High dietary Fructose Drives Metabolic Dysfunction-Associated Steatotic Liver Disease via Activating ubiquitin-specific peptidase 2/11ß-hydroxysteroid dehydrogenase type 1 Pathway in Mice.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common cause of chronic liver-related morbidity and mortality. Though high fructose intake is acknowledged as a metabolic hazard, its role in the etiology of MASLD requires further clarification. Here, we demonstrated that high dietary fructose drives MASLD development and promotes MASLD progression in mice, and identified Usp2 as a fructose-responsive gene in the liver. Elevated USP2 levels were detected in the hepatocytes of MASLD mice; a similar increase was observed following fructose exposure in primary hepatocytes and mouse AML12 cells. Notably, hepatocytes overexpressing USP2 presented with exaggerated lipid accumulation and metabolic inflammation when exposed to fructose. Conversely, USP2 knockdown mitigated these fructose-induced changes. Furthermore, USP2 was found to activate the C/EBPα/11ß-HSD1 signaling, which further impacted the equilibrium of cortisol and cortisone in the circulation of mice. Collectively, our findings revealed the role of dietary fructose in MASLD pathogenesis and identified the USP2-mediated C/EBPα/ 11ß-HSD1 signaling as a potential target for the management of MASLD.

KHK-A promotes fructose-dependent colorectal cancer liver metastasis by facilitating the phosphorylation and translocation of PKM2.

Excessive fructose diet is closely associated with colorectal cancer (CRC) progression. Nevertheless, fructose's specific function and precise mechanism in colorectal cancer liver metastasis (CRLM) is rarely known. Here, this study reported that the fructose absorbed by primary colorectal cancer could accelerate CRLM, and the expression of KHK-A, not KHK-C, in liver metastasis was higher than in paired primary tumors. Furthermore, KHK-A facilitated fructose-dependent CRLM in vitro and in vivo by phosphorylating PKM2 at Ser37. PKM2 phosphorylated by KHK-A inhibited its tetramer formation and pyruvic acid kinase activity but promoted the nuclear accumulation of PKM2. EMT and aerobic glycolysis activated by nuclear PKM2 enhance CRC cells' migration ability and anoikis resistance during CRLM progression. TEPP-46 treatment, targeting the phosphorylation of PKM2, inhibited the pro-metastatic effect of KHK-A. Besides, c-myc activated by nuclear PKM2 promotes alternative splicing of KHK-A, forming a positive feedback loop.

A complex metabolic network and its biomarkers regulate laccase production in white-rot fungus Cerrena unicolor 87613.

BACKGROUND: White-rot fungi are known to naturally produce high quantities of laccase, which exhibit commendable stability and catalytic efficiency. However, their laccase production does not meet the demands for industrial-scale applications. To address this limitation, it is crucial to optimize the conditions for laccase production. However, the regulatory mechanisms underlying different conditions remain unclear. This knowledge gap hinders the cost-effective application of laccases. RESULTS: In this study, we utilized transcriptomic and metabolomic data to investigate a promising laccase producer, Cerrena unicolor 87613, cultivated with fructose as the carbon source. Our comprehensive analysis of differentially expressed genes (DEGs) and differentially abundant metabolites (DAMs) aimed to identify changes in cellular processes that could affect laccase production. As a result, we discovered a complex metabolic network primarily involving carbon metabolism and amino acid metabolism, which exhibited contrasting changes between transcription and metabolic patterns. Within this network, we identified five biomarkers, including succinate, serine, methionine, glutamate and reduced glutathione, that played crucial roles in co-determining laccase production levels. CONCLUSIONS: Our study proposed a complex metabolic network and identified key biomarkers that determine the production level of laccase in the commercially promising Cerrena unicolor 87613. These findings not only shed light on the regulatory mechanisms of carbon sources in laccase production, but also provide a theoretical foundation for enhancing laccase production through strategic reprogramming of metabolic pathways, especially related to the citrate cycle and specific amino acid metabolism.

GFPT2 expression is induced by gemcitabine administration and enhances invasion by activating the hexosamine biosynthetic pathway in pancreatic cancer.

Our previous studies revealed a novel link between gemcitabine (GEM) chemotherapy and elevated glutamine-fructose-6-phosphate transaminase 2 (GFPT2) expression in pancreatic cancer (PaCa) cells. GFPT2 is a rate-limiting enzyme in the hexosamine biosynthesis pathway (HBP). HBP can enhance metastatic potential by regulating epithelial-mesenchymal transition (EMT). The aim of this study was to further evaluate the effect of chemotherapy-induced GFPT2 expression on metastatic potential. GFPT2 expression was evaluated in a mouse xenograft model following GEM exposure and in clinical specimens of patients after chemotherapy using immunohistochemical analysis. The roles of GFPT2 in HBP activation, downstream pathways, and cellular functions in PaCa cells with regulated GFPT2 expression were investigated. GEM exposure increased GFPT2 expression in tumors resected from a mouse xenograft model and in patients treated with neoadjuvant chemotherapy (NAC). GFPT2 expression was correlated with post-operative liver metastasis after NAC. Its expression activated the HBP, promoting migration and invasion. Treatment with HBP inhibitors reversed these effects. Additionally, GFPT2 upregulated ZEB1 and vimentin expression and downregulated E-cadherin expression. GEM induction upregulated GFPT2 expression. Elevated GFPT2 levels promoted invasion by activating the HBP, suggesting the potential role of this mechanism in promoting chemotherapy-induced metastasis.

Investigation of the relationship between inflammation and microbiota in the intestinal tissue of female and male rats fed with fructose: Modulatory role of metformin.

BACKGROUND: It has been reported that High-Fructose (HF) consumption, considered one of the etiological factors of Metabolic Syndrome (MetS), causes changes in the gut microbiota and metabolic disorders. There is limited knowledge on the effects of metformin in HF-induced intestinal irregularities in male and female rats with MetS. OBJECTIVES: In this study, we investigated the sex-dependent effects of metformin treatment on the gut microbiota, intestinal Tight Junction (TJ) proteins, and inflammation parameters in HF-induced MetS. METHODS: Fructose was given to the male and female rats as a 20% solution in drinking water for 15 weeks. Metformin (200 mg/kg) was administered by gastric tube once a day during the final seven weeks. Biochemical, histopathological, immunohistochemical, and bioinformatics analyses were performed. Differences were considered statistically significant at p < 0.05. RESULTS: The metformin treatment in fructose-fed rats promoted glucose, insulin, Homeostasis Model Assessment of Insulin Resistance Index (HOMA-IR), and Triglyceride (TG) values in both sexes. The inflammation score was significantly decreased with metformin treatment in fructose-fed male and female rats (p < 0.05). Moreover, metformin treatment significantly decreased Interleukin-1 Beta (IL-1ß) and Tumor Necrosis Factor-Alpha (TNF-α) in ileum tissue from fructose-fed males (p < 0.05). Intestinal immunoreactivity of Occludin and Claudin-1 was increased with metformin treatment in fructose-fed female rats. HF and metformin treatment changed the gut microbial composition. Firmicutes/Bacteroidetes (F/B) ratio increased with HF in females. In the disease group, Bifidobacterium pseudolongum; in the treatment group, Lactobacillus helveticus and Lactobacillus reuteri are the prominent species in both sexes. When the male and female groups were compared, Akkermansia muciniphila was prominent in the male treatment group. CONCLUSION: In conclusion, metformin treatment promoted biochemical parameters in both sexes of fructose-fed rats. Metformin showed a sex-dependent effect on inflammation parameters, permeability factors, and gut microbiota. Metformin has partly modulatory effects on fructose-induced intestinal changes.

The predictive value of PFKFB3 in bladder cancer prognosis.

6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3 (PFKFB3) influences cancer progression via participating in tumor aerobic glycolysis. In this study, we aimed to evaluate the prognostic significance of PFKFB3 in bladder cancer (BLCA) patients by analyzing a combination of publicly available databases, clinical patient data, and bladder tumor samples from our hospital. Single-cell and bulk RNA-seq data of bladder cancer, obtained from ENA, GEO, and TCGA databases, were utilized for our analysis. The results indicated that PFKFB3 mRNA expression was markedly elevated in bladder cancer compared to paired normal tissue. Furthermore, BLCA patients with high PFKFB3 expression exhibited a significantly worse prognosis (P < 0.05). To validate these findings, clinical data and immunohistochemistry staining were performed on specimens obtained from 89 BLCA patients who underwent radical cystectomy at either Qingdao University Affiliated Hospital or Peking Union Medical College Hospital. The findings from this verification process confirmed that high expression of PFKFB3 serves as a biomarker for predicting worse prognosis in BLCA patients (OR: 2.462, 95 % CI: 1.202-5.042, P = 0.012). To facilitate clinical application, we developed a nomogram based on four variables, including PFKFB3 expression, to predict the survival of BLCA patients. Importantly, this nomogram demonstrated a low mean prediction error of 0.03. Taken together, our findings suggest that PFKFB3 has the potential to serve as both a prognostic biomarker and a therapeutic target for BLCA patients.

Fructose-induced metabolic reprogramming of cancer cells.

Excess dietary fructose consumption has been long proposed as a culprit for the world-wide increase of incidence in metabolic disorders and cancer within the past decades. Understanding that cancer cells can gradually accumulate metabolic mutations in the tumor microenvironment, where glucose is often depleted, this raises the possibility that fructose can be utilized by cancer cells as an alternative source of carbon. Indeed, recent research has increasingly identified various mechanisms that show how cancer cells can metabolize fructose to support their proliferating and migrating needs. In light of this growing interest, this review will summarize the recent advances in understanding how fructose can metabolically reprogram different types of cancer cells, as well as how these metabolic adaptations can positively support cancer cells development and malignancy.

Hepatic steatosis induced by nicotine plus Coca-Cola™ is prevented by nicotinamide riboside (NR).

Introduction: Cigarettes containing nicotine (Nic) are a risk factor for the development of cardiovascular and metabolic diseases. We reported that Nic delivered via injections or e-cigarette vapor led to hepatic steatosis in mice fed with a high-fat diet. High-fructose corn syrup (HFCS) is the main sweetener in sugar-sweetened beverages (SSBs) in the US. Increased consumption of SSBs with HFCS is associated with increased risks of non-alcoholic fatty liver disease (NAFLD). Nicotinamide riboside (NR) increases mitochondrial nicotinamide adenine dinucleotide (NAD+) and protects mice against hepatic steatosis. This study evaluated if Nic plus Coca-Cola™ (Coke) with HFCS can cause hepatic steatosis and that can be protected by NR. Methods: C57BL/6J mice received twice daily intraperitoneal (IP) injections of Nic or saline and were given Coke (HFCS), or Coke with sugar, and NR supplementation for 10 weeks. Results: Our results show that Nic+Coke caused increased caloric intake and induced hepatic steatosis, and the addition of NR prevented these changes. Western blot analysis showed lipogenesis markers were activated (increased cleavage of the sterol regulatory element-binding protein 1 [SREBP1c] and reduction of phospho-Acetyl-CoA Carboxylase [p-ACC]) in the Nic+Coke compared to the Sal+Water group. The hepatic detrimental effects of Nic+Coke were mediated by decreased NAD+ signaling, increased oxidative stress, and mitochondrial damage. NR reduced oxidative stress and prevented mitochondrial damage by restoring protein levels of Sirtuin1 (Sirt1) and peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1) signaling. Conclusion: We conclude that Nic+Coke has an additive effect on producing hepatic steatosis, and NR is protective. This study suggests concern for the development of NAFLD in subjects who consume nicotine and drink SSBs with HFCS.

Polyphenol-rich black currant and cornelian cherry juices ameliorate metabolic syndrome induced by a high-fat high-fructose diet in Wistar rats.

Diets high in fat and sugar lead to metabolic syndrome (MetS) and related chronic diseases. We investigated the effects of commercially available, cold-pressed polyphenol-rich black currant (BC) and cornelian cherry (CC) juices on the prevention of MetS in Wistar rats induced by a 10-weeks high-fat high-fructose (HFF) diet. Juice consumption, either BC or CC, with a HFF diet resulted in lower serum triglycerides compared to only the HFF consumption. Both juices also mitigated the effects of HFF on the liver, pancreas, and adipose tissue, by preserving liver and pancreas histomorphology and reducing visceral fat and adipocyte size. Furthermore, supplementation with both juices reduced glucagon and up-regulated insulin expression in the pancreas of the rats on the HFF diet, whereas the BC also showed improved glucose regulation. BC juice also reduced the expression of IL-6 and hepatic inflammation compared to the group only on HFF diet. Both juices, especially BC, could be a convenient solution for the prevention of MetS in humans.

Dietary Fructose and Sodium Consumed during Early Mid-Life Are Associated with Hypertensive End-Organ Damage by Late Mid-Life in the CARDIA Cohort.

We aimed to investigate how dietary fructose and sodium impact blood pressure and risk of hypertensive target organ damage 10 years later. Data from n = 3116 individuals were obtained from the Coronary Artery Risk Development in Young Adults (CARDIA) study. Four groups were identified based on the four possible combinations of the lower and upper 50th percentile for sodium (in mg) and fructose (expressed as percent of total daily calories). Differences among groups were ascertained and logistic regression analyses were used to assess the risk of hypertensive target organ damage (diastolic dysfunction, coronary calcification and albuminuria). Individuals in the low-fructose + low-sodium group were found to have lower SBP compared to those in the low-fructose + high-sodium and high-fructose + high-sodium groups (p < 0.05). The highest risk for hypertensive target organ damage was found for albuminuria only in the high-fructose + high-sodium group (OR = 3.328, p = 0.006) while female sex was protective across all groups against coronary calcification. Our findings highlight that sodium alone may not be the culprit for hypertension and hypertensive target organ damage, but rather when combined with an increased intake of dietary fructose, especially in middle-aged individuals.

Mechanisms Underlying Memory Impairment Induced by Fructose.

Fructose consumption has increased over the years, especially in adolescents living in urban areas. Growing evidence indicates that daily fructose consumption leads to some pathological conditions, including memory impairment. This review summarizes relevant data describing cognitive deficits after fructose intake and analyzes the underlying neurobiological mechanisms. Preclinical experiments show sex-related deficits in spatial memory; that is, while males exhibit significant imbalances in spatial processing, females seem unaffected by dietary supplementation with fructose. Recognition memory has also been evaluated; however, only female rodents show a significant decline in the novel object recognition test performance. According to mechanistic evidence, fructose intake induces neuroinflammation, mitochondrial dysfunction, and oxidative stress in the short term. Subsequently, these mechanisms can trigger other long-term effects, such as inhibition of neurogenesis, downregulation of trophic factors and receptors, weakening of synaptic plasticity, and long-term potentiation decay. Integrating all these neurobiological mechanisms will help us understand the cellular and molecular processes that trigger the memory impairment induced by fructose.

Descriptive Analysis of Carrier and Affected Hereditary Fructose Intolerance in Women during Pregnancy.

(1) Background: Hereditary fructose intolerance (HFI) is a rare autosomal recessive metabolic disorder resulting from aldolase B deficiency, requiring a fructose, sorbitol and sucrose (FSS)-free diet. Limited information exists on the relationship between pregnancy outcomes and HFI. This study aims to analyze pregnancy-related factors in a cohort of thirty Spanish women, with twenty-three being carriers and seven being HFI-affected (45 pregnancies). (2) Methods: A descriptive, cross-sectional and retrospective study utilized an anonymous questionnaire. (3) Results: Findings encompassed physical and emotional states, nutritional habits, pathology development and baby information. Notable results include improved physical and emotional states compared to the general population, with conventional analyses mostly within normal ranges. Persistent issues after pregnancy included hepatic steatosis, liver adenomas and hemangiomas. Carrier mothers' babies exhibited higher weight than those of patient mothers, while the weights of carrier children born with HFI were similar to disease-affected children. (4) Conclusions: Pregnant women with HFI did not significantly differ in physical and emotional states, except for nausea, vomiting, and cravings. Post-pregnancy, HFI patients and carriers exhibited persistent hepatic issues. Significantly, babies born to HFI-affected mothers had lower weights. This study sheds light on pregnancy outcomes in HFI, emphasizing potential complications and the need for ongoing monitoring and care.

The Effects of Chia Defatted Flour as a Nutritional Supplement in C57BL/6 Mice Fed a Low-Quality Diet.

Today, consumption of diets rich in saturated fat and fructose, associated with a variety of metabolic deregulations, has increased. The aim of this study was to evaluate the effect of dietary supplementation with a residue of defatted chia seed on a diet with low nutritional quality. To do this, C57BL/6 male mice were fed with the Control (C), Low-Nutritional-Quality (LNQ), or supplemented-with-chia-defatted-flour (LNQ+C) diets. After 12 weeks, the glucose and lactate levels were determined in the serum, liver, and kidney, along with reactive oxygen species (ROS) levels, antioxidant enzyme activity, reduced glutathione (GSH), and protein oxidation (AOPP). The LNQ diet increased the glucose and lactate levels (+25% and +50% approx. in the liver, with respect to the control group) and generated oxidative stress by modifying the levels of ROS and the activity of antioxidant enzymes, causing oxidative damage to proteins (+12% in the liver, with respect to the control). Chia supplementation helped to restore the glucose to control levels and modulate the endogenous antioxidant system, resulting in a decrease in protein oxidation products with no differences compared to the control group. In conclusion, supplementation with chia showed beneficial effects on the general health of mice, even when fed a low-nutritional-quality diet.

Genistein and Sex Hormone Supplementation Modulated Hepatic PPARα, δ, and γ Subtypes and STAT1 Expressions in a NASH Rat Model with Bilateral Orchidectomy.

Nonalcoholic steatohepatitis (NASH) is a progressive form of nonalcoholic fatty liver disease (NAFLD) that is characterized by hepatic inflammation and steatosis. Currently, limited data exist regarding the risk of NASH in transgender women and the treatment options for this particular population. The use of testosterone supplementation is unfavorable for transgender women, and estrogen supplementation is linked to an increased risk of breast cancer; thus, an isoflavone derivative compound known as "genistein" could serve as a viable substitute for a hormone supplement in this context. The purpose of this study was to investigate the treatment effects and mechanisms of actions of genistein and sex hormones in orchidectomized (ORX) rats with nonalcoholic steatohepatitis induced via a high-fat high-fructose diet (HFHF) model. Male Sprague-Dawley rats (n = 42) were randomly assigned into seven groups; control, ORX + standard diet, HFHF, ORX + HFHF, ORX + HFHF diet + testosterone (50 mg/kg body weight (BW) once weekly), ORX + HFHF diet + estradiol (1.6 mg/kg BW daily), and ORX + HFHF diet + genistein (16 mg/kg BW daily). The duration of the study was 6 weeks. Some parts of liver tissue were used for histological examination by H&E staining. The determination of fat accumulation was performed using Oil Red O staining. SREBP1c and FAS gene expression were quantified using real-time PCR technique. The levels of all types of peroxisome proliferator-activated receptors (PPARs; α, δ, γ), proteins, and signal transducer and activator of transcription 1 (STAT1) signaling pathway were determined by both immunoblotting and immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, and hepatocyte ballooning, and showed higher levels of genes related to de novo lipogenesis, including SREBP1c and FAS. The expression of PPARγ and STAT1 were upregulated, while the expression of PPARα and PPARδ were downregulated in the ORX + HFHF group. Testosterone, estradiol and genistein treatments improved NASH histopathology together with the reversal of all types of PPAR protein expressions. Interestingly, genistein decreased the levels of STAT1 protein expression more than those of testosterone and estradiol treatment. Genistein and sex hormone treatment could ameliorate NASH through the upregulation of PPARα, and PPARδ, and the suppression of PPARγ and STAT1 expression.

Polymeric liposomes targeting dual transporters for highly efficient oral delivery of paclitaxel.

A novel delivery system comprising N-succinic anhydride (N-SAA) and D-fructose co-conjugated chitosan (NSCF)-modified polymeric liposomes (NSCF-PLip) were designed to enhance oral delivery of paclitaxel (PTX) by targeting monocarboxylate transporters (MCT) and glucose transporters (GLUT). The synthesized NSCF was characterised by FT-IR and 1H NMR spectra. The prepared 30.78 % (degree of substitution of N-SAA) NSCF-PTX-PLip were approximately 150 nm in size, with a regular spherical shape, the zeta potential of -25.4 ± 5.13 mv, drug loading of 2.35 % ± 0.05 %, and pH-sensitive and slow-release characteristics. Compared with PTX-Lip, 30.78 % NSCF-PTX-PLip significantly enhanced Caco-2 cellular uptake via co-mediation of MCT and GLUT, showing relatively specific binding of propionic acid and MCT. Notably, the NSCF modification of PTX-Lip had no appreciable influence on their original cellular uptake pathway. The fructose modification of 30.78 % NSC-PTX-PLip significantly increased the concentration after tmax, indicating their continuous and efficient absorption. Compared with PTX-Lip, the 30.78 % NSCF-PTX-PLip resulted in a 2.09-fold extension of MRT, and a 6.06-fold increase of oral bioavailability. It significantly increased tumour drug distribution and tumour growth inhibition rate. These findings confirm that 30.78 % NSCF-PLip offer a potential oral delivery platform for PTX and targeting the dual transporters of MCT and GLUT is an effective strategy for enhancing the intestinal absorption of drugs.

Baroreflex afferent function is a part of insights of Leptin-mediated blood pressure reduction and Leptin-resistance hypertension.

The aim of this study is to verify the impact of Leptin in blood pressure (BP) regulation and Leptin-resistance in metabolic/neurogenic hypertension through baroreflex afferents and dysregulation. Artery BP/heart rate (HR) were measured while nodose (NG) microinjection of Leptin, membrane depolarization/inward current were obtained by whole-cell patch from NG neurons isolated from adult female rats. Baroreflex sensitivity (BRS) tested with PE/SNP, distribution/expression of Leptin/receptors in the NG/nucleus tractus solitary (NTS) examined using immumostaining and qRT-PCR, and serum concentrations of Leptin/NE measured by ELISA were observed in control and high fructose-drinking induced hypertension (HTN-HFD) rats. The results showed that BP was significantly/dose-dependently reduced by Leptin NG microinjection likely through direct excitation of female-specific subpopulation of Ah-type neurons showing a potent membrane depolarization/inward currents. Sex-specific distribution/expression of OB-Ra/OB-Rb in the NG were detected with estrogen-dependent manner, similar observations were also confirmed in the NTS. As expected, BRS was dramatically decreased in the presence of PE/SNP in both male and female rats except for the female with PE at given concentrations. Additionally, serum concentration of Leptin was elevated in HFD-HTN model rats of either sex with more obvious in females. Under hypertensive condition, the mean fluorescent density of OB-R and mRNA expression for OB-Ra/OB-Rb in the NG/NTS were significantly down-regulated. These results have demonstrated that Leptin play a role in dominant parasympathetic drive via baroreflex afferent activation to buffer Leptin-mediated sympathetic activation systemically and Leptin-resistance is an innegligible mechanism for metabolic/neurogenic hypertension through baroreflex afferent dysregulation.

Sports drinks do not increase acute kidney injury risk in males during industrial work in the heat when euhydration is maintained, a randomized crossover trial.

Industrial workers regularly perform physical labor under high heat stress, which may place them at risk for dehydration and acute kidney injury. Current guidelines recommend that workers should consume sports drinks to maintain euhydration during work shifts. However, the impact of fructose sweetened sports drinks on acute kidney injury risk is unknown. The purpose of this study was to investigate the effects of sports drink consumption on markers of acute kidney injury following simulated industrial work in the heat. Twenty males completed two matched 2 h simulated industrial work trial visits in a warm and humid environment (30 °C and 55% relative humidity). During and following the bout of simulated work, participants consumed either a commercially available sports drink or a noncaloric placebo. Urine and blood samples, collected pre-, post-, and 16 h post-work were assayed for markers of hydration (plasma/urine osmolality, and urine specific gravity) and acute kidney injury (KIM-1 and NGAL). There were no differences in physiological or perceptual responses to the bout of work (interaction p > 0.05 for all indices), and markers of hydration were similar between trials (interaction p > 0.05 for all indices). KIM-1 (Placebo: Δ Ln 1.18 ± 1.64; Sports drink: Δ Ln 1.49 ± 1.10 pg/mL; groupwide d = 0.89, p < 0.001) and NGAL (Placebo: Δ Ln 0.44 ± 1.11; Sports drink: Δ Ln 0.67 ± 1.22 pg/mL; groupwide d = 0.39, p = 0.03) were elevated pre- to post-work, but there were no differences between trials (interaction p > 0.05). These data provide no evidence that consumption of fructose sweetened sports drinks increases the risk of acute kidney injury during physical work in the heat.

Genistein and sex hormone treatment alleviated hepatic fat accumulation and inflammation in orchidectomized rats with nonalcoholic steatohepatitis.

Testosterone deficiency has been reported to accelerate nonalcoholic fatty liver disease (NAFLD). However, there are minimal data on the risk of NAFLD in transgender women and the treatment of NAFLD in this population. This study aimed to investigate the treatment effects and the mechanisms of action of genistein and sex hormones in orchiectomized (ORX) rats with nonalcoholic steatohepatitis (NASH) induced by a high fat high fructose diet (HFHF). Seven-week old male Sprague-Dawley rats were randomly divided into 7 groups (n = 6 each group); 1) control group, 2) ORX + standard diet group, 3) HFHF group, 4) ORX + HFHF group, 5) ORX + HFHF diet + testosterone group (50 mg/kg body weight (BW) once weekly), 6) ORX + HFHF diet + estradiol group (1.6 mg/kg BW daily), and 7) ORX + HFHF diet + genistein group (16 mg/kg BW daily). The duration of treatment was 6 weeks. Liver tissue was used for histological examination by hematoxylin and eosin staining and hepatic fat measurement by Oil Red O staining. Protein expression levels of histone deacetylase3 (HDAC3) and peroxisome proliferator-activated receptor delta (PPARδ) were analyzed by immunoblotting. Hepatic nuclear factor (NF)-ĸB expression was evaluated by immunohistochemistry. Rats in the ORX + HFHF group had the highest degree of hepatic steatosis, lobular inflammation, hepatocyte ballooning and the highest percentage of positive Oil Red O staining area among all groups. The expression of HDAC3 and PPARδ was downregulated, while NF-ĸB expression was upregulated in the ORX + HFHF group when compared with control and ORX + standard diet groups. Testosterone, estradiol and genistein treatment improved histological features of NASH together with the reversal of HDAC3, PPARδ and NF-ĸB protein expression comparing with the ORX + HFHF group. In summary, genistein and sex hormone treatment could alleviate NASH through the up-regulation of HDAC3 and PPARδ, and the suppression of NF-ĸB expression.

Preparation of red jujube powder with high content of Amadori compounds and higher antioxidant activity by controlling the Maillard reaction.

Amadori compounds (ACs) are stable compounds produced in the early stage of the Maillard reaction (MR) with health benefits such as immunomodulatory, antithrombosis, and tumor-preventive effects. Jujube is a medicinal and edible fruit in China. It is rich in free amino acids and reducing sugar, but traditionally, little attention was paid to the formation of ACs when jujube was processed, neither the influence of ACs on health effects. In this paper, we aimed to increase ACs through controlling the MR during different heating processes of jujube powder with adjusted water content and find the most effective AC that contributed to the antioxidant effects of jujube powder. The optimal dry-heating conditions to produce ACs were as follows: The water activity was 0.294, the heating temperature was 90°C, and the time was 120 min. After processing, the ACs content of jujube powder was 18.55 ± 0.19 mg/g dry weight (DW), which was more than 100 times of those in the unheated jujube powder (0.153 ± 0.003 mg/g DW). Besides, the antioxidant activity of jujube powder after dry-heating process was higher than that of unheated one. As the most abundant AC in the dry-heated jujube powder (12.90 ± 0.75 mg/g DW), N-(1-deoxy-d-fructose-1-yl) proline (Fru-Pro) showed the highest antioxidant activity (62% of equivalent l-ascorbic acid) among 12 ACs in ferric reducing antioxidant power assay. This result provided a method to produce jujube product with high content of ACs and confirmed the positive contribution of Fru-Pro to the antioxidant activity of the jujube powder.

Fructose overconsumption accelerates renal dysfunction with aberrant glomerular endothelial-mesangial cell interactions in db/db mice.

For the advancement of DKD treatment, identifying unrecognized residual risk factors is essential. We explored the impact of obesity diversity derived from different carbohydrate qualities, with an emphasis on the increasing trend of excessive fructose consumption and its effect on DKD progression. In this study, we utilized db/db mice to establish a novel diabetic model characterized by fructose overconsumption, aiming to uncover the underlying mechanisms of renal damage. Compared to the control diet group, the fructose-fed db/db mice exhibited more pronounced obesity yet demonstrated milder glucose intolerance. Plasma cystatin C levels were elevated in the fructose model compared to the control, and this elevation was accompanied by enhanced glomerular sclerosis, even though albuminuria levels and tubular lesions were comparable. Single-cell RNA sequencing of the whole kidney highlighted an increase in Lrg1 in glomerular endothelial cells (GECs) in the fructose model, which appeared to drive mesangial fibrosis through enhanced TGF-ß1 signaling. Our findings suggest that excessive fructose intake exacerbates diabetic kidney disease progression, mediated by aberrant Lrg1-driven crosstalk between GECs and mesangial cells.