3 (GH3), is a promising catalyst for the industrial production of sesaminol. We determined the X-ray crystal structure of PSTG1 with bound glycerol molecule in the putative active site. PSTG1 monomer contained typical three domains of GH3 with the active site in domain 1 (TIM barrel). In addition, PSTG1 contained an additional domain (domain 4) at the C-terminus that interacts with the active site of the other protomer as a lid in the dimer unit. Interestingly, the interface of domain 4 and the active site forms a hydrophobic cavity probably for recognizing the hydrophobic aglycone moiety of substrate. The short flexible loop region of TIM barrel was found to be approaching the interface of domain 4 and the active site. We found that n-heptyl-ß-D-thioglucopyranoside detergent acts as an inhibitor for PSTG1. Thus, we propose that the recognition of hydrophobic aglycone moiety is important for PSTG1-catalyzed reactions. Domain 4 might be a potential target for elucidating the aglycone recognition mechanism of PSTG1 as well as for engineering PSTG1 to create a further excellent enzyme to degrade STG more efficiently to produce sesaminol.

Natural products from reconstructed bacterial genomes of the Middle and Upper Paleolithic.

Major advances over the past decade in the field of ancient DNA are providing access to past paleogenomic diversity, but the diverse functions and biosynthetic capabilities of this growing paleome remain largely elusive. We investigated the dental calculus of 12 Neanderthals and 52 anatomically modern humans ranging from 100,000 years ago to the present and reconstructed 459 bacterial metagenome-assembled genomes. We identified a biosynthetic gene cluster shared by seven Middle and Upper Paleolithic individuals that allows for the heterologous production of a class of previously unknown metabolites that we name "paleofurans." This paleobiotechnological approach demonstrates that viable biosynthetic machinery can be produced from the preserved genetic material of ancient organisms, allowing access to natural products from the Pleistocene and providing a promising area for natural product exploration.

Injectable chondroitin sulfate-grafted self-antioxidant hydrogels ameliorate nucleus pulposus degeneration against overactive inflammation.

Overactive inflammatory cascade accompanied by oxidative stress in the nucleus pulposus exacerbates intervertebral disc degeneration (IVDD). Hydrogels have been demonstrated to be promising in treating IVDD, yet they remain less efficacious in the case of anti-inflammation associated with antioxidation. In this study, we designed an injectable self-antioxidant hydrogel (HA/CS) with enhanced inflammation inhibitory performance for delivering chondroitin sulfate (CS) with well-documented anti-inflammatory property to treat IVDD. The hydrogel was rapidly formed via dynamic boronate ester bonding between furan/phenylboronic acid and furan/dopamine-modified hyaluronic acid (HA), and mechanically enhanced by Diels-Alder reaction-induced secondary crosslinking, partial dopamine groups of which contribute to grafting phenylboronic acid-modified CS (CS-PBA). This hydrogel exhibits favorable injectability, mechanical property, and pH-responsive delivery behavior. The dopamine moiety endows the hydrogel with efficient antioxidative property. By sustained delivery of CS, the HA/CS hydrogel is well competent to inhibit inflammatory cytokine expression and maintain anabolic/catabolic balance in an inflammation-simulated environment. Most importantly, the HA/CS hydrogel significantly ameliorates degeneration in a puncture-induced IVDD rat model. The self-antioxidant HA/CS hydrogel designed in this work may serve as a novel and promising therapeutic platform for IVDD.

Role of thiols and ascladiol production in patulin degradation by lactobacilli.

Patulin is a mycotoxin contaminant in various foods with apple products being its major dietary source. Yeast can reduce patulin levels during fermentation via biotransformation and thiol-adduct formation, with the ability of patulin to react with thiols being well known. Conversion of patulin to ascladiol by lactobacilli has been sparsely reported, while the contribution of thiols in reduction of patulin levels by lactobacilli remains undocumented. In this study, 11 strains of lactobacilli were screened for ascladiol formation in apple juice fermentation. Highest bioconversion was obtained for Lactiplantibacillus plantarum strains followed by Levilactobacillus brevis TMW1.465. Ascladiol production was also detected in several other lactobacilli species albeit in trace amounts. Reduction in patulin levels by Fructilactobacillus sanfranciscensis DMS 20451 and its glutathione reductase (ΔgshR) negative mutant was also assayed to determine the contribution of thiols. The hydrocinnamic acid reductase of Furfurilactobacillus milii did not contribute to reduction of patulin levels. In conclusion, this study demonstrated the potential of various lactobacilli in reduction of patulin levels via biotransformation of patulin to ascladiol, while also providing evidence for the role of thiol formation by lactobacilli and its presence in reducing patulin levels during fermentation.

Xylose consumption and ethanol production by Pichia guilliermondii and Candida oleophila in the presence of furans, phenolic compounds, and organic acids commonly produced during the pre-treatment of plant biomass.

For 2G ethanol production, pentose fermentation and yeast tolerance to lignocellulosic hydrolyzate components are essential to improve biorefinery yields. Generally, physicochemical pre-treatment methodologies are used to facilitate access to cellulose and hemicellulose in plant material, which consequently can generate microbial growth inhibitory compounds, such as furans, weak acids, and phenolic compounds. Because of the unsatisfactory yield of wild-type Saccharomyces cerevisiae during pentose fermentation, the search for xylose-fermenting yeasts tolerant to microbial growth inhibitors has gained attention. In this study, we investigated the ability of the yeasts Pichia guilliermondii G1.2 and Candida oleophila G10.1 to produce ethanol from xylose and tolerate the inhibitors furfural, 5-hydroxymethylfurfural (HMF), acetic acid, formic acid, ferulic acid, and vanillin. We demonstrated that both yeasts were able to grow and consume xylose in the presence of all single inhibitors, with greater growth limitation in media containing furfural, acetic acid, and vanillin. In saline medium containing a mixture of these inhibitors (2.5-3.5 mM furfural and HMF, 1 mM ferulic acid, 1-1.5 mM vanillin, 10-13 mM acetic acid, and 5-7 mM formic acid), both yeasts were able to produce ethanol from xylose, similar to that detected in the control medium (without inhibitors). In future studies, the proteins involved in the transport of pentose and tolerance to these inhibitors need to be investigated.

Furan Metabolites Are Elevated in Users of Various Tobacco Products and Cannabis.

Humans are exposed to furan, a toxicant and possible human carcinogen, through multiple sources including diet and tobacco smoke. The urinary metabolites of furan are derived from the reaction of its toxic metabolite with protein nucleophiles and are biomarkers of exposure and potential harm. An established isotopic dilution liquid-chromatography mass spectrometry method was used to measure these biomarkers in urine from users of e-cigarettes, cannabis, and/or combustible tobacco with/without reduced nicotine levels. Amounts of furan mercapturic acid metabolites were higher in these individuals relative to nonsmokers, indicating that they may be at risk for potential furan-derived toxicities.

A comprehensive review of furan in foods: From dietary exposures and in vivo metabolism to mitigation measures.

Furan is a thermal food processing contaminant that is ubiquitous in various food products such as coffee, canned and jarred foods, and cereals. A comprehensive summary of research progress on furan is presented in this review, including discussion of (i) formation pathways, (ii) occurrence and dietary exposures, (iii) analytical techniques, (iv) toxicities, (v) metabolism and metabolites, (vi) risk assessment, (vii) potential biomarkers, and (viii) mitigation measures. Dietary exposure to furan varies among different countries and age groups. Furan acts through various toxicological pathways mediated by its primary metabolite, cis-2-butene-1,4-dial (BDA). BDA can readily react with glutathione, amino acids, biogenic amines, or nucleotides to form corresponding metabolites, some of which have been proposed as potential biomarkers of exposure to furan. Present risk assessment of furan mainly employed the margin of exposure approach. Given the widespread occurrence of furan in foods and its harmful health effects, mitigating furan levels in foods or exploring potential dietary supplements to protect against furan toxicity is necessary for the benefit of food safety and public health.