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Background: FBPase deficiency as an autosomal recessive disorder is due pathogenic variants in the FBP1 gene. It usually presents with hyperlactic acidemia and hypoglycaemia starting from early childhood. Here, genotypes and phenotypes of all reported patients and their distributions are presented. In addition, we present an Iranian family with two affected children presenting with unusual symptoms due to pathogenic variants in the FBP1 gene.Clinical evaluations and laboratory assessments were performed for the affected members. Whole exome sequencing (WES) was applied in order to find the causal variant. In addition to segregation analysis within the family, variant pathogenicity analyses and predictions were done via bioinformatics tools and according to ACMG guidelines. The genotypes and detailed clinical features were documented for all patients. Results: The study included a population of 104 patients with different variants of the FBP1 gene; 75 were homozygotes. The average age of onset was 14.97 months. The most frequent clinical features were metabolic acidosis (71 cases), hypoglycemia (70 cases), vomiting (46 cases), hyperuricemia (37 cases), and respiratory distress (25 cases). 74 families were from Asia. The most common genotypes were c.841G > A/c.841G > A and c.472C > T/c.472C > T. WES test showed a pathogenic homozygous variant, c.472C > T in two cases of a family: a six-and-a-half-year-old girl with an older brother with different symptoms. All laboratory evaluations in the patient were normal except for the blood sugar. The patient experienced her first hypoglycemic episode at age 3. Conclusions: This is an unusual presentation of FBPase deficiency with intrafamilial phenotypic variability.

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Rice bran, which is abundant in dietary fiber and phytochemicals, provides multiple health benefits. Nonetheless, its effects on neuroinflammation and gut microbiota in postmenopausal conditions are still not well understood. This study investigated the effects of rice bran and/or tea seed oil supplementation in d-galactose-injected ovariectomized (OVX) old mice fed a fructose drink. The combination of d-galactose injection, ovariectomy, and fructose drink administration creates a comprehensive model that simulates aging in females under multiple metabolic stressors, including oxidative stress, estrogen deficiency, and high-sugar diets, and allows the study of their combined impact on metabolic disorders and related diseases. Eight-week-old and 6-8-month-old female C57BL/6 mice were used. The mice were divided into six groups: a sham + young mice, a sham + old mice, an OVX + soybean oil, an OVX + soybean oil with rice bran, an OVX + tea seed oil (TO), and an OVX + TO with rice bran diet group. The OVX groups were subcutaneously injected with d-galactose (100 mg/kg/day) and received a 15% (v/v) fructose drink. The rice bran and tea seed oil supplementation formed 10% of the diet (w/w). The results showed that the rice bran with TO diet increased the number of short-chain fatty acid (SCFA)-producing Clostridia and reduced the number of endotoxin-producing Tannerellaceae, which mitigated imbalances in the gut-liver-brain axis. Rice bran supplementation reduced the relative weight of the liver, levels of hepatic triglycerides and total cholesterol; aspartate transaminase and alanine aminotransferase activity; brain levels of proinflammatory cytokines, including interleukin-1ß and tumor necrosis factor-α; and plasma 8-hydroxy-2-deoxyguanosine. This study concludes that rice bran inhibits hepatic fat accumulation, which mitigates peripheral metaflammation and oxidative damage and reduces neuroinflammation in the brain.

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The long-term high-fat, high-sugar diet exacerbates type 2 diabetes mellitus (T2DM)-related cognitive impairments. Phlorizin, a well-studied natural compound found in apples and other plants, is recognized for its bioactive properties, including modulation of glucose and lipid metabolism. Despite its established role in mitigating metabolic disorders, the neuroprotective effects of phlorizin, particularly against diabetes-related cognitive dysfunction, have not been fully elucidated. Therefore, the present study aimed to investigate the effect of dietary supplementation of phlorizin on high-fat and high-fructose diet (HFFD)-induced cognitive dysfunction and evaluate the crucial role of the microbiota-gut-brain axis. We found that dietary supplementation of phlorizin for 14 weeks effectively prevented glucolipid metabolism disorder, spatial learning impairment, and memory impairment in HFFD mice. In addition, phlorizin improved the HFFD-induced decrease in synaptic plasticity, neuroinflammation, and excessive activation of microglia in the hippocampus. Transcriptomics analysis shows that the protective effect of phlorizin on cognitive impairment was associated with increased expression of neurotransmitters and synapse-related genes in the hippocampus. Phlorizin treatment alleviated colon microbiota disturbance, mainly manifested by an increase in gut microbiota diversity and the abundance of short-chain fatty acid (SCFA)-producing bacteria. The level of microbial metabolites, including SCFA, inosine 5'-monophosphate (IMP), and D (-)-beta-hydroxybutyric acid (BHB) were also significantly increased after phlorizin treatment. Integrating multiomics analysis observed tight connections between phlorizin-regulated genes microbiota, and metabolites. Furthermore, removal of the gut microbiota via antibiotics treatment diminished the protective effect of phlorizin against HFFD-induced cognitive impairment, underscoring the critical role of the gut microbiota in mediating cognitive behavior. Importantly, supplementation with SCFA and BHB alone mimicked the regulatory effects of phlorizin on cognitive function. Therefore phlorizin shows promise as a potential nutritional therapy for addressing cognitive impairment associated with metabolic disorders. Further research is needed to explore its effectiveness in preventing and alleviating neurodegenerative diseases.

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Advanced glycation end products (AGEs) are a heterogeneous group of compounds formed both endogenously and exogenously through reactions between reducing sugars and amino acids within the proteins. The digestive tract may also serve as a site for endogenous AGEs generation. This study examined whether additional AGEs are formed during the digestion of glycated protein diets and meal-resembling systems (dietary proteins with fructose or glyoxal). The digestion of glycated protein showed that free AGEs were gradually released, but no additional AGEs were generated. In contrast, co-digestion of dietary proteins with fructose or glyoxal resulted in the formation of additional AGEs, and the reaction substrates (fructose or glyoxal) were depleted during digestion. Additionally, the lysine released from proteins decreased, leading to a loss of nutritional value of the food during co-digestion. The formation of AGEs and the depletion of essential amino acids in the gut may have significant implications for human health.

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Oral cancer remains a significant global health concern and its early detection plays a crucial role in improving patient outcomes. Identifying reliable prognostic markers is essential to guide treatment decisions and enhance survival rates. Fructose 1,6-bisphosphate aldolase (FBA), a glycolytic enzyme, has emerged as a promising candidate for prognostic assessment of oral cancer. This communication highlights the role of FBA in tumorigenesis, its potential utility in predicting disease progression and patient survival, and its influence on response to radiotherapy. Recent studies have suggested that dysregulated metabolic pathways involving FBA may contribute to radiation resistance in oral cancer, emphasizing the need for further exploration of FBA-targeted therapeutic strategies. Understanding the role of FBA in oral cancer pathogenesis could pave the way for the development of personalized treatment strategies, including combined radiotherapy.

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Natural deep eutectic solvents (NADESs) showing higher cryoprotective effects are attracting concerns, because during the storage, system browning always occurs in aldose/amino acid-based NADESs, which generated brown substances remarkably weaken the cryoprotective effects. In this study, proline/glucose-based (PG) and proline/sorbitol-based (PS) NADESs were prepared, of which storage stability, browning profile, brown substance, and cryoprotective effects were investigated. Results showed that PG at molar ratios of 1:1, 2:1, and 3:1, as well as PS at 1:1, and 2:1 can form NADESs, among which only the PG-based ones could get browning after storage. The predominant brown substance was identified as 1-deoxy-1-L-proline-d-fructose (C11H19O7N, 278 m/z), which was subsequently verified to show cytotoxicity and decrease Saccharomyces cerevisiae cells viability after cryopreservation, suggesting that the brown substance could take a negative effect on cryopreservation. This study may help to attract more concerns to the storage and cryopreservation stabilities of the NADESs in food-related applications.

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Introduction: The combination of a high fructose and high salt diet typical of western diet induces high blood pressure, aortic stiffening, left ventricular (LV) diastolic dysfunction and impaired renal function in rodents. Despite an activated renin-angiotensin system (RAS) in rats fed high fructose and high salt, acute inhibition of the RAS pathway does not improve cardiac and vascular parameters. It may well be that longer term treatment is required to permit remodeling and improve cardiovascular function. Thus, we hypothesized that chronic RAS inhibition fructose+high salt-fed rats to restore blood pressure (BP) to levels similar to glucose plus normal salt-fed controls will improve cardiorenal function and histopathology. Methods: Male and female Sprague Dawley rats monitored by hemodynamic telemetry were fed 0.4% NaCl chow during baseline, then changed to chow containing either 20% glucose+0.4% NaCl (G) or 20% fructose+4% NaCl (F) and treated with vehicle, enalapril (Enal, 4 mg/kg/d) or losartan (Los, 8 mg/kg/d) by osmotic minipump for 25-26 days. Results: BP was elevated in the fructose+high salt groups of both sexes (P < 0.05) and restored to control levels by Enal or Los. Pulse wave velocity (PWV) was lower in female F+Los rats and cardiac output higher in female F+Enal rats. GFR was not changed by diet or treatment. Fructose+high salt groups of both sexes displayed higher albuminuria that was decreased by Enal in male rats. Cardiac fibrosis and mesangial hypercellularity were greater in fructose+high salt-fed rats of both sexes and improved with either Los or Enal. Discussion: Thus, inhibition of the RAS improves early changes in cardiac and renal histopathology in both sexes and albuminuria in male rats fed high fructose and high salt diet. Functional improvements in cardiorenal parameters may require longer treatment.

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Diabetes is a well-known risk factor for atherosclerosis (AS), but the underlying molecular mechanism remains unknown. The dysregulated immune response is an important reason. High glucose is proven to induce foam cell formation under lipidemia situations in clinical patients. Exploring the potential regulatory programs of accelerated foam cell formation stimulated by high glucose is meaningful. Macrophage-derived foam cells were induced in vitro, and high-throughput sequencing was performed. Coexpression gene modules were constructed using weighted gene co-expression network analysis (WGCNA). Highly related modules were identified. Hub genes were identified by multiple integrative strategies. The potential roles of selected genes were further validated in bulk-RNA and scRNA datasets of human plaques. By transfection of the siRNA, the role of the screened gene during foam cell formation was further explored. Two modules were found to be both positively related to high glucose and ox-LDL. Further enrichment analyses confirmed the association between the brown module and AS. The high correlation between the brown module and macrophages was identified and 4 hub genes (Aldoa, Creg1, Lgmn, and Pkm) were screened. Further validation in external bulk-RNA and scRNA revealed the potential diagnostic and therapeutic value of selected genes. In addition, the survival analysis confirmed the prognostic value of Aldoa while knocking down Aldoa expression alleviated the foam cell formation in vitro. We systematically investigated the synergetic effects of high glucose and ox-LDL during macrophage-derived foam cell formation and identified that ALDOA might be an important diagnostic, prognostic, and therapeutic target in these patients.

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Berberine (BBR) is a major active component of traditional Chinese medicine Rhizoma Coptidis and Cortex Phellodendri, which have been frequently used to treat liver diseases. Oxidative stress and inflammation are two pivotal hepatic pathological hallmarks. This study aimed to explore the potential effect and underlying mechanism of BBR on fructose-induced rat liver injury model, and hepatocyte damage in HepG2 and BRL-3A cells. Our results indicated that BBR effectively reversed fructose-induced body weight gain, glucose intolerance, and insulin resistance, observably attenuated abnormal histopathological alterations and ameliorated serum activities of ALT and AST. In vivo and in vitro, BBR significantly alleviated the secretion of pro-inflammatory cytokines IL-6 and TNF-α, and elevated levels of anti-inflammatory cytokine IL-10. BBR also attenuated oxidative stress by markedly decreasing intracellular contents of ROS and MDA, and increasing SOD enzymatic activity and GSH level. Furthermore, BBR substantially upregulated the protein expression of Nrf2, HO-1 and p-AMPK, and the fluorescence level of p-AMPK. In addition, BBR significantly increased the level of AMP, the ratio of AMP/ATP, and promoted the expression of ADK. Nevertheless, siADK abolished the benefits exerted by BBR on HepG2 and BRL-3A cells. Conclusively, the hepatoprotective effect of BBR was believed to be intimately associated with anti-inflammatory and antioxidant action mediated, at least partially, via ADK/AMPK/Nrf2 signaling. This work provided further support for the traditional application of Rhizoma Coptidis and Cortex Phellodendri in liver protection and might shed novel dimension to the clinical application of BBR, providing a promising lead compound for drug design.

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Fructose 1,6-bisphosphatase 2 (Fbp2) is a regulatory enzyme of gluco- and glyconeogenesis which, in the course of evolution, acquired non-catalytic functions. Fbp2 promotes cell survival during calcium stress, regulates glycolysis via inhibition of Hif-1α activity, and is indispensable for the formation of long-term potentiation in hippocampus. In hippocampal astrocytes, the amount of Fbp2 protein is reduced by signals delivered in neuronal extracellular vesicles (NEVs) through an unknown mechanism. The physiological role of Fbp2 (determined by its subcellular localization/interactions) depends on its oligomeric state and thus, we asked whether the cargo of NEVs is sufficient to change also the ratio of Fbp2 dimer/tetramer and, consequently, influence astrocyte basal metabolism. We found that the NEVs cargo reduced the Fbp2 mRNA level, stimulated the enzyme degradation and affected the cellular titers of different oligomeric forms of Fbp2. This was accompanied with increased glucose uptake and lactate release by astrocytes. Our results revealed that neuronal signals delivered to astrocytes in NEVs provide the necessary balance between enzymatic and non-enzymatic functions of Fbp2, influencing not only its amount but also subcellular localization. This may allow for the metabolic adjustments and ensure protection of mitochondrial membrane potential during the neuronal activity-related increase in astrocytic [Ca2+].

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Objectives: Exhaled breath tests (BTs) are the main diagnostic method for fructose and lactose malabsorption/intolerance (FI and LI, respectively) and for detecting small intestine bacterial or methanogen overgrowth (SIBO/IMO). Although FI/LI-BTs may provide evidence of the presence of SIBO/IMO, there is limited literature evaluating their reliability for this purpose. The objective of this study was to assess the sensitivity and specificity of FI/LI-BTs in detecting SIBO and their concordance with SIBO-BTs in the identification of IMO. Methods: In this retrospective observational study, FI/LI-BTs and SIBO-BTs performed in the same patients within a period of 6 weeks were selected from 652 gas chromatography-based BTs. Results: A total of 146 BTs from 67 eligible adult patients were identified. LI-BTs had higher specificity than FI-BT in detecting SIBO (93.8 % vs. 72.7 %). In contrast, FI-BTs showed higher sensitivity (60.0 % vs. 28.6 %) as FI was more frequently established in SIBO-positive patients (70 % vs. 29 %). With regard to IMO, concordance with LI-BT was 100 %, with a 27 % of false negatives on FI-BTs. Conclusions: Findings suggestive of SIBO or IMO on LI-BTs were highly consistent with those of SIBO-BTs. In contrast, the rate of false positives for SIBO and the rate of false negative for IMO on FI-BTs was 27 % in both cases.

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BACKGROUND: Hyperglycemia is involved in malignant transformation of pancreatic cancer via the hexosamine biosynthetic pathway (HBP). However, few studies have verified this mechanism based on clinical data. This study investigated the complementary effects of hyperglycemia and HBP on pancreatic cancer prognosis using detailed clinical data. METHODS: The study analyzed data of 477 patients with pancreatic cancer who underwent pancreatectomy between 2006 and 2020. The patients were divided into normoglycemia and hyperglycemia groups based on their HbA1c levels. Immunostaining for glutamine fructose-6-phosphate transaminase-1 (GFAT-1), the rate-limiting enzyme in HBP, CD4, CD8, and Foxp3, was performed to evaluate the association between survival outcomes, HBP, and local tumor immunity. RESULTS: Overall survival (OS) was significantly poorer in the hyperglycemia group than in the normoglycemia group (mean survival time [MST]: 35.0 vs. 47.9 months; p = 0.007). The patients in the hyperglycemia group with high GFAT-1 expression had significantly poorer OS than those with low GFAT-1 expression (MST, 49.0 vs. 27.6 months; p < 0.001). However, the prognosis did not differ significantly between the patients with high and low GFAT-1 expression in the normoglycemia group. In addition, the patients with hyperglycemia and high GFAT-1 expression had fewer CD4+ (p = 0.015) and CD8+ (p = 0.017) T cells and a lower CD8+/Foxp3+ ratio (p = 0.032) than those with hyperglycemia and low GFAT-1 expression. CONCLUSIONS: The patients with hyperglycemia and high GFAT-1 expression levels had an extremely poor prognosis. Furthermore, the tumors in these patients were characterized as immunologically cold tumors.

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BACKGROUND: High fructose consumption increases blood pressure through microglia-related neuroinflammation in rats. Since intermediate-conductance calcium-activated potassium channels (KCa3.1) potentiates microglial reactivity, we examined whether the pretreatment with the KCa3.1 channel blocker TRAM-34 or minocycline prevents hypertension development in fructose-fed rats. METHODS: The study involved male Wistar rats that were given either a high fructose (10% in drinking water) or a tap water for 21 days. Fructose groups also received minocycline or TRAM-34 systemically for 21 days. We measured systolic and diastolic blood pressure (SBP and DBP), heart rate (HR) periodically with tail-cuff; proinflammatory cytokines and insulin levels in plasma via ELISA, and neuroinflammatory markers in the nucleus tractus solitarii (NTS) by qPCR at the end of 21 days. We also examined endothelium-dependent hyperpolarization (EDH)-type vasorelaxations in isolated mesenteric arteries of the rats ex vivo. RESULTS: SBP, DBP, and HR increased in the fructose group. Both minocycline and TRAM-34 significantly prevented these increases. Fructose intake also increased plasma IL-6, IL-1ß, TNF-α, and insulin levels, whereas pretreatment with TRAM-34 prevented these increases as well. Iba-1, but not CD86 levels were significantly higher in the NTS samples of fructose-fed hypertensive rats which implied microglial proliferation. EDH-type vasorelaxations mediated by endothelial KCa3.1 attenuated in the fructose group; however, TRAM-34 did not cause further deterioration in the relaxations. CONCLUSIONS: TRAM-34 is as effective as minocycline in preventing fructose-induced hypertension without interfering with the EDH-type vasodilation. Furthermore, TRAM-34 relieves high fructose-associated systemic inflammation.

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BACKGROUND: Chronic consumption of a high-fructose diet causes oxidative stress that compromises kidney and liver health. ß-sitosterol (Bst), a phytosterol, is a functional nutrient with health benefits. ß-sitosterol antioxidant activity protects the liver and kidney from ROS-mediated damage and lipid peroxidation. We evaluated the potential renoprotective and hepatoprotective effects of orally administrated ß-sitosterol in high-fructose diet-fed growing female rats. Thirty-five 21-day old female Sprague-Dawley rat pups were randomly assigned to and administered the following treatments for 12 weeks: group I- standard rat chow (SRC) + plain drinking water (PW) + plain gelatine cube (PC); group II- SRC + 20% w/v fructose solution (FS) as drinking fluid + PC; group III- SRC + FS + 100 mg/kg body mass (BM) fenofibrate in gelatine cube; group IV- SRC + FS + 20 mg/kg BM ß-sitosterol gelatine cube (Bst) and group V- SRC + PW + Bst. The rats were fasted overnight, weighed then euthanised. Blood was collected, centrifuged and plasma harvested. Livers and kidneys were excised, weighed and samples preserved for histological assessments. Plasma biomarkers of oxidative stress, liver and kidney function and renal tubular injury were assessed. RESULTS: High fructose diet fed rats had increased plasma KIM-1, NGAL (p < 0.001) and MDA levels (p < 0.05). Dietary fructose caused microvesicular and macrovesicular steatosis, and reduced glomerular density, Bowman's capsule area and urinary space. ß-sitosterol protected against the high-fructose diet-induced hepatic steatosis and glomerular disturbances without adverse effects on liver and kidney function. CONCLUSIONS: ß-sitosterol, as a dietary supplement, could potentially be exploited to prevent high-fructose diet-induced NAFLD and to protect against high-fructose diet-induced renal tubular injury.

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Fructose occurs in foods and as a metabolite in vivo. It can be degraded, leading to the formation of reactive carbonyl compounds, which may influence food properties and have an impact on health. The present study performed an in-depth qualitative and quantitative profiling of fructose degradation products. Thus, the α-dicarbonyl compounds 3-deoxyglucosone, glucosone, methylglyoxal, glyoxal, hydroxypyruvaldehyde, threosone, 3-deoxythreosone, and 1-desoxypentosone and the monocarbonyl compounds formaldehyde, acetaldehyde, glycolaldehyde, glyceraldehyde, and dihydroxyacetone were detected in fructose solutions incubated at 37 °C. Quantitative profiling after 7 days revealed 4.6-271.6-fold higher yields of all degradation products from fructose compared to glucose. Except for 3-deoxyglucosone, the product formation appeared to be metal dependent, indicating oxidative pathways. CaCl2 and MgCl2 partially reduced fructose degradation. Due to its high reactivity compared to glucose, particularly toward metal-catalyzed pathways, fructose may be a strong contributor to sugar degradation and Maillard reaction in foods and in vivo.

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OBJECTIVES: Pharmacological postconditioning can protect against myocardial ischaemia-reperfusion injury during cardiac surgery with extracorporeal circulation. The aim of this study was to observe the protective effects of fructose-1,6-bisphosphate (FDP) postconditioning on myocardial ischaemia-reperfusion injury in patients undergoing cardiac valve replacement with extracorporeal circulation. METHODS: Patients undergoing elective mitral valve replacement and/or aortic valve replacement were divided into normal saline postconditioning group (NS group) and FDP postconditioning group (FDP group). The primary outcome was the plasma concentration of creatine kinase-MB (CK-MB). The secondary outcomes were the plasma concentrations of lactate dehydrogenase, CK, high-sensitivity C-reactive protein, alpha-hydroxybutyrate dehydrogenase and cardiac troponin I, the spontaneous cardiac rhythm recovery profile, the extracorporeal circulation time and duration of surgery, intensive care unit and postoperative hospitalization. RESULTS: Forty patients were randomly assigned to receive intervention and included in the analysis. The serum concentrations of CK-MB, lactate dehydrogenase, CK, cardiac troponin I, alpha-hydroxybutyrate dehydrogenase and high-sensitivity C-reactive protein at T1∼4 were lower in the FDP group than in the NS group (P < 0.001). Compared with the NS group, the dosage of dopamine administered 1-90 min after cardiac resuscitation, the spontaneous cardiac rhythm recovery time and the incidence of ventricular fibrillation were lower in the FDP group (P < 0.001, P < 0.001 and P = 0.040, respectively). The values of ST- changes were increased more significantly in the NS group than in the FDP group (median [standard deviation] 1.3 [0.3] mm vs 0.7 [0.2] mm; P < 0.001). Compared with the NS group, the time of recovery of ST-segment deviations was shorter in the FDP group (50.3 [12.3] min vs 34.6 [6.9] min; P < 0.001). CONCLUSIONS: The FDP postconditioning could improve both myocardial ischaemia-reperfusion injury and the spontaneous cardiac rhythm recovery during cardiac valve surgery with extracorporeal circulation.

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This study shows for the first time the feasibility of Raman spectroscopy as a non-destructive method to follow the ripening process of apple fruits. Two different varieties of apples were studied: 'Aroma' and 'Elstar'. By visual inspection, Raman spectra showed that the starch content was higher in 'Elstar' apples compared to 'Aroma'. The degradation of starch over time could be detected in the Raman spectra, indicating that the method can be used to monitor the ripening process. The ripeness markers starch index, soluble solids content (SSC), and the sugars glucose, fructose and sucrose were determined with traditional destructive methods. Cross validated calibration models based on Raman spectroscopy were obtained for all quality parameters, and test set validation offered good results, with R2 in the range 0.4-0.86 for 'Aroma' and 0.4-0.95 for 'Elstar', respectively. The regression coefficients showed that the calibrations relied on Raman bands associated with starch and different sugars. The results suggest that Raman spectroscopy in the future could be used to determine the optimal time of harvesting and to sort apples into different degrees of ripeness.

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d-Tagatose is a highly promising functional sweetener known for its various physiological functions. In this study, a novel tagatose 4-epimerase from Thermoprotei archaeon (Thar-T4Ease), with the ability to convert d-fructose to d-tagatose, was discovered through a combination of structure similarity search and sequence-based protein clustering. The recombinant Thar-T4Ease exhibited optimal activity at pH 8.5 and 85 °C, in the presence of 1 mM Ni2+. Its kcat and kcat/Km values toward d-fructose were measured to be 248.5 min-1 and 2.117 mM-1·min-1, respectively. Notably, Thar-T4Ease exhibited remarkable thermostability, with a t1/2 value of 198 h at 80 °C. Moreover, it achieved a conversion ratio of 18.9% using 100 g/L d-fructose as the substrate. Finally, based on sequence and structure analysis, crucial residues for the catalytic activity of Thar-T4Ease were identified by molecular docking and site-directed mutagenesis. This research expands the repertoire of enzymes with C4-epimerization activity and opens up new possibilities for the cost-effective production of d-tagatose from d-fructose.

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BACKGROUND: The intake of high-fructose corn syrup (HFCS) may increase the risk of colorectal cancer (CRC). This study aimed to explore the potential effects and mechanisms of resistant starch (RS) in HFCS-induced colon tumorigenesis. METHODS: The azoxymethane/dextran sodium sulfate (AOM/DSS) and ApcMin/+ mice models were used to investigate the roles of HFCS and RS in CRC in vivo. An immunohistochemistry (IHC) staining analysis was used to detect the expression of proliferation-related proteins in tissues. 16S rRNA sequencing for microbial community, gas chromatography for short-chain fatty acids (SCFAs), and mass spectrometry analysis for glycolysis products in the intestines were performed. Furthermore, lactic acid assay kit was used to detect the glycolysis levels in vitro. RESULTS: RS suppressed HFCS-induced colon tumorigenesis through reshaping the microbial community. Mechanistically, the alteration of the microbial community after RS supplement increased the levels of intestinal SCFAs, especially butyrate, leading to the suppression of glycolysis and CRC cell proliferation by downregulating HK2. CONCLUSIONS: Our study identified RS as a candidate of protective factors in CRC and may provide a potential target for HFCS-related CRC treatment.

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Sex differences may play a role in the etiopathogenesis and severity of metabolic dysfunction-associated steatotic liver disease (MASLD), a disorder characterized by excessive fat accumulation associated with increased inflammation and oxidative stress. We previously observed the development of steatosis specifically in female rats fed a high-fat diet enriched with liquid fructose (HFHFr) for 12 weeks. The aim of this study was to better characterize the observed sex differences by focusing on the antioxidant and cytoprotective pathways related to the KEAP1/NRF2 axis. The KEAP1/NRF2 signaling pathway, autophagy process (LC3B and LAMP2), and endoplasmic reticulum stress response (XBP1) were analyzed in liver homogenates in male and female rats that were fed a 12-week HFHFr diet. In females, the HFHFr diet resulted in the initial activation of the KEAP1/NRF2 pathway, which was not followed by the modulation of downstream molecular targets; this was possibly due to the increase in KEAP1 levels preventing the nuclear translocation of NRF2 despite its cytosolic increase. Interestingly, while in both sexes the HFHFr diet resulted in an increase in the levels of LC3BII/LC3BI, a marker of autophagosome formation, only males showed a significant upregulation of LAMP2 and XBP1s; this did not occur in females, suggesting impaired autophagic flux in this sex. Overall, our results suggest that males are characterized by a greater ability to cope with an HFHFr metabolic stimulus mainly through an autophagic-mediated proteostatic process while in females, this is impaired. This might depend at least in part upon the fine modulation of the cytoprotective and antioxidant KEAP1/NRF2 pathway resulting in sex differences in the occurrence and severity of MASLD. These results should be considered to design effective therapeutics for MASLD.

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