Fibroblast Growth Factor 21 Research Articles

The relationship between the expression of fibroblast growth factor 19 and insulin-like growth factor 1 in colorectal polyp tissues and the occurrence of colorectal adenomas

Objective: This investigation sought to delineate the associations among colorectal adenomatous polyps, diabetes, and biomolecules involved in glucose metabolism. Method: Data were collected from 40 patients who underwent endoscopic polypectomy at the Endoscopy Department of Shandong Cancer Hospital between June 2019 and September 2021. This cohort included 27 patients with inflammatory polyps and 13 with adenomatous polyps. We assessed fasting insulin (Fins), fasting blood glucose (FBG), and the mRNA expressions of fibroblast growth factor 19 (FGF-19) and insulin-like growth factor 1 (IGF-1) in the polyp tissues. Both univariate and multivariate logistic regression analyses were employed to ascertain the determinants influencing the emergence of adenomatous polyps. From these analyses, a predictive nomogram was constructed to forecast the occurrence of adenomatous polyps, and evaluations on the discriminative capacity, calibration, and clinical utility of the model were conducted. Results: The adenomatous polyp group exhibited markedly elevated levels of glucose, insulin, FGF-19, and IGF-1, with respective concentrations of (8.67±2.70) mmol/L, (12.72±7.69) μU/L, 2.20±1.88, and 1.36±0.69. These figures were significantly higher compared to the inflammatory polyp group, which showed levels of (5.51±0.72) mmol/L, (5.49±2.68) μU/L, 0.53±0.97, and 0.41±0.46, respectively, P=0.001. Multivariate logistic regression revealed that the relative expression of IGF-1 served as an independent risk factor for the development of colorectal adenomatous polyps (OR=5.622, 95% CI:1.085-29.126). The nomogram displayed a C-index of 0.849, indicating substantial discriminative capability. The calibration curve affirmed the model's accuracy in aligning predicted probabilities with actual outcomes, and the clinical decision curve demonstrated thepractical clinical applicability of the model. Conclusions: There was a significant correlation between the occurrence of colorectal adenomatous polyps and glucose metabolic pathways. Individuals with diabetes showed a higher propensity to develop such polyps.

The effects of Hibiscus sabdariffa Linn. on the levels of FGF21 and AMPK in the Heart of Diabetic Mice

Background : Diabetes Mellitus (DM) is a metabolic disorder characterized by pancreatic cell dysfunction and insulin resistance. Fibroblast Growth Factor 21 (FGF21) is thought to have a cardioprotective role. Through FGF21 signaling, AMP-activated protein kinase (AMPK) activity reduces apoptosis, inflammation, hypertrophy, and fibrosis in the heart. Hibiscus sabdariffa Linn. (HSL) contains flavonoids that have hypoglycemic effects and are anti-inflammatory and antioxidant-active. This study aims to assess the effect of HSL on FGF21 and AMPK levels in the heart of diabetic mice models. Methods : An experimental study using Deutschland Denken Yoken (DDY) mice aged eight weeks were divided into four groups: Control, DM Control, HSL 200, and HSL 400. In the DM control, HSL 200, and HSL 400 groups, diabetes was induced by giving a High Fat Diet(HFD) and STZ 40mg/kgbb. The HSL 200 group was given HSL 200mg/kgBB supplementation for three weeks, and the HSL 400 group was given HSL 400 mg/kgBB supplementation for three weeks. FGF21 and AMPK levels were measured using the enzyme-linked immunosorbent assay (ELISA) method. Results : There was no significant difference between FGF21 and AMPK levels between the control and DM control groups. FGF21 and AMPK levels in the HSL 400 group were higher than in the control, DM control, and HSL 200 groups. Conclusions : These findings suggest that HSL supplementation at specific doses can potentially increase the activation of FGF 21 and AMPK signaling in the heart of diabetic mice models.

Potential teratogenic effect of prenatal dexamethasone administration on palate development: Experimental study in rats

BackgroundThe interaction of cell populations and synchronization of cell signaling pathways during craniofacial development can cause malformations such as facial clefts when interrupted by teratogenic agents including synthetic corticosteroids. Therefore, this study aimed to determine the potentially disturbing dexamethasone (Dex) effect on palatal shelf development in rat embryos and the possible reasons for this teratogenic potential in relation to fibroblast growth factor 10 (FGF10) as well as FGF10 receptor2 (FGFR2) signaling. MethodsThirty pregnant rats were used, which were then randomly categorized into three groups of ten animals each: the control group, where pregnant rats received no treatment, Sham group in which pregnant rats were injected subcutaneously with saline (0.4 mg/kg body weight) during the mid-pregnancy period at gestational day 9–14, and Dex-treated group, where pregnant rats received 0.4 mg/kg of Dex at mid-gestational period. Pregnant animals from all groups were sacrificed on day 20 of gestation before birth and the fetuses were removed for examination of the palatal shelves using a light microscope (LM). In addition, a real-time polymerase chain reaction and a reverse transcription-polymerase chain reaction (RT-PCR) were done to evaluate FGF10 and its receptor FGFR2 gene expression. ResultsThe cleft palate incidence rates in the groups of embryos were determined. Only the offspring in the Dex group showed a cleft palate. Moreover, the cleft palate incidence rate in the Dex group was significantly different compared to controls. Moreover, a significant decrease in FGF10 and FGFR2 expression levels was reported in the Dex group than in the controls. ConclusionsDex treatment in mid-gestation may increase the incidence of cleft palate development, which may be due to modulation of FGF signaling. This calls for caution when using this medication in the first half of pregnancy unless absolutely necessary and under close medical supervision.

FGF21 mediating the Sex-dependent Response to Dietary Macronutrients.

Sex is key variable influencing body composition and substrate utilization. At rest, females maintain greater adiposity than males and resist the mobilization of fat. Males maintain greater lean muscle mass and mobilize fat readily. Determining the mechanisms that direct these sex-dependent effects is important for both reproductive and metabolic health. Here, we highlight the fundamental importance of sex in shaping metabolic physiology and assess growing evidence that the hepatokine fibroblast growth factor-21 (FGF21) plays a mechanistic role to facilitate sex-dependent responses to a changing nutritional environment. First, we examine the importance of sex in modulating body composition and substrate utilization. We summarize new data that point toward sex-biased effects of pharmacologic FGF21 administration on these endpoints. When energy is not limited, metabolic responses to FGF21 mirror broader sex differences; FGF21-treated males conserve lean mass at the expense of increased lipid catabolism, whereas FGF21-treated females conserve fat mass at the expense of reduced lean mass. Next, we examine the importance of sex in modulating the endogenous secretion of FGF21 in response to changing macronutrient and energy availability. During the resting state when energy is not limited, macronutrient imbalance increases the secretion of FGF21 more so in males than females. When energy is limited, the effect of sex on both the secretion of FGF21 and its metabolic actions may be reversed. Altogether, we argue that a growing literature supports FGF21 as a plausible mechanism contributing to the sex-dependent mobilization vs preservation of lipid storage and highlight the need for further research.

Comparison of fibroblast growth factor 19 concentrations between dogs with and without gallbladder mucoceles.

Fibroblast growth factor 19 (FGF19) is an enterohepatic hormone the synthesis of which is stimulated by bile acid activation of the nuclear farnesoid X receptor (FXR) in ileal enterocytes. Increased production of FGF19 downregulates hepatocyte bile acid synthesis and gluconeogenesis, while concurrently upregulating hepatocyte glycogenesis and gallbladder (GB) filling. The physiologic impact of this regulatory cycle is illustrated in cholecystectomized humans, in whom the disturbed meal-related flux of GB bile decreases serum FGF19 concentrations. Determine if serum FGF19 concentrations are lower in dogs with clinical GB mucoceles (GBMs) than in control dogs. Seven dogs with GBM diagnosed using abdominal ultrasonography, biochemical markers, and GB histopathology. Forty-two control dogs without gastrointestinal or hepatobiliary disorders also were evaluated. Health status of controls was assessed by physical examination and diagnostic hematologic and biochemical test results. Prospective cross-sectional study to compare fasting plasma or serum FGF19 concentrations between groups. Concentrations of FGF19 were quantified by a commercially available FGF19 ELISA. Concentrations of FGF19 were significantly lower in dogs with clinical GBM (median, 14.0 pg/mL; range, 12.8-67.2) than in control dogs (median, 145.3 pg/mL; range, 36.5-285.1). In dogs, GBM is associated with significantly decreased serum FGF19 concentrations. We speculate that this finding reflects compromised GB contraction and decreased enterohepatic circulation of bile flow. Subnormal FGF19 concentrations may influence bile acid synthesis and hepatic metabolism.

Brown adipose tissue-derived FGF21 mediates the cardioprotection of dexmedetomidine in myocardial ischemia/reperfusion injury

Brown adipose tissue (BAT) plays a critical role in regulating cardiovascular homeostasis through the secretion of adipokines, such as fibroblast growth factor 21 (FGF21). Dexmedetomidine (DEX) is a selective α2-adrenergic receptor agonist with a protection against myocardial ischemia/reperfusion injury (MI/RI). It remains largely unknown whether or not BAT-derived FGF21 is involved in DEX-induced cardioprotection in the context of MI/RI. Herein, we demonstrated that DEX alleviated MI/RI and improved heart function through promoting the release of FGF21 from interscapular BAT (iBAT). Surgical iBAT depletion or supplementation with a FGF21 neutralizing antibody attenuated the beneficial effects of DEX. AMPK/PGC1α signaling-induced fibroblast growth factor 21 (FGF21) release in brown adipocytes is required for DEX-mediated cardioprotection since blockade of the AMPK/PGC1α axis weakened the salutary effects of DEX. Co-culture experiments showed that DEX-induced FGF21 from brown adipocytes increased the resistance of cardiomyocytes to hypoxia/reoxygenation (H/R) injury via modulating the Keap1/Nrf2 pathway. Our results provided robust evidence that the BAT-cardiomyocyte interaction is required for DEX cardioprotection, and revealed an endocrine role of BAT in DEX-mediating protection of hearts against MIRI.

Evaluating Fibroblast Growth Factor 21 (FGF21) Levels Post-Gastric Sleeve Surgery in Obese Patients.

Background and objectives Obesity is a major global health concern linked with increased risk of chronic diseases. This study aimed to assess the levels of fibroblast growth factor 21 (FGF21) insubjects with obesity after gastric sleeve surgery and explore its correlation with lipid and glycemic parameters. Methods This retrospective cohort study included 28 obese male subjects aged 25 to 50 years, undergoing gastric sleeve surgery. Plasma levels of FGF21 were measured by enzyme-linked immunosorbent assay (ELISA) before and six to 12 months after surgery. Other parameters including body mass index (BMI), fasting glucose, lipid profile, and insulin were also assessedand homeostatic model assessment (HOMA) was used to estimate insulin resistance. Results There was a significant increase in systemic FGF21 levels after surgery (45.12 vs. 126.16 pg/mL, p = 0.007). There was also a notable reduction in BMI (51.55 vs. 39.14, p < 0.001), insulin levels (20.06 vs. 8.85 mIU/L, p < 0.001), HOMA scores (6.94 to 2.49, p < 0.001), and glucose levels (7.33 vs. 6.08, p = 0.039). Lipid profile analysis post-surgery showed an increase in total cholesterol (4.38 vs. 5.09 mmol/L, p < 0.001) and high-density lipoprotein (HDL) (0.88 vs. 1.52 mmol/L, p < 0.001), with a decrease in triglycerides (1.75 vs. 1.01 mmol/L, p = 0.007). FGF21 positively correlated with growth hormone (GH), p = 0.0015, r = 0.59, and with insulin like growth factor 1 (IGF-1), p = 0.03, r = 0.431. Conclusion FGF21 levels were increased following gastric sleeve surgery in obese male patients and were positively correlated with growth hormone and insulin IGF-1. These findings provide insights into the metabolic alterations following bariatric surgery and highlight the potential role of FGF21 as an important molecule in obesity management and treatment.

Connecting the Dots: FGF21 as a Potential Link between Obesity and Cardiovascular Health in Acute Coronary Syndrome Patients.

Fibroblast growth factor 21 (FGF21) is a hormone involved in regulating the metabolism, energy balance, and glucose homeostasis, with new studies demonstrating its beneficial effects on the heart. This study investigated the relationship between FGF21 levels and clinical, biochemical, and echocardiographic parameters in patients with acute coronary syndromes (ACSs). This study included 80 patients diagnosed with ACS between May and July 2023, categorized into four groups based on body mass index (BMI): Group 1 (BMI 18.5-24.9 kg/m2), Group 2 (BMI 25-29.9 kg/m2), Group 3 (BMI 30-34.9 kg/m2), and Group 4 (BMI ≥ 35 kg/m2). Serum FGF21 levels were measured by ELISA (Abclonal Catalog NO.: RK00084). Serum FGF21 levels were quantifiable in 55 samples (mean ± SD: 342.42 ± 430.17 pg/mL). Group-specific mean FGF21 levels were 238.98 pg/mL ± SD in Group 1 (n = 14), 296.78 pg/mL ± SD in Group 2 (n = 13), 373.77 pg/mL ± SD in Group 3 (n = 12), and 449.94 pg/mL ± SD in Group 4 (n = 16), with no statistically significant differences between groups (p = 0.47). Based on ACS diagnoses, mean FGF21 levels were 245.72 pg/mL for STEMI (n = 21), 257.89 pg/mL for NSTEMI (n = 9), and 456.28 pg/mL for unstable angina (n = 25), with no significant differences observed between these diagnostic categories. Significant correlations were identified between FGF21 levels and BMI, diastolic blood pressure, and serum chloride. Regression analyses revealed correlations with uric acid, chloride, and creatinine kinase MB. This study highlights the complex interplay between FGF21, BMI, and acute coronary syndromes. While no significant differences were found in FGF21 levels between the different BMI and ACS diagnostic groups, correlations with clinical and biochemical parameters suggest a multifaceted role of FGF21 in cardiovascular health. Further research with a larger sample size is warranted to elucidate these relationships.

FGF4 ameliorates the liver inflammation by reducing M1 macrophage polarization in experimental autoimmune hepatitis

BackgroundThe global prevalence of autoimmune hepatitis (AIH) is increasing due in part to the lack of effective pharmacotherapies. Growing evidence suggests that fibroblast growth factor 4 (FGF4) is crucial for diverse aspects of liver pathophysiology. However, its role in AIH remains unknown. Therefore, we investigated whether FGF4 can regulate M1 macrophage and thereby help treat liver inflammation in AIH.MethodsWe obtained transcriptome-sequencing and clinical data for patients with AIH. Mice were injected with concanavalin A to induce experimental autoimmune hepatitis (EAH). The mechanism of action of FGF4 was examined using macrophage cell lines and bone marrow-derived macrophages.ResultsWe observed higher expression of markers associated with M1 and M2 macrophages in patients with AIH than that in individuals without AIH. EAH mice showed greater M1-macrophage polarization than control mice. The expression of M1-macrophage markers correlated positively with FGF4 expression. The loss of hepatic Fgf4 aggravated hepatic inflammation by increasing the abundance of M1 macrophages. In contrast, the pharmacological administration of FGF4 mitigated hepatic inflammation by reducing M1-macrophage levels. The efficacy of FGF4 treatment was compromised following the in vivo clearance of macrophage populations. Mechanistically, FGF4 treatment activated the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT)-signal pathway in macrophages, which led to reduced M1 macrophages and hepatic inflammation.ConclusionWe identified FGF4 as a novel M1/M2 macrophage-phenotype regulator that acts through the PI3K–AKT-signaling pathway, suggesting that FGF4 may represent a novel target for treating inflammation in patients with AIH.

Cross-sectional and Mendelian randomization study of fibroblast growth factor 19 reveals causal associations with metabolic diseases.

Fibroblast growth factor 19 (FGF19) is an intestinal-derived factor that plays a role in metabolic diseases. We performed a differential study of circulating FGF19 levels and investigated the causal effects of FGF19 on metabolic diseases using Mendelian randomization (MR). Firstly, 958 subjects were included in the physical examination center of affiliated hospital from January 2019 to January 2021. Dividing the subjects into different subgroups to compare FGF19 levels. We conducted a two-sample MR analysis of genetically predicted circulating FGF19 in relation to alcohol, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available genome-wide association study summary statistics data. The circulating FGF19 levels in nonalcoholic fatty liver disease (NAFLD) patients were lower than those without NAFLD (P<0.001). The FGF19 levels in participants with obese were lower than those without obese (P<0.001). In two-sample MR analyses, genetically predicted higher circulating FGF19 levels was significantly associated with lower aspartate aminotransferase, γ-glutamyltransferase, triglycerides, total cholesterol, low-density lipoprotein, and C-reactive protein concentrations (P<0.05) and a negative correlation with cardiovascular disease and cirrhosis whereas a positive association with type 2 diabetes mellitus (P<0.05). Our study found that circulating FGF19 levels were lower in NAFLD and obese populations. Additionally, our MR research results support the causal effects of FGF19 on improved liver function, lipids, and reduced the occurrence of inflammation, cardiovascular disease, and cirrhosis. We found a positive correlation with diabetes, which may indicate a compensatory increase in regulating above FGF19 resistance states in humans.

Alcohol-induced fibroblast growth factor 21 secretion is increased in individuals with alcohol use disorder

BackgroundAlcohol use disorder (AUD) affects 5% of the global population. Despite its high prevalence, the pathophysiology of AUD remains enigmatic, hindering the development of novel therapeutics. Interestingly, the liver hormone fibroblast growth factor 21 (FGF21), which is currently in late-stage clinical trials for the treatment of non-alcoholic steatohepatitis, has been implicated by recent genome-wide association studies as a regulator of alcohol consumption. MethodsThis study aimed to evaluate plasma responses of FGF21 to an alcohol challenge in three groups: 15 males with AUD, 15 healthy males with a father with AUD (Predisposed), and 15 healthy males without any predisposition to AUD (Controls). All participants were investigated after an overnight fast. Assessments, including blood sampling and visual analog scale-assessed desire for alcohol intake, were performed before and for 10 h after ingesting 0.5 g alcohol per kg body weight over 10 min. ResultsThe three groups were age and body-mass index-matched and had normal plasma concentrations of transaminases and FibroScan®-assessed elastography. Baseline FGF21 concentrations did not differ between groups, but individuals with AUD exhibited greater FGF21 responses to alcohol (area under the curve (AUC0–600 min): 954 ± 665 ng/ml × min (mean (standard deviation)) compared to Controls (AUC0–600 min: 453 ± 333 ng/ml × min, P = 0.03) but not Predisposed (AUC0–600 min: 556 ± 429 ng/ml × min, P = 0.11). ConclusionIn conclusion, we demonstrate greater alcohol-induced FGF21 responses in individuals with AUD compared to healthy individuals without paternal predisposition to AUD, suggesting a role for FGF21 in AUD pathophysiology.

Single Injection AAV2-FGF18 Gene Therapy Reduces Cartilage Loss and Subchondral Bone Damage in a Mechanically Induced Model of Osteoarthritis.

Osteoarthritis (OA) is a highly debilitating, degenerative pathology of cartilaginous joints affecting over 500 million people worldwide. The global economic burden of OA is estimated at $260-519 billion and growing, driven by aging global population and increasing rates of obesity. To date, only the multi-injection chondroanabolic treatment regimen of Fibroblast Growth Factor 18 (FGF18) has demonstrated clinically meaningful disease-modifying efficacy in placebo-controlled human trials. Our work focuses on the development of a novel single injection disease-modifying gene therapy, based on FGF18's chondroanabolic activity. OA was induced in Sprague-Dawley rats using destabilization of the medial meniscus (DMM) (3 weeks), followed by intra-articular treatment with 3 dose levels of AAV2-FGF18, rh- FGF18 protein, and PBS. Durability, redosability, and biodistribution were measured by quantifying nLuc reporter bioluminescence. Transcriptomic analysis was performed by RNA-seq on cultured human chondrocytes and rat knee joints. Morphological analysis was performed on knee joints stained with Safranin O/Fast Green and anti-PRG antibody. Dose-dependent reductions in cartilage defect size were observed in the AAV2-FGF18- treated joints relative to the vehicle control. Total defect width was reduced by up to 76% and cartilage thickness in the thinnest zone was increased by up to 106%. Morphologically, the vehicle- treated joints exhibited pronounced degeneration, ranging from severe cartilage erosion and bone void formation, to subchondral bone remodeling and near-complete subchondral bone collapse. In contrast, AAV2-FGF18-treated joints appeared more anatomically normal, with only regional glycosaminoglycan loss and marginal cartilage erosion. While effective at reducing cartilage lesions, treatment with rhFGF18 injections resulted in significant joint swelling (19% increase in diameter), as well as a decrease in PRG4 staining uniformity and intensity. In contrast to early-timepoint in vitro RNA-seq analysis, which showed a high degree of concordance between protein- and gene therapy-treated chondrocytes, in vivo transcriptomic analysis, revealed few gene expression changes following protein treatment. On the other hand, the gene therapy treatment exhibited a high degree of durability and localization over the study period, upregulating several chondroanabolic genes while downregulating OA- and fibrocartilage-associated markers. FGF18 gene therapy treatment of OA joints can provide benefits to both cartilage and subchondral bone, with a high degree of localization and durability.

MVP enhances FGF21-induced ferroptosis in hepatocellular carcinoma by increasing lipid peroxidation through regulation of NOX4.

Ferroptosis is a novel, iron-dependent regulatory cell death mainly caused by an imbalance between the production and degradation of intracellular reactive oxygen species (ROS). Recently, ferroptosis induction has been considered a potential therapeutic approach for hepatocellular carcinoma (HCC). Fibroblast growth factor 21 (FGF21) is a new modulator of ferroptosis; however, the regulatory role of FGF21 in HCC ferroptosis has not been investigated. In this study, we explored the role of FGF21 and its underlying molecular mechanism in the ferroptotic death of HCC cells. We identified Major vault protein (MVP) as a target of FGF21 and revealed that knockdown of MVP inhibited the lipid peroxidation levels of HCC cells by decreasing NADPH oxidase 4 (NOX4, a major source of ROS) transcription, thereby attenuating the effect of FGF21-mediated ferroptosis. On the other hand, MVP overexpression showed the opposite results. Mechanistically, MVP binds to IRF1 and thus interferes with the interaction between IRF1 and the YAP1 promoter, leading to an increase in NOX4 transcription. Importantly, forced expression of IRF1 or downregulation of YAP1 partially reversed the effect of MVP overexpression on HCC ferroptosis. Furthermore, the results in xenograft tumor models suggested that overexpression of MVP can efficiently increase the level of lipid peroxidation invivo. Taken together, these results provide new insights into the regulatory mechanism of ferroptosis in HCC.

Caffeic acid ameliorates metabolic dysfunction-associated steatotic liver disease via alleviating oxidative damage and lipid accumulation in hepatocytes through activating Nrf2 via targeting Keap1

Metabolic-associated steatotic liver disease (MASLD), known as non-alcoholic fatty liver disease (NAFLD) in the past, encompasses a range of liver pathological conditions marked by the excessive lipid accumulation. Consumption of coffee is closely associated with the reduced risk of MASLD. Caffeic acid (CA), a key active ingredient in coffee, exhibits notable hepatoprotective properties. This study aims to investigate the improvement of CA on MASLD and the engaged mechanism. Mice underwent a 12-week high-fat diet (HFD) regimen to induce MASLD, and liver pathology was assessed using hematoxylin-eosin (H&E) and oil red O (ORO) staining. Hepatic inflammation was evaluated by F4/80 and Ly6G immunohistochemistry (IHC) and myeloperoxidase (MPO) measurement. Pathways and transcription factors relevant to MASLD were analyzed by using microarray data from patients' livers. Oxidative damage was evaluated by detecting reactive oxygen species (ROS), malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD). Co-immunoprecipitation (CoIP), cellular thermal shift assay (CETSA) and surface plasmon resonance (SPR) were used to validate the binding between CA and its target protein. CA significantly alleviated liver damage, steatosis and inflammatory injury, and reduced the elevated NAFLD activity score (NAS) in HFD-fed mice. Clinical data indicate that fatty acid metabolism and ROS generation are pivotal in MASLD progression. CA increased the expression of fibroblast growth factor 21 (FGF21), FGF receptor 1 (FGFR1) and β-Klotho (KLB), and promoted fatty acid consumption. Additionally, CA mitigated oxidative stress injury and activated nuclear factor erythroid 2-related factor-2 (Nrf2). In primary hepatocytes isolated from Nrf2 knockout mice, CA's promotion on FGF21 release and inhibition on oxidative stress and lipotoxicity was disappeared. CA could directly bind to kelch-like ECH-associated protein 1 (Keap1) that is an Nrf2 inhibitor protein. This study suggests that CA alleviates MASLD by reducing hepatic lipid accumulation, lipotoxicity and oxidative damage through activating Nrf2 via binding to Keap1.

PF-05231023 reduces lipid deposition in apolipoprotein E-deficient mice by inhibiting the expression of lipid synthesis genes.

Fibroblast growth factor 21 (FGF21) is a peptide hormone that is primarily expressed and secreted by the liver. The hormone is crucial for regulation of glucose homeostasis, lipid metabolism, and energy balance. Compared with natural FGF21, FGF21 analogs have become drug candidates for the treatment of cardiovascular and metabolic diseases owing to their long half-life and greater stability in vitro. Apolipoprotein E (Apoe)-knockout (Apoe -/-) mice exhibit progressive disruptions in lipid metabolism in vivo and develop further atherosclerosis pathological features owing to Apoe deletion. Therefore, this study used an Apoe -/- mouse model to investigate the effects of a long-acting FGF21 analog (PF-05231023) on lipid metabolism and related parameters. Eighteen Apoe -/- female mice were fed a Western diet equivalent for 12 weeks, and then randomly assigned to intraperitoneally receive either physiological saline (the control group) or 10 mg/kg PF-05231023 (the treatment group) three times a week for seven consecutive weeks. Body composition, glucose tolerance, blood and liver cholesterol, triglyceride levels, liver vacuolization levels, peri-ovarian white adipocyte hypertrophy, aortic atherosclerotic plaque formation, and the expression of genes related to lipid metabolism in adipose tissue were subsequently assessed before and after treatment. The aortic atherosclerotic plaque area was reduced in mice in the PF-05231023 treatment group compared with that in the saline group. Although the effect of PF-05231023 on the plasma biochemical indexes of mice was small, it significantly reduced lipid levels and lipid droplet accumulation in the liver, and reduced adipocyte hypertrophy in white adipose tissue. Transcriptome analysis of adipose tissue showed that PF-05231023 treatment downregulated the expression of lipid synthesis-related genes and inhibited the sterol regulatory element binding transcription factor 1 gene, thereby improving lipid deposition. PF-05231023 effectively improved the lipid metabolism of Apoe -/- mice, demonstrating an anti-atherosclerotic effect and providing a scientific basis and experimental foundation for the clinical treatment of cardiovascular diseases by using long-acting FGF21 analogs.

Dynamic pattern of postprandial bile acids in paediatric non-alcoholic fatty liver disease.

Dysregulation of bile acids (BAs), as important signalling molecules in regulating lipid and glucose metabolism, contributes to the development of non-alcoholic fatty liver disease (NAFLD). However, static BA profiles during fasting may obscure certain pathogenetic aspects. In this study, we investigate the dynamic alterations of BAs in response to an oral glucose tolerance test (OGTT) among children with NAFLD. We recruited 230 subjects, including children with overweight/obesity, or complicated with NAFLD, and healthy controls. Serum BAs, 7-hydroxy-4-cholesten-3-one (C4) and fibroblast growth factor 19 (FGF19) were quantified during OGTT. Clinical markers related to liver function, lipid metabolism and glucose metabolism were assessed at baseline or during OGTT. Conjugated BAs increased while unconjugated ones decreased after glucose uptake. Most BAs were blunted in response to glucose in NAFLD (p > .05); only glycine and taurine-conjugated chenodeoxycholic acid (CDCA) and cholic acid (CA) were responsive (p < .05). Primary BAs were significantly increased while secondary BAs were decreased in NAFLD. C4 and FGF19 were significantly increased while their ratio FGF19/C4 ratio was decreased in NAFLD. The dynamic pattern of CDCA and taurine-conjugated hyocholic acid (THCA) species was closely correlated with glucose (correlation coefficient r = .175 and -.233, p < .05), insulin (r = .327 and -.236, p < .05) and c-peptide (r = .318 and -.238, p < .05). Among which, CDCA was positively associated with liver fat content in NAFLD (r = .438, p < .05). Additionally, glycochenodeoxycholic acid (GCDCA), CDCA and THCA were potential biomarkers to discriminate paediatric NAFLD from healthy controls and children with obesity. This study provides novel insights into the dynamics of BAs during OGTT in paediatric NAFLD. The observed variations in CDCA and HCA species were associated with liver dysfunction, dyslipidaemia and dysglycaemia, highlighting their potential roles as promising diagnostic and therapeutic targets in NAFLD.

Effect of whey protein-derived decapeptide on mood status and blood variables in healthy adults: a randomized, double-blind, placebo-controlled cross-over trial.

The importance of maintaining good mental health with overall well-being has recently drawn attention from various fields. Functional peptides found from various protein sources reportedly reduce mental health problems. We found a new decapeptide (AJI-801) from whey proteins, which can possibly improve mood status and increase blood acetyl-L-carnitine (ALC) and fibroblast growth factor 21 (FGF21) levels. In this study, we assessed the effects of a single intake of whey protein hydrolysate containing a high amount of AJI-801 (WPH) on blood variables and mood status. A randomized, double-blind, placebo-controlled cross-over trial of two doses of WPH (100 and 500mg) was conducted. Participants, aged between 20 and 59years with fatigue were allocated to two groups based on the WPH doses received, and set first test food in each study. The blood ALC and FGF21 levels at baseline and after 60, 120, and 180min of test food intake were analyzed and the responses to the questionnaire items for mood status were obtained at baseline and after 60 and 180min of test food intake. There were no significant differences in the blood ALC and FGF21 levels between the two groups. As mood status, intake of 500-mg WPH (including 2.5-mg AJI-801) showed significant improvement in Depression/Dejection of the Profile of Mood States Questionnaire second edition and visual analog scale score for depression, as compared to the placebo. Intake of AJI-801 500-mg WPH (including 2.5-mg AJI-801) contributes to the improvement of feeling down in healthy persons with fatigue. University Hospital Medical Information Network Clinical Trial Registry (UMIN 000046829).

FGF-21 Level is higher in patients with breast cancer, a candidate for a new biomarker?

Aims: Fibroblast Growth Factor 21 (FGF-21) is a member of the FGF family involved in biological processes such as embryonic development. cell growth. morphogenesis. tissue repair. tumour growth and invasion. with mitogenic and cytogenetic activity at 19q13.33.Breast cancer is a deadly and increasing disease in women. and recent studies have shown a relationship between some cancers. including breast cancer. and hormones secreted from adipose tissue.The aim of the present study was the measurement of FGF-21 levels in patients with breast cancer and its association with breast cancer. Methods: The study included 39 patients with newly diagnosed breast cancer and 39 healthy controls. During the patients’ routine blood tests. a venous blood sample was taken and the serum levels of FGF-21 were determined by ELISA. Results: Demographic and laboratory data were compared between the newly diagnosed breast cancer group and the control group. The control group consisted of 39 participants with a mean age of 52.49 ± 7.02 years. In the patient group. 39 participants with a mean age of 52.15 ± 6.21 years were included in the study. there was no statistical difference regarding age(p&gt;0.05).In the control group. the mean FGF-21 level was 121.35 ± 88.4 pg/ml. while the mean FGF-21 level in the patient group was 171 ± 117.45 pg/ml. a statistically significant difference was detected(p value=0.036). Conclusion: FGF-21 is thought to have significant and beneficial effects on glucose. lipid and energy metabolism. as well as slowing the growth of cancer cells. and may later be used as a biological marker for breast cancer.

Association between inflammatory cytokines and prostate cancer

IntroductionWe conducted bidirectional two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 91 inflammatory cytokines and prostate cancer (PCa).Material and methodsThe Inverse Variance Weighted (IVW) model served as the primary two-sample MR analysis method, utilized to estimate the causal effect of exposure on the outcome. The Weighted Median (WM) and MR Egger methods were additionally employed to complement the IVW model. Sensitivity analyses were performed using Cochran's Q test for both the IVW and MR Egger methods. To assess the presence of horizontal pleiotropy, the instrumental variables (IVs) were subjected to the MR-Egger intercept test.ResultsFollowing Bonferroni correction, the IVW analysis revealed positive correlations between PCa and the levels of C-C motif chemokine 20 (CCL20), C-C motif chemokine 23 (CCL23), fibroblast growth factor 19 (FGF19), fibroblast growth factor 23 (FGF23), and interleukin-6 (IL-6). Notably, IL-6 exhibited the strongest positive association effect (odds ratio [95% confidence interval]: 1.0076 [1.0014, 1.0139]), followed by CCL-20 (1.0067 [1.0004, 1.0129]) and FGF23 ([1.0002, 1.0119]). Reverse MR analysis indicated a negative causal relationship between PCa and interleukin-22 receptor subunit alpha-1 levels (IL22RA1) (0.4852 [0.2390, 0.9847]).ConclusionsThis study proposes that there exists a positive correlation between the levels of CCL20, CCL23, FGF19, FGF23, and IL-6 and the occurrence of PCa. Furthermore, we found evidence to support the causal relationship between decreased levels of IL22RA1 and the development of PCa. These findings unveil novel biomarkers and pathways that could potentially be targeted for the prevention and clinical treatment of PCa.

Heightened Serum Mitochondrial Biomarkers; FGF21 and NOS in Pediatric Anemia and a Negative Correlation between GDF15 and Serum Ferritin.

Objective: Mitochondrial dysfunction is closely linked to chronic disorders. This study aims to explore the correlation between pediatric anemia and mitochondrial markers, specifically fibroblast growth factor 21 (FGF21), growth/differentiation factor 15 (GDF-15), and nitric oxide synthase (eNOS). Method: This study included 66 children, with 34 diagnosed with anemia and 32 in the healthy control group. Statistically significant biomarkers were determined through cutoff levels. Results: Among the participants, 34 children were classified as anemic, while 32 were categorized as healthy. The study revealed that FGF21 levels ≥ 0.745 pg/mL and eNOS levels ≥ 1.265 µg/mL predicted anemia. Hemoglobin levels exhibited a negative correlation with FGF21 (r = -0.381; p = 0.002) and eNOS levels (r = -0.462; p < 0.001). Furthermore, a significant negative correlation was observed between GDF-15 and ferritin (r = -0.311; p = 0.019), while eNOS levels correlated positively with folate (r = 0.313; p = 0.019). Conclusions: Anemia induced elevated mitochondrial biomarkers; FGF21 and eNOS levels. The findings suggest that the long-term ramifications of anemia in childhood may be associated with mitochondrial dysfunction.