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Obesity-induced insulin resistance (IR) is known to influence hepatic cytokines (hepatokines), including fibroblast growth factor (FGF-21), fetuin-A, and chemerin. This study aimed to investigate the association between hepatokines and markers of endothelial dysfunction and vascular reactivity in obese adolescents. A total of 45 obese adolescents were categorized into three groups based on glucose tolerance: normal glucose tolerance (NGT), prediabetes (PD), and type 2 diabetes (T2D). We examined the relationships between FGF-21, fetuin-A, and chemerin with endothelial markers (plasminogen activator inhibitor-1 [PAI-1], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion marker-1 [VCAM-1]) and vascular surrogates (brachial artery reactivity testing [BART] and peak reactive hyperemia [PRH]). Obese adolescents (age 16.2±1.2 years; 62 % female, 65 % Hispanic) with NGT (n=20), PD (n=14), and T2D (n=11) had significant differences between groups in BMI; waist-hip ratio (p=0.05), systolic BP (p=0.008), LDL-C (p=0.02), PAI-1 (p<0.001). FGF-21 pg/mL (mean±SD: NGT vs. PD vs. T2D 54±42; 266±286; 160±126 p=0.006) and fetuin-A ng/mL (266±80; 253±66; 313±50 p=0.018), were significantly different while chemerin ng/mL (26±5; 31±10; 28±2) did not significantly differ between the groups. Positive correlations were found between chemerin and both PAI-1 (r=0.6; p=0.05) and ICAM-1 (r=0.6; p=0.05), FGF-21 and PAI-1 (r=0.6; p<0.001), and fetuin-A with TNFα (r=−0.4; p=0.05). Negative correlations were found between chemerin and PRH (r= −0.5; p=0.017) and fetuin-A and PRH (r=−0.4; p=0.05). In our cohort, IR predicted higher FGF-21 levels suggesting a linear relationship may exist between the two parameters. Hepatokines can augment alterations in the microvascular milieu in obese adolescents as demonstrated by their associations with the markers PAI-1, ICAM-1, and PRH. [ABSTRACT FROM AUTHOR]

Background: Wound healing is a complex biological process that can be impaired in individuals with diabetes. Diabetic wounds are a serious complication of diabetes that require promoting diagnosis and effective treatment. FGF-21, a member of the endocrine FGF factors family, has caught the spotlight in the treatment of diabetes for its beneficial effects on accelerating human glucose uptake and fat catabolism. However, the therapeutic efficacy of FGF-21 in promoting diabetic wounds remains unknown. This study aims to evaluate the therapeutic potential of FGF-21 in promoting diabetic wound healing. Methods: we investigated the effects of FGF-21 on wound healing related-cells under high-glucose conditions using various assays such as CCK8, scratch assay, flow cytometry analysis, endothelial tube-formation assay, and transmission electron microscopy. Furthermore, we used db/db mice to verify the healing-promoting therapeutic effects of FGF-21 on diabetic wounds. We also conducted qRT-PCR, Western blot, and immunofluorescence staining analyses to elucidate the underlying mechanism. Result: Our results indicate that FGF-21 treatment restored hyperglycemic damage on endothelial cell proliferation, migration, and tube-forming ability. It also reduced endothelial cell death rates under high-glucose conditions. TEM analysis showed that FGF-21 treatment effectively restored mitochondrial damage and morphological changes in endothelial cells caused by glucose. Additionally, qRT-PCR and Western blot analysis indicated that FGF-21 treatment restored inflammatory responses caused by hyperglycemic damage. Animal experiments confirmed these findings, suggesting that FGF-21 may be a promising candidate for the treatment of non-healing diabetic wounds due to its effectiveness in stimulating angiogenesis and anti-inflammatory function. Conclusion: Our study provides evidence that FGF-21 is an essential regulator of wound-related cells under high-glucose conditions and has the potential to be a novel therapeutic target for accelerating diabetic wound healing.

Background: Wound healing is a complex biological process that can be impaired in individuals with diabetes. Diabetic wounds are a serious complication of diabetes that require promoting diagnosis and effective treatment. FGF-21, a member of the endocrine FGF factors family, has caught the spotlight in the treatment of diabetes for its beneficial effects on accelerating human glucose uptake and fat catabolism. However, the therapeutic efficacy of FGF-21 in promoting diabetic wounds remains unknown. This study aims to evaluate the therapeutic potential of FGF-21 in promoting diabetic wound healing., Methods: we investigated the effects of FGF-21 on wound healing related-cells under high-glucose conditions using various assays such as CCK8, scratch assay, flow cytometry analysis, endothelial tube-formation assay, and transmission electron microscopy. Furthermore, we used db/db mice to verify the healing-promoting therapeutic effects of FGF-21 on diabetic wounds. We also conducted qRT-PCR, Western blot, and immunofluorescence staining analyses to elucidate the underlying mechanism., Result: Our results indicate that FGF-21 treatment restored hyperglycemic damage on endothelial cell proliferation, migration, and tube-forming ability. It also reduced endothelial cell death rates under high-glucose conditions. TEM analysis showed that FGF-21 treatment effectively restored mitochondrial damage and morphological changes in endothelial cells caused by glucose. Additionally, qRT-PCR and Western blot analysis indicated that FGF-21 treatment restored inflammatory responses caused by hyperglycemic damage. Animal experiments confirmed these findings, suggesting that FGF-21 may be a promising candidate for the treatment of non-healing diabetic wounds due to its effectiveness in stimulating angiogenesis and anti-inflammatory function., Conclusion: Our study provides evidence that FGF-21 is an essential regulator of wound-related cells under high-glucose conditions and has the potential to be a novel therapeutic target for accelerating diabetic wound healing., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jianda Zhou reports was provided by Xiangya Third Hospital of Central South University. Jianda Zhou reports a relationship with Xiangya Third Hospital of Central South University that includes: employment. Jianda Zhou has patent pending to Jianda Zhou. No conflicts of interest that require special declaration If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)

Analysis of liver biopsy specimens showed that SARS-CoV-2 might have led to liver damage. This study aimed to evaluate the role of selected hepatokines and myokines in the development and progression of COVID-19. Seventy patients with laboratory-confirmed COVID-19 and 20 healthy volunteers were enrolled in the study. Irisin, pentraxin 3, fetuin-A, and FGF-21 serum concentrations and biochemical parameters were assessed using an immunoenzymatic method with commercially available enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) kits. Serum fetuin-A concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers. The serum concentration of FGF-21 was significantly increased in obese COVID-19 patients compared to overweight ones. Moreover, the FGF-21 level was higher in COVID-19 patients diagnosed with metabolic syndrome than in patients without metabolic syndrome. PTX3 concentration was higher in COVID-19 patients with higher HOMA-IR values than those with lower HOMA-IR values. COVID-19 patients with HOMA-IR ≤ 3 and >3 had significantly lower fetuin-A levels than the control group. Irisin concentration was significantly decreased in the HOMA-IR ≤ 3 COVID-19 subgroup when comparing with the control group. Lower levels of fetuin-A observed in COVID-19 patients despite higher HOMA-IR, CRP, and ferritin levels, pneumonia, patients requiring ICU care suggests that fetuin-A deficiency predisposes to more severe COVID-19 course. Upregulated pentraxin 3 may be used as a potential predictor of COVID-19 severity.

Objective: The purpose of this study was to investigate the effects of a long-term weight loss therapy in two groups (insulin resistance [IR] and non-insulin resistance [non-IR]) of obese adolescents based on metabolic profile, biomarkers of inflammation, and fibroblast growth factor-21 (FGF-21) concentrations. Methods: Obese adolescents (15–19 years) were randomised into two groups (IR=8 and non-IR=9) and monitored through clinical, exercise training, nutritional, and psychological counselling over 1 year. Measurements of inflammatory biomarkers and FGF-21 were performed. The effects of therapy were verified by two-way ANOVA and post hoc analyses were performed (α ≤5%). Results: A reduction in body mass, visceral fat, and an increase in adiponectin in both groups was found. Only the non-IR group demonstrated improved BMI, body fat mass, lean body mass, and waist circumference. Indeed, in the non-IR group, FGF-21 presence was positively correlated with high-density lipoprotein cholesterol and lean body mass and inversely correlated with plasminogen activator inhibitor-1 and triglycerides. In the IR group, there was a reduction in FGF-21 concentration, adiponectin/leptin ratio, insulin, total cholesterol, low-density lipoprotein cholesterol, and plasminogen activator inhibitor-1. FGF-21 was negatively correlated with delta-triglycerides, waist circumference, and low-density lipoprotein cholesterol. The IR prevalence reduced from 47% to 23.5% in the studied population. Conclusions: Although the multicomponent clinical approach improves, in both analysed groups and in both metabolic and inflammatory states, the presence of IR resulted in a reduction in both FGF-21 concentration and adiponectin/leptin ratio. Additionally, in the IR group, FGF-21 was negatively correlated with proinflammatory markers, and in the non-IR group it was positively associated with high-density lipoprotein, suggesting its role in the control of inflammation counteracting IR. In this way, we suggest that IR can impair the anti-inflammatory effects of FGF-21. It will be helpful if these results can be confirmed in a large cohort, underlying physiological mechanisms to explore how these results can help in setting up more prospective studies.

Abstract: Background: Disorders of oxidative phosphorylation (OXPHOS) cause an increase in the NADH/NAD+ ratio, which impairs the glycolysis pathway. Treatment with pyruvate is expected to decrease the ratio and thereby restore glycolysis. There are some case reports on the efficacy of pyruvate treatment for mitochondrial diseases. However, few of these reports assessed their results using a standardized scale. Methods: We monitored 4 bedridden patients with OXPHOS disorders who continued therapies of 0.5–1.0g/kg/day of sodium pyruvate for more than 12months. The efficacies of these treatments were evaluated with the Newcastle Pediatric Mitochondrial Disease Scale and the Gross Motor Function Measure with 88 items. Results: The ages of the patients at the treatment initiation ranged from 8–100months. Of the 4 patients, 3 exhibited improvements within 1–3months from the initiation of treatment. Among these 3 patients, one maintained the improvement for over 2years. The remaining 2 regressed 3–6months after the initiation of treatment. The blood lactate/pyruvate ratios did not correlate with the efficacy of treatment. Conclusion: Pyruvate was effective even in bedridden patients with OXPHOS disorders, at least in the short term. Clinical trials with more patients and less severe disabilities are necessary to evaluate the long-term efficacy of this treatment. Biomarkers other than lactate and pyruvate need to be identified to biochemically monitor the efficacy of this treatment. [Copyright &y& Elsevier]

Mitochondrial respiratory chain deficiencies are a group of more than 100 disorders of adults and children, with highly variable phenotypes. The high prevalence of mitochondrial disorders (MIDs) urges the clinician to diagnose these disorders accurately, which is difficult in the light of highly variable and overlapping phenotypes, transmission patterns and molecular backgrounds. Fibroblast growth factor 21 (FGF-21) is an important endocrine and paracrine regulator of metabolic homeostasis. The FGF-21 transcript is reported to be abundantly expressed in liver, but little is known about the regulation of FGF-21 expression in other tissues. FGF-21 could play a role in the metabolic alterations that are often associated with mitochondrial diseases. The aim of this study was to show the association of the FGF-21 biomarker with human primary MIDs and secondary MIDs in suspected patients in Iran. Serum FGF-21 levels were determined using ELISA in 47 mitochondrial patients, including 32 with primary MIDs, 15 patients with Friedreich ataxia as a secondary MID and 30 control subjects. Serum FGF-21 levels were significantly higher in subjects with the primary MIDs ( p < 0.05), compared to subjects without MIDs. However, serum FGF-21 levels did not show significant increase in subjects with FA as a secondary MID. There is an association between increasing concentrations of FGF-21 with mitochondrial diseases, suggesting FGF-21 as a biomarker for diagnosis of primary MIDs in humans. However, this biomarker is not appropriate for the diagnosis of FA. [ABSTRACT FROM AUTHOR]

Analysis of liver biopsy specimens showed that SARS-CoV-2 might have led to liver damage. This study aimed to evaluate the role of selected hepatokines and myokines in the development and progression of COVID-19. Seventy patients with laboratory-confirmed COVID-19 and 20 healthy volunteers were enrolled in the study. Irisin, pentraxin 3, fetuin-A, and FGF-21 serum concentrations and biochemical parameters were assessed using an immunoenzymatic method with commercially available enzyme immunoassay (EIA) or enzyme-linked immunosorbent assay (ELISA) kits. Serum fetuin-A concentrations were significantly decreased in COVID-19 patients compared to healthy volunteers. The serum concentration of FGF-21 was significantly increased in obese COVID-19 patients compared to overweight ones. Moreover, the FGF-21 level was higher in COVID-19 patients diagnosed with metabolic syndrome than in patients without metabolic syndrome. PTX3 concentration was higher in COVID-19 patients with higher HOMA-IR values than those with lower HOMA-IR values. COVID-19 patients with HOMA-IR ≤ 3 and >3 had significantly lower fetuin-A levels than the control group. Irisin concentration was significantly decreased in the HOMA-IR ≤ 3 COVID-19 subgroup when comparing with the control group. Lower levels of fetuin-A observed in COVID-19 patients despite higher HOMA-IR, CRP, and ferritin levels, pneumonia, patients requiring ICU care suggests that fetuin-A deficiency predisposes to more severe COVID-19 course. Upregulated pentraxin 3 may be used as a potential predictor of COVID-19 severity. [ABSTRACT FROM AUTHOR]

Background: This study aimed to investigate the relationship between serum level of fibroblast growth factor 21 (FGF-21) and long-term prognosis in patients with both diabetes mellitus (DM) and coronary artery calcification (CAC)., Methods: The study included 1,132 patients with DM and CAC according to inclusion and exclusion criteria. Based on the baseline serum level of FGF-21, patients were divided into four groups (283 in each group): low-FGF-21 group (LFG), lower-medium-FGF-21 group (LMFG), higher-medium-FGF-21 group (HMFG), and high-FGF-21 group (HFG). Major adverse cardiovascular events (MACEs), including coronary revascularization, acute coronary syndrome (ACS), heart failure (HF), malignant arrhythmia, and sudden cardiac death (SCD), were recorded. Renal function, serum level of NT-proBNP, and left ventricular function were watched and observed during follow-up., Results: All patients were followed up for 1.5-5.1 (2.7±2.2) years. The range of baseline serum level of FGF-21 was 67.5-314.7 pg/mL. The serum level of FGF-21 was ≤103.8 pg/mL in LFG, 108.6-184.9 pg/mL in LMFG, 199.3-271.2 pg/mL in LHFG, and >276.1 pg/mL in HFG. The baseline CAC score (CACS) was 83.2-524.9 and the mean CACS was 124.6±37.5, 186.8±51.9, 271.3±62.7, and 349.2±80.6, respectively. During follow-up, 481 patients underwent percutaneous coronary intervention (PCI) with 71, 107, 141, and 162 in subgroups, respectively. Malignant arrhythmia occurred in 89 patients, HF in 127, and SCD in 9. At the end of the 1-year follow-up, the average eGFR, NT-proBNP, and left ventricular ejection fraction (LVEF) differed significantly among groups., Conclusions: Lower baseline serum level of FGF-21 is a prediction for a better long-term prognosis.