Promotion effect of FGF23 on osteopenia in congenital scoliosis through FGFr3/TNAP/OPN pathway / 中华医学杂志(英文版)

BACKGROUND@#Congenital scoliosis (CS) is a complex spinal malformation of unknown etiology with abnormal bone metabolism. Fibroblast growth factor 23 (FGF23), secreted by osteoblasts and osteocytes, can inhibit bone formation and mineralization. This research aims to investigate the relationship between CS and FGF23.@*METHODS@#We collected peripheral blood from two pairs of identical twins for methylation sequencing of the target region. FGF23 mRNA levels in the peripheral blood of CS patients and age-matched controls were measured. Receiver operator characteristic (ROC) curve analyses were conducted to evaluate the specificity and sensitivity of FGF23. The expression levels of FGF23 and its downstream factors fibroblast growth factor receptor 3 (FGFr3)/tissue non-specific alkaline phosphatase (TNAP)/osteopontin (OPN) in primary osteoblasts from CS patients (CS-Ob) and controls (CT-Ob) were detected. In addition, the osteogenic abilities of FGF23-knockdown or FGF23-overexpressing Ob were examined.@*RESULTS@#DNA methylation of the FGF23 gene in CS patients was decreased compared to that of their identical twins, accompanied by increased mRNA levels. CS patients had increased peripheral blood FGF23 mRNA levels and decreased computed tomography (CT) values compared with controls. The FGF23 mRNA levels were negatively correlated with the CT value of the spine, and ROCs of FGF23 mRNA levels showed high sensitivity and specificity for CS. Additionally, significantly increased levels of FGF23, FGFr3, OPN, impaired osteogenic mineralization and lower TNAP levels were observed in CS-Ob. Moreover, FGF23 overexpression in CT-Ob increased FGFr3 and OPN levels and decreased TNAP levels, while FGF23 knockdown induced downregulation of FGFr3 and OPN but upregulation of TNAP in CS-Ob. Mineralization of CS-Ob was rescued after FGF23 knockdown.@*CONCLUSIONS@#Our results suggested increased peripheral blood FGF23 levels, decreased bone mineral density in CS patients, and a good predictive ability of CS by peripheral blood FGF23 levels. FGF23 may contribute to osteopenia in CS patients through FGFr3/TNAP / OPN pathway.

Research progress of fibroblast growth factor in nervous system diseases / 浙江大学学报·医学版

Fibroblast growth factors (FGF) are a group of structurally related polypeptides which constitute an elaborate signaling system with their receptors. Evidence accumulated in the years suggests that the FGF family plays a key role in the repair of central nervous system injury. The main protective mechanisms include activating the expression of PI3K-Akt, peroxisome proliferator-activated receptor (PPARγ) and other signals; inhibiting NF-κB-mediated inflammatory response, oxidative stress and apoptosis; regulating neuronal differentiation and neuronal excitability as well as participating in protection of neurovascular units and nerve function repair. This paper comprehensively summarizes the latest research progress in FGF signaling related to diseases of the central nervous system such as cerebral infarction, cerebral hemorrhage, traumatic brain injury, Alzheimer's disease, Parkinson's disease, epilepsy and depression, aiming to provide scientific basis and reference for the development of innovative FGF drugs for the prevention and treatment of neurological diseases.

Value of serum fibroblast growth factor 23 in diagnosis of hypophosphatemic rickets in children / 中国当代儿科杂志

OBJECTIVES@#To study the value of serum fibroblast growth factor 23 (FGF23) in the diagnosis of hypophosphatemic rickets in children.@*METHODS@#A total of 28 children who were diagnosed with hypophosphatemic rickets in Children's Hospital of Nanjing Medical University from January 2016 to June 2021 were included as the rickets group. Forty healthy children, matched for sex and age, who attended the Department of Child Healthcare of the hospital were included as the healthy control group. The serum level of FGF23 was compared between the two groups, and the correlations of the serum FGF23 level with clinical characteristics and laboratory test results were analyzed. The value of serum FGF23 in the diagnosis of hypophosphatemic rickets was assessed.@*RESULTS@#The rickets group had a significantly higher serum level of FGF23 than the healthy control group (P<0.05). In the rickets group, the serum FGF23 level was positively correlated with the serum alkaline phosphatase level (rs=0.38, P<0.05) and was negatively correlated with maximum renal tubular phosphorus uptake/glomerular filtration rate (rs=-0.64, P<0.05), while it was not correlated with age, height Z-score, sex, and parathyroid hormone (P>0.05). Serum FGF23 had a sensitivity of 0.821, a specificity of 0.925, an optimal cut-off value of 55.77 pg/mL, and an area under the curve of 0.874 in the diagnosis of hypophosphatemic rickets (P<0.05).@*CONCLUSIONS@#Serum FGF23 is of valuable in the diagnosis of hypophosphatemic rickets in children, which providing a theoretical basis for early diagnosis of this disease in clinical practice.

Effects of different exercise on liver lipid accumulation and FGF21 secretion in obese rats / 中国应用生理学杂志

Objective: To investigate the effects of continuous exercise training (CT) and high-intensity interval exercise training (HIIT) on liver lipid metabolism and the correlation of the level of fibroblast growth factor 21(FGF21) in serum and liver tissues. Methods: Male SD rats were randomly divided into normal diet group (N) and obesity model group (H) after 1 week of adaptive feeding. Rats in the obesity model group were fed with 45% high-fat diet for about 8 weeks, and 20% weight increase compared with normal rats was considered as obesity. The rats were divided into normal diet control group (LC), normal diet HIIT group (LHI), normal diet CT group (LCT), High fat diet-induced obese control group (OC), obese HIIT group (OHI), and obese CT group (OCT) (n=10). Exercised rats were given weight-bearing swimming training intervention for 8 weeks. Blood samples were collected at least 24h after the last exercise intervention to detect the serum levels of inflammatory factors and FGF21. Liver tissue samples were collected to detect the lipid content, lipid metabolic enzyme content and FGF21 expression level. Results: Compared with LC group, the body weight, serum inflammatory factors levels and hepatic triglyceride content were increased significantly (P＜0.05). Hepatic triglyceride content was downregulated in LHI group and FGF21 expression level was enhanced in LCT group (P＜0.05). Compared with OC group, the body weight and hepatic triglyceride content were decreased significantly (P＜0.05), mitochondrial CPT-1β and β-HAD enzyme contents in liver were increased significantly (P＜0.05) in OHI group, the contents of LPL and FAT/CD36 enzyme in liver and the levels of FGF21 in serum and liver of OCT group were increased significantly (P＜0.05). Conclusion: Both exercise modes can reduce the body weight in normal and obese rats, and lipid deposition in the liver of obese rats. HIIT has a more significant effect on alleviating liver lipid deposition in obese rats by upregulating mitochondrial lipid oxidation level in normal and obese rats. CT improves the levels of FGF21 in serum and liver tissues of normal and obese rats, enhances enzyme contents that involved in fatty acids uptake to the liver, which has limited effect on alleviating lipid deposition in liver of obese rats.

Effects of an interdisciplinary weight loss program on fibroblast growth factor 21 and inflammatory biomarkers in women with overweight and obesity

ABSTRACT Objective: To investigate the effects of an interdisciplinary intervention on biomarkers of inflammation and their relationship with fibroblast growth factor 21 (FGF21) concentrations in women with overweight and obesity. Subjects and methods: Thirty-one women were enrolled in a 12-week interdisciplinary weight loss program delivered by a team comprising an endocrinologist, nutritionist and exercise physiologist. Body composition; anthropometric measures; metabolic and inflammatory markers including adiponectin, leptin, and atrial natriuretic peptide (ANP) were assessed at baseline and post-therapy. The homeostasis model assessment of insulin resistance (HOMA-IR) and the homeostasis model assessment of adiponectin (HOMA-AD) were calculated. The participants were divided into two groups: those with increased FGF21, and those with decreased FGF21. Results: The sample comprised women aged 32 ± 5 years with a body mass index of 33.64 ± 3.49 kg/m2. Body weight, waist circumference and leptin concentration were decreased in the whole sample after therapy. However, only the group with an increase in FGF21 concentration presented significant improvements in adiponectin concentration and adiponectin/leptin ratio. Moreover, although there was a reduction of leptin in both groups, it was greater in the increased FGF21 groups. There was a reduction in ANP in the decreased FGF21 group. Conclusions: Changes in FGF21 concentrations were different among the women participating in the weight loss program, with some having increased levels and some reduced levels. Furthermore, improvements in adiponectin and the adiponectin/leptin ratio were found only in the group with increased FGF21 concentration.

Ulmoplus® increases FGF-2 expression and promote burn wound healing / Ulmoplus® incrementa la expresión de FGF-2 y promueve la cicatrización de heridas por quemadura

SUMMARY: The role of fibroblast growth factor (FGF) in the wound repair process has been described, particularly during the stimulation of angiogenesis in the proliferative phase. Ulmo honey (Eucryphia cordifolia) has demonstrated important bactericidal, fungicidal, antioxidant and healing properties. Ulmoplus®, a honey-based medicinal product, accelerates healing time and promotes fibroblast activation and collagen fiber production. The aim of this study was to evaluate the immunohistochemical expression of endogenous FGF-2 in burns treated with Ulmoplus® vs. the gold standard (hydrogel-tull), and Ulmo honey as the first step to clarifying the regulatory mechanism of this therapeutic option. 15 adult guinea pigs (Cavia porcellus) were used, divided into three groups: C+: positive control treated with hydrogel-tull (gold standard); E1: experimental group treated with Ulmo; and E2: experimental group treated with Ulmoplus®. A deep uniform burn was made under anesthetic that covered 1 cm2 of the skin on the back of each animal. The daily treatments were administered with hydrogel-tull, Ulmo honey or Ulmoplus®, where appropriate. On treatment day 10 the biopsies were taken and processed for histological and immunohistochemical analysis. The immunolabeling was quantified through an integrated optical density (IOD) analysis, expressed as lum/ µm2 using the Image- ProPremier 9.1 software. The endogenous expression of FGF-2 was consistent with the stage of healing presented by the study groups, varying in its localization and IOD intensity. The E2 group presented a significantly higher IOD (60053.55 ± 59877.84 lum/µm2) than the C+ (p = 0.001) and E1 (p = 0.001) groups. Our findings indicated that the medicinal Ulmoplus® honey is effective at facilitating wound closing, and the promoter effect of FGF-2 expression accelerated the healing process compared to the treatments with hydrogel-tull (gold standard) and Ulmo honey.

RESUMEN: Se ha descrito el papel del factor de crecimiento fibroblaástico (FGF) en el proceso de reparación de heridas, particularmente durante la estimulación de la angiogénesis en la fase proliferativa. La miel de Ulmo (Eucryphia cordifolia) ha demostrado importantes propiedades bactericidas, fungicidas, antioxidantes y cicatrizantes. Ulmoplus®, un medicamento a base de miel, acelera el tiempo de cicatrización y promueve la activación de fibroblastos y la producción de fibras colágenas. El objetivo de este estudio fue evaluar la expresión inmunohistoquímica del FGF-2 endógeno en quemaduras tratadas con Ulmoplus® frente al gold standard (hidrogel-tull) y miel de Ulmo como primer paso para esclarecer el mecanismo regulador de esta opción terapéutica. Se utilizaron 15 cobayas adultos (Cavia porcellus), divididos en tres grupos: C +: control positivo tratado con hidrogel-tull (gold standard); E1: grupo experimental tratado con Ulmo; y E2: grupo experimental tratado con Ulmoplus®. Se realizó una quemadura profunda uniforme bajo anestesia que cubrió 1 cm2 de la piel del lomo de cada animal. Los tratamientos diarios se administraron con hidrogel-tull, miel de Ulmo o Ulmoplus®, en cada caso. El día 10 de tratamiento se tomaron biopsias y se procesaron para análisis histológico e inmunohistoquímico. El inmunomarcaje se cuantificó mediante análisis de densidad óptica integrado (DOI), expresado como lum/µm2 utilizando el software Image-ProPremier 9.1. La expresión endógena de FGF-2 fue consistente con la etapa de cicatrización presentada por los grupos de estudio, variando en su localización e intensidad de DOI. El grupo E2 presentó una DOI significativamente mayor (60053,55 ± 59877,84 lum/µm2) que los grupos C + (p = 0,001) y E1 (p = 0,001). Nuestros hallazgos indicaron que la miel de uso médico Ulmoplus® es eficaz para facilitar el cierre de heridas, y el efecto promotor de la expresión de FGF-2 aceleró el proceso de curación en comparación con los tratamientos con hidrogel-tull (gold standard) y miel de Ulmo.

Association between fibroblast growth factor 23 and functional capacity among independent elderly individuals / Associação entre fator de crescimento de fibroblastos 23 e capacidade funcional em idosos independentes

ABSTRACT Objective To examine the association of between serum fibroblast growth factor 23 and the functional capacity among independent individuals, aged 80 or older. Methods The functional capacity of 144 elderly was assessed by Instrumental Activities of Daily Living, cognitive tests, handgrip strength and the timed ability to rise from a chair and sit down five times. Fibroblast growth factor 23 was measured using an ELISA assay. Results Participants in the lowest fibroblast growth factor 23 tertile had the highest mean±standard deviation estimated glomerular filtration rate, the highest mean hemoglobin level, the lowest average number of diseases and the lowest number of medications used. In participants with the estimated glomerular filtration rate >45mL/minute/1.73m2, mean fibroblast growth factor 23 level was higher in those with 25(OH) vitamin D <20ng/mL than in those with 25(OH) vitamin D ≥20ng/mL (75.6RU/mL±42.8 versus 68.5RU/mL±41.7; p<0.001). There was an increase in the mean serum cystatin C (from 1.3mg/mL±0.3 to 1.5mg/mL±0.3 to 1.7mg/mL±0.4) as function of higher fibroblast growth factor 23 tertile (p<0.001). Fibroblast growth factor 23 levels were not significantly associated with capacity in physical or cognitive tests. Conclusion In independent community-dwelling elderly, aged ≥80 years, fibroblast growth factor 23 was associated with aged-related comorbidities and renal function but not with functional capacity.

RESUMO Objetivo Examinar a associação entre o fator de crescimento de fibroblastos 23 sérico e a capacidade funcional em indivíduos independentes, com 80 anos ou mais. Métodos A capacidade funcional de 144 idosos foi avaliada por meio de Atividades Instrumentais da Vida Diária, testes cognitivos, força de preensão manual e capacidade de levantar de uma cadeira e sentar cinco vezes. O fator de crescimento de fibroblastos 23 foi medido pelo teste ELISA. Resultados Os participantes no tercil mais baixo de fator de crescimento de fibroblastos 23 tiveram a maior média±desvio-padrão da taxa de filtração glomerular estimada, concentração média de hemoglobina mais alta, menor número médio de doenças e menor número de medicamentos utilizados. Em participantes com taxa de filtração glomerular estimada >45mL/minuto/1,73m2, o nível médio do fator de crescimento de fibroblastos 23 foi maior naqueles com 25(OH) vitamina D <20ng/mL do que naqueles com 25(OH) vitamina D ≥20ng/mL (75,6RU/mL±42,8 versus 68,5RU/mL±41,7; p<0,001). Houve aumento na cistatina C sérica média (de 1,3mg/mL±0,3 a 1,5mg/mL±0,3 a 1,7mg/mL±0,4) em função do tercil de fator de crescimento 23 de fibroblastos mais alto (p<0,001). Os níveis de fator de crescimento de fibroblastos 23 não foram significativamente associados à capacidade em testes físicos ou cognitivos. Conclusão Em idosos independentes residentes na comunidade ≥80 anos, o fator de crescimento de fibroblastos 23 foi associado a comorbidades relacionadas à idade e à função renal, mas não à capacidade funcional.

The role of FGF21 in the pathogenesis of cardiovascular disease / 中华医学杂志(英文版)

The morbidity and mortality of cardiovascular diseases (CVDs) are increasing worldwide and seriously threaten human life and health. Fibroblast growth factor 21 (FGF21), a metabolic regulator, regulates glucose and lipid metabolism and may exert beneficial effects on the cardiovascular system. In recent years, FGF21 has been found to act directly on the cardiovascular system and may be used as an early biomarker of CVDs. The present review highlights the recent progress in understanding the relationship between FGF21 and CVDs including coronary heart disease, myocardial ischemia, cardiomyopathy, and heart failure and also explores the related mechanism of the cardioprotective effect of FGF21. FGF21 plays an important role in the prediction, treatment, and improvement of prognosis in CVDs. This cardioprotective effect of FGF21 may be achieved by preventing endothelial dysfunction and lipid accumulating, inhibiting cardiomyocyte apoptosis and regulating the associated oxidative stress, inflammation and autophagy. In conclusion, FGF21 is a promising target for the treatment of CVDs, however, its clinical application requires further clarification of the precise role of FGF21 in CVDs.

Calcinosis cutis congénita tumoral asociada con encefalopatía epiléptica infantil temprana con variante patogénica en el gen FGF12 / Tumorous congenital calcinosis cutis associated with early childhood epileptic encephalopathy with a pathogenic FGF12 gene variant

Resumen Introducción: La calcinosis cutis es el depósito de sales insolubles de calcio en la piel y se clasifica, de acuerdo con su patogénesis, en distrófica, metastásica, idiopática, iatrogénica y calcifilaxis. La calcinosis idiopática se presenta en pacientes sanos y es asintomática; incluye la calcinosis escrotal, la calcinosis nodular de Winer o nódulos calcificados subepidérmicos y la calcinosis tumoral familiar. Esta última es una condición rara que se caracteriza por el depósito de calcio periarticular en pacientes normocalcémicos sin conexión al hueso. Caso clínico: Paciente de sexo masculino de 5 meses de edad, quien al séptimo día de vida fue hospitalizado por ictericia multifactorial, sepsis neonatal tardía y apnea con crisis epilépticas. La evolución fue tórpida, con ingresos hospitalarios por crisis epilépticas de difícil manejo, respuesta parcial a la difenilhidantoína y descontrol electrolítico. Mediante la secuenciación del exoma dirigido se detectó una variante patogénica de sentido equivocado en FGF12 que confirmó el diagnóstico de encefalopatía epiléptica temprana número 47. Además, el paciente presentó dermatosis congénita diseminada a las extremidades inferiores con afección en muslos, asintomática, bilateral y simétrica, constituida por hipopigmentación y fóveas duras a la palpación profunda. La biopsia mostró calcificación distrófica. Conclusiones: Se presenta el caso de un lactante con calcinosis cutis congénita profunda asociada con una variante patogénica en el gen FGF12 y con encefalopatía epiléptica, situación clínica que, a la fecha, no había sido reportada en la literatura.

Abstract Background: Calcinosis cutis is the deposit of insoluble calcium salts in the skin. It is classified according to its pathogenesis in dystrophic, metastatic, idiopathic, iatrogenic, and calciphylaxis. Idiopathic calcinosis is asymptomatic, occurs in healthy patients, and includes scrotal calcinosis, Winer's nodular calcinosis or subepidermal calcified nodules, and familial tumor calcinosis. The latter is a rare condition characterized by periarticular calcium deposition in normocalcemic patients with no bone connection. Case report: The case of a 5-month-old male patient, who on the seventh day of life was hospitalized for multifactorial jaundice, late neonatal sepsis, and apnea with epileptic seizures is described. His evolution was torpid, with hospital admissions due to epileptic seizures that were difficult to manage with partial response to the use of diphenylhydantoin and electrolyte alterations. By means of exome sequencing directed, a pathogenic variant of wrong direction in FGF12 was detected and the diagnosis of early epileptic encephalopathy number 47 was confirmed. Also, the patient showed disseminated congenital dermatosis to lower extremities affecting thighs, asymptomatic, bilateral and symmetrical, constituted by hypopigmentation and fovea hard to deep palpation. The biopsy showed dystrophic calcification Conclusions: The case of an infant with deep congenital cutis calcinosis associated with a pathogenic variant in the FGF12 gene with epileptic encephalopathy is described. To date, this clinical situation has not been previously reported in the literature.

Higher increase degree of FGF21 post long-term interdisciplinary weight loss therapy preserves the free fat mass and rest metabolic rate in adolescents with obesity

ABSTRACT Objective Fibroblast growth factor 21 (FGF21) is among the activators that can stimulate thermogenesis in the white adipose tissue and brown adipose tissue. People with obesity have elevated blood levels of FGF21, but also develop resistance to its action, impairing its beneficial role. Inversely, clinical treatments to weight loss has been pointed out as an important therapy for increasing and recovering sensitivity to FGF21. The aim was to analyse the effect of long-term weight loss interdisciplinary intervention on FGF21 and body composition. Subjects and methods Eighty-six post-pubertal obese adolescents (14-19 years-old), were submitted to 20 weeks of weight loss therapy (clinical, nutritional, psychological and physical exercise support). Anthropometric measures, body composition and rest metabolic rate (RMR) by bioelectrical impedance, and serum FGF21 sample by ELISA were evaluated. The adolescents were grouped according to FGF21 individual delta variations after therapy: Higher Increase (HI); lower increase (LI); lower decrease (LD); higher decrease (HD). Results All groups present weight loss. Only in FGF21 ≥ 76,5 pg/mL variation the free-fat-mass and rest metabolic rate were preserved and to others group these variables were significantly reduced. Conclusion High increase in FGF21 can contribute to preservation of FFM and RMR after weight loss therapy, could have important implications for energy balance regulation. Future studies are necessary to continue determining the role of magnitude effects of FGF21 levels in obesity to improve clinical practice, especially in paediatrics population.

Mineral bone disorder and osteoporosis in hemodialysis patients

Abstract Background: Bone disease is common in patients undergoing hemodialysis. It is the result of bone turnover abnormalities and the decrease of bone mineral density (BMD). We aimed to determine the usefulness of serum bone turnover markers and BMD measurement by dual-energy x-ray absorptiometry (DXA) in hemodialysis patients. Methods: We conducted a cross-sectional study including 90 hemodialysis for more than 12 months. Bone mineral density was assessed by DXA. Peripheral blood samples were obtained from each patient before dialysis in a fasting state within a week of the DXA. Biochemical variables of calcium and phosphate were measured. One bone formation marker (bone-specific alkaline phosphatase (bAP), one bone resorption marker (carboxy-terminal telopeptides of type 1 collagen (CTX)) were measured. Total alkaline phosphatase (TAP), intact parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) which is a bone-derived hormone were also measured. Results: CTX values were 6.25 times higher than the normal limit of the assay. Bone alkaline phosphatase levels were less than 10 ng/mL in 28.8% of cases. 23% of patients have osteoporosis and 45% have osteopenia. Femoral BMD had negative correlations with age and PTH levels. FGF23 levels were significantly increased in patients with osteoporosis affecting the lumbar. The levels of bAP and CTX showed a positive correlation. Both circulating bAP and CTX levels showed also positive correlations with PTH levels. Fractures, observed in 12.2% of cases, were associated with low PTH values and the existence of osteoporosis. Conclusions: Our study showed that osteoporosis and fracture are common in dialysis patients. The reduced BMD was associated with advanced age and elevated levels of PTH. Markers of bone turnover and FGF23 may play a role in the diagnosis of bone disease in hemodialysis patients. DXA measurement is necessary for the monitoring for bone loss.(AU)

Therapeutic Angiogenesis with Somatic Stem Cell Transplantation

Therapeutic angiogenesis is an important strategy to rescue ischemic tissues in patients with critical limb ischemia having no other treatment option such as endovascular angioplasty or bypass surgery. Studies indicated so far possibilities of therapeutic angiogenesis using autologous bone marrow mononuclear cells, CD34⁺ cells, peripheral blood mononuclear cells, adipose-derived stem/progenitor cells, and etc. Recent studies indicated that subcutaneous adipose tissue contains stem/progenitor cells that can give rise to several mesenchymal lineage cells. Moreover, these mesenchymal progenitor cells release a variety of angiogenic growth factors including vascular endothelial growth factor, fibroblast growth factor, hepatocyte growth factor and chemokine stromal cell-derived factor-1. Subcutaneous adipose tissues can be harvested by less invasive technique. These biological properties of adipose-derived regenerative cells (ADRCs) implicate that autologous subcutaneous adipose tissue would be a useful cell source for therapeutic angiogenesis in humans. In this review, I would like to discuss biological properties and future perspective of ADRCs-mediated therapeutic angiogenesis.

Fibroblast Growth Factor 21 Attenuates Diabetes-Induced Renal Fibrosis by Negatively Regulating TGF-β-p53-Smad2/3-Mediated Epithelial-to-Mesenchymal Transition via Activation of AKT

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study.METHODS: Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4′-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months.RESULTS: DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-β)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2).CONCLUSION: FGF21 prevents renal fibrosis via negative regulation of the TGF-β/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.

Fibroblast Growth Factor-23 is associated with High-density lipoprotein in Systemic sclerosis Female patients

@#INTRODUCTION: Fibroblast growth factor-23 (FGF23) is a circulating regulator of phosphate and vitamin D metabolism and has been implicated as a putative pathogenic factor in cardiovascular disease. The objectives of this study were: to compare serum FGF23 levels between systemic sclerosis (SSc) patients and healthy controls and to investigate possible associations between FGF23 and serum lipid profile in SSc patients. METHODS: This cross-sectional study was performed in San Cecilio Hospital, Granada (Spain) from November 2017 to May 2019. We enrolled 62 consecutive female patients affected by SSc and 62 healthy women who served as controls. Cardiovascular risk factors and related biochemical parameters were collected. Serum FGF23 was analyzed using enzyme- linked immunosorbent assay (ELISA). Linear regression was used to examine the cross-sectional associations of serum FGF23 concentrations with high density lipoprotein-cholesterol (HDL-c). RESULTS: There was no significant differences in FGF23 levels between the patients and controls (78.2 ± 60.5 vs. 80.3 ± 56.3 pg/mL, p= 0.662), but we found a statistically significant inverse relationship between FGF23 and HDL-c measurements (r= -0.27; p= 0.03) in women with SSc. In addition, in the linear regression model, higher FGF23 concentrations were associated with lower HDL-c [β = -1.45 95% CI (-2.81, -0.08); p < 0.05]. CONCLUSIONS: We report an association between circulating FGF23 and HDL-c in SSc female patients, representing a novel pathway linking high FGF23 to an increased cardiovascular risk.

The molecular mechanism of fibroblast growth factor 21-inhibited leptin expression in adipocytes / 生理学报

The present study was aimed to clarify the signaling molecular mechanism by which fibroblast growth factor 21 (FGF21) regulates leptin gene expression in adipocytes. Differentiated 3T3-F442A adipocytes were used as study object. The mRNA expression level of leptin was detected by fluorescence quantitative RT-PCR. The phosphorylation levels of proteins of signal transduction pathways were detected by Western blot. The results showed that FGF21 significantly down-regulated the mRNA expression level of leptin in adipocytes, and FGF21 receptor inhibitor BGJ-398 could completely block this effect. FGF21 up-regulated the phosphorylation levels of ERK1/2 and AMPK in adipocytes. Either ERK1/2 inhibitor SCH772984 or AMPK inhibitor Compound C could partially block the inhibitory effect of FGF21, and the combined application of these two inhibitors completely blocked the effect of FGF21. Neither PI3K inhibitor LY294002 nor Akt inhibitor AZD5363 affected the inhibitory effect of FGF21 on leptin gene expression. These results suggest that FGF21 may inhibit leptin gene expression by activating ERK1/2 and AMPK signaling pathways in adipocytes.

Plasma Fibroblast Growth Factor 23 Concentration Is Associated with Intracranial Cerebral Atherosclerosis in Acute Ischemic Stroke Patients

Rol de la osteocalcina más allá del hueso / Role of osteocalcin beyond bone

Los hallazgos osteológicos se intensi!caron en los últimos años. Se demostró que el esqueleto se comporta, además de sus funciones clásicas, como un órgano de secreción endocrina que sintetiza al menos dos hormonas: el factor de crecimiento de !broblastos 23 (FGF-23) y la osteocalcina (Ocn). La Ocn es un péptido pequeño que contiene 3 residuos de ácido glutámico. Estos residuos se carboxilan postraduccionalmente, quedando retenida en la matriz ósea. La forma decarboxilada en el primer residuo de ácido glutámico (GluOcn) fue reportada por poseer efectos biológicos; la resorción ósea es el mecanismo clave para su bioactivación. La presente revisión se centra en los conocimientos actuales sobre la función hormonal de la Ocn. A la fecha se reporta que la Ocn regularía el metabolismo energético aumentando la proliferación de células ` pancreáticas, y la secreción de insulina y de adiponectina. Sobre el músculo esquelético actuaría favoreciendo la absorción y el catabolismo de nutrientes. La función reproductiva masculina estaría regulada mediante el estímulo a las células de Leydig para sintetizar testosterona; en el desarrollo cerebral y la cognición, la Ocn aumentaría la síntesis de neurotransmisores monoaminados y disminuiría el neurotransmisor inhibidor GABA. Si bien son indispensables mayores evidencias para dilucidar los mecanismos reguladores por medio de los cuales actuaría la Ocn, los resultados enumerados en los distintos estudios experimentales establecen la importancia de este novedoso integrante molecular. Dilucidar su rol dentro de estos procesos interrelacionados en seres humanos abriría la posibilidad de utilizar a la Ocn en el tratamiento de enfermedades endocrino-metabólicas. (AU)

Osteological !ndings have intensi!ed in recent years. The skeleton behaves as an endocrine secretion organ that synthesizes at least two hormones: osteocalcin (Ocn) and !broblast growth factor 23 (FGF-23). Ocn is a small peptide that contains 3 glutamic acid residues. After translation, these residues are carboxylated to make possible its retention into the bone matrix. Decarboxylation on the !rst glutamic acid residue (GluOcn) has been reported to have biological effects. Bone resorption is the key mechanism for its bioactivation. This review focuses on current knowledge on Ocn hormonal function. It has been reported that Ocn regulates energy metabolism by increasing the proliferation of pancreatic ` cells, and the secretion of insulin and adiponectin. On the skeletal muscle, it may act by favoring the absorption and catabolism of nutrients. Male reproductive function might be regulated by stimulating Leydig cells to synthesize testosterone. Regarding brain development and cognition, Ocn would increase monoamine neurotransmitters synthesis and decrease inhibitory neurotransmitter GABA. Although more evidence is needed to elucidate the regulatory mechanisms of Ocn, different experimental studies establish the importance of this novel molecular mediator. Clarifying its role within interrelated processes in humans, might open the possibility of using Ocn in different treatments of endocrine-metabolic diseases. (AU)

Fasting insulin and alanine amino transferase, but not FGF21, were independent parameters related with irisin increment after intensive aerobic exercising

Abstract Background Irisin is a protein cleaved from fibronectin type III domain-containing protein 5 and has been implicated in the beneficial effects of exercise. However, it is unknown which factors contribute to irisin increment after intensive exercising in humans. This study aimed to assess independent factors related with serum irisin after 2 weeks of supervised physical activity in young sedentary healthy women. Design and Methods We developed a comparative, interventional, longitudinal, and prospective study at a third-level specialty health center. Between March 2010 and August 2011, 82 sedentary young adult women, without chronic diseases or regular medical treatments, were recruited. A total of 38 women fulfilled selection criteria, and irisin concentrations were quantified before and after the intervention. Independent factors related with irisin increment were evaluated according to mild to moderate and vigorous intensity of physical activity. A supervised treadmill exercise test following the Bruce’s protocol was conducted from Monday to Friday during 2 weeks. In addition, anthropometric measurements were taken, and fibroblast growth factor 21 (FGF21), glucose, insulin, and liver transaminases were measured. Results Intensity of exercising was directly related to irisin (p = 0.02) and FGF21 (p = 0.01) serum levels. However, an independent and significant relationship between FGF21 and irisin was not confirmed. A novel association was found between alanine aminotransferase (ALT) and irisin, showing a positive and significant correlation (r = 0.37, p = 0.02). The association was particularly strong with higher intensity of aerobic exercising (r = 0.64, p = 0.01). Linear regression model adjusted for glucose and body mass index confirmed an independent association between ALT and irisin and also between insulin and irisin (adjusted R² = 0.12, p = 0.04). Such association increased after grouping in moderate to vigorous physical activity intensity (adjusted R² = 0.46, F = 4.7, p = 0.03). Conclusions Serum irisin and FGF21 levels significantly increased after 2 weeks of supervised physical activity. However, only fasting insulin and ALT, but not FGF21, were independent parameters explaining irisin increment, mainly after moderate to vigorous exercising.

The Effect of Fibroblast Growth Factors in Grafted Fascia into the Vocal Fold of Rabbits

Abstract Introduction The human larynx is a very important organ for communication. Many conditions lead to scarring of the vocal folds, decreasing voice quality. Objective We aimed to determine whether fibroblast growth factors (FGFs) may influence tissue integration of grafted fascia into the vocal folds of an animal model. Methods This is an experimental animal study with 12 adult rabbits that were submitted to a grafting fragment obtained from superficial cervical fascia into the vocal fold lamina propria, bilaterally. The right vocal fold was injected with FGFs. The animals were sacrificed after 1 month or 12 months, depending on the group they were assigned to, and a histological analysis of their vocal folds was performed.We analyzed the histological changes (such as the presence of fibrosis and neovascularization) induced by the acute or chronic inflammatory reactions. Results The FGFs induced acute inflammatory changes in all animals after 1 month of the initial experiment. The presence of FGFs triggered more fibrosis than the expected due to the surgical procedure itself when compared with the control side of all animals after 12 months of the initial experiment. Conclusions Fibroblast growth factors alone do not represent a good therapeutic option in phonosurgery, since we observed higher levels of fibrosis in the vocal fold lamina propria. Further studies combining more substances may be necessary to elucidate the best option to be used in this kind of surgery. (AU)

The wound healing potential of collagen peptides derived from the jellyfish Rhopilema esculentum / 中华创伤杂志(英文版)

PURPOSE@#Wound represents a major health challenge as they consume a large amount of healthcare resources to improve patient's quality of life. Many scientific studies have been conducted in search of ideal biomaterials with wound-healing activity for clinical use and collagen has been proven to be a suitable candidate biomaterial. This study intended to investigate the wound healing activity of collagen peptides derived from jellyfish following oral administration.@*METHODS@#In this study, collagen was extracted from the jellyfish--Rhopilema esculentum using 1% pepsin. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and fourier transform infrared (FTIR) were used to identify and determine the molecular weight of the jellyfish collagen. Collagenase II, papain and alkaline proteinase were used to breakdown jellyfish collagen into collagen peptides. Wound scratch assay (in vitro) was done to determine migration potential of human umbilical vein endothelial cells (HUVEC) covering the artificial wound created on the cell monolayer following treatment with collagen peptides. In vivo studies were conducted to determine the effects of collagen peptides on wound healing by examining wound contraction, re-epithelialization, tissue regeneration and collagen deposition on the wounded skin of mice. Confidence level (p < 0.05) was considered significant using GraphPad Prism software.@*RESULTS@#The yield of collagen was 4.31%. The SDS-PAGE and FTIR showed that extracted collagen from jellyfish was type I. Enzymatic hydrolysis of this collagen using collagenase II produced collagen peptides (CP) and hydrolysis with alkaline proteinase/papain resulted into collagen peptides (CP). Tricine SDS-PAGE revealed that collagen peptides consisted of protein fragments with molecular weight <25 kDa. Wound scratch assay showed that there were significant effects on the scratch closure on cells treated with collagen peptides at a concentration of 6.25 μg/mL for 48 h as compared to the vehicle treated cells. Overall treatment with collagen peptide on mice with full thickness excised wounds had a positive result in wound contraction as compared with the control. Histological assessment of peptides treated mice models showed remarkable sign of re-epithelialization, tissue regeneration and increased collagen deposition. Immunohistochemistry of the skin sections showed a significant increase in β-fibroblast growth factor (β-FGF) and the transforming growth factor-β (TGF-β) expression on collagen peptides treated group.@*CONCLUSION@#Collagen peptides derived from the jellyfish-Rhopilema esculentum can accelerate the wound healing process thus could be a therapeutic potential product that may be beneficial in wound clinics in the future.