Serum Hepatocyte Growth Factor Levels Research Articles

Gender effect of glucose, insulin/glucagon ratio, lipids, and nitrogen-metabolites on serum HGF and EGF levels in patients with diabetes type 2.

Hepatocyte growth factor (HGF) exhibits potent growth-inducing properties across various tissues, while epidermal growth factor (EGF) acts as a molecular integration point for diverse stimuli. HGF plays a crucial role in hepatic metabolism, tissue repair, and offers protective effects on epithelial and non-epithelial organs, in addition to its involvement in reducing apoptosis and inflammation, underscoring its anti-inflammatory capabilities. The HGF-Met system is instrumental in hepatic metabolism and enhancing insulin sensitivity in animal diabetes models. Similarly, the EGF and its receptor tyrosine kinase family (EGFR) are critical in regulating cell growth, proliferation, migration, and differentiation in both healthy and diseased states, with EGF also contributing to insulin sensitivity. In this observational study, we aimed to identify correlations between serum levels of HGF and EGF, insulin, glucagon, glucose, and primary serum lipids in patients with type 2 diabetes mellitus (DM), taking into account the impact of gender. We noted differences in the management of glucose, insulin, and glucagon between healthy men and women, potentially due to the distinct influences of sexual hormones on the development of type 2 DM. Additionally, metabolites such as glucose, albumin, direct bilirubin, nitrites, and ammonia might influence serum levels of growth factors and hormones. In summary, our results highlight the regulatory role of insulin and glucagon in serum glucose and lipids, along with variations in HGF and EGF levels, which are affected by gender. This link is especially significant in DM, where impaired cell proliferation or repair mechanisms lead to metabolic changes. The gender-based differences in growth factors point to their involvement in the pathophysiology of the disease.

Postoperative Intimal Hyperplasia: Review from My Research.

Postoperative intimal hyperplasia is the major cause of the vein graft occlusion. It is very important to establish an animal model for the start of research. After my vascular surgery residency in Japan, I started my research work on postoperative intimal hyperplasia at the University of Wisconsin-Madison. My research showed that endothelial injury and monocyte infiltration is the key for postoperative intimal hyperplasia, which is very similar to Ross' pathogenesis of atherosclerosis as an inflammatory disease. Focusing on postoperative intimal hyperplasia as an inflammatory disease, especially on tumor necrosis factor-α, FR-167653 (tumor necrosis factor-α suppressive agent, inhibitor of p 38 mitogen-activated protein kinase; Fujisawa Pharmaceutical Co., Ltd., Japan) is found to suppress postoperative intimal hyperplasia in a rat model by reducing serum monocyte chemoattractant protein-1 levels. However, FR-167653 is not commercially available today. Because endothelial injury is the first step of postoperative intimal hyperplasia, I investigated whether the free radical scavenger, edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan), which alleviates the endothelial injury in vitro , can also suppress postoperative intimal hyperplasia. Moreover, the free radical scavenger edaravone (Radicut®, Mitsubishi Tanabe Pharma Co.) is also found to suppress postoperative intimal hyperplasia, by alleviating endothelial injury. In clinical settings, it is very important to detect postoperative intimal hyperplasia before its establishment. Hepatocyte growth factor is not only a hepatic growth factor but also a vascular endothelial growth factor. Recently, serum hepatocyte growth factor level was found to be a candidate biomarker for postoperative intimal hyperplasia in our rat model.

The protective effects of Nigella sativa, thymoquinone and bentonite in experimental aflatoxicosis model in broilers

The aim of this study was to determine the preventive efficacy of black seed (Nigella sativa L.), thymoquinone and Na bentonite on biomarkers of tissue degeneration in the liver and other organs induced by aflatoxin (AF) in broilers. One hundred broiler chicks were divided into 10 equal groups and fed for 28 days. The animals received feed with 2 mg/kg total aflatoxin, Nigella sativa (NS; 5%), thymoquinone (TMQ; 300 mg/kg) and Na bentonite (BNT; 10 g/kg) both individually and in combination. At the end of the experiment, blood and liver tissue samples were collected. AF treatment significantly increased serum and liver 8-hydroxy-2’-deoxyguanosine(8-OHdG), serum transforming growth factor β (TGF-β), and liver total antioxidant capacity (TAC) levels, whereas it significantly decreased liver TGF-β and serum TAC levels compared to the control. However, there were no changes in the serum and liver hepatocyte growth factor (HGF) levels from AF. Both individual and combined addition of NS, BNT and TMQ to AF-contaminated feed significantly improved liver 8-OHdG, liver TAC and serum TGF-β levels. Serum 8-OHdG levels were ameliorated only in the AF+BNT+TMQ group. In addition, the AF+BNT+NS and AF+BNT+TMQ groups showed significant improvement in liver 8-OHdG, liver TGF-β and liver TAC levels. We conclude that NS and TMQ supplementation to AF-contaminated feed may be beneficial against aflatoxicosis in broilers.

Glycoprotein non-metastatic melanoma protein B expression correlates with the prognosis of acute liver injury/failure.

Background: Glycoprotein non-metastatic melanoma protein B (GPNMB) is expressed in macrophages during recovery from acute liver injury (ALI) in carbon tetrachloride (CCl4)-induced liver injury model mice. In this retrospective study, we assessed whether GPNMB levels in the serum and injured liver correlate with liver injury severity and prognosis in patients with ALI or acute liver failure (ALF). Methods: The study involved 56 patients with ALI or ALF who visited the Kagoshima University Hospital. Serum GPNMB level was measured over time, and the localization, proportion, origin, and phenotype of GPNMB-expressing cells in the injured liver were assessed. Finally, the phenotypes of human monocyte-derived macrophages and peripheral blood mononuclear cells (PBMCs) of patients with ALI and ALF were analyzed. Results: Peak GPNMB levels were significantly higher in patients with ALF and hepatic encephalopathy (HE), as well as in those who underwent liver transplantation or died, than in others. The peak GPNMB level correlated with prothrombin activity, prothrombin time-international normalized ratio, Model for End-stage Liver Disease score, and serum hepatocyte growth factor level. GPNMB was expressed in CD68-positive macrophages, and its level increased with the severity of liver injury. The macrophages showed the same polarization as M2c macrophages induced with interleukin-10 from human monocytes. Moreover, PBMCs from patients with ALF exhibited an immunosuppressive phenotype. Conclusion: We found that GPNMB levels in the serum and injured liver, which increased in patients with ALF, especially in those with HE, correlated with the severity of liver injury and prognosis of ALI and ALF. Moreover, GPNMB-positive macrophages exhibited the M2c phenotype. Our results indicate that persistently high GPNMB levels may be a prognostic marker in patients with ALI and ALF.

Association of Serum Hepatocyte Growth Factor Level with Systemic Inflammatory Biomarkers in Patients with Pancreatobiliary Cancer.

Hepatocyte growth factor is a cytokine secreted by the stromal cells in the tumor microenvironment. There is little information about the clinical significance of serum hepatocyte growth factor level in patients diagnosed with pancreatobiliary cancer. The objective of the current study was to investigate the relationship between serum hepatocyte growth factor level with inflammation markers and the clinical features of patients with pancreatobiliary cancer. A total of 62 patients with pancreatobiliary cancer were included in this study. Serum hepatocyte growth factor concentrations were evaluated utilizing the enzyme-linked immunosorbent assay method. The median serum hepatocyte growth factor level was 329.1 ng/mL (1.4-1051.1). The patients were categorized into 2 groups as those below the median hepatocyte growth factor level (low hepatocyte growth factor) and those above the median hepatocyte growth factor level (high hepatocyte growth factor). While 40.9% of the patients without metastasis were observed to be in the high hepatocyte growth factor group, 72.2% of the metastatic patients were observed to be in the high hepatocyte growth factor group (P = .025). The median levels of monocyte, monocyte-to-lymphocyte ratio, C-reactive protein, and C-reactive protein-to-albumin ratio were found to be significantly higher in the high hepatocyte growth factor group as compared to the low hepatocyte growth factor group (P < .050). The significant relationship between serum hepatocyte growth factor level and systemic inflammation markers in patients with pancreatobiliary cancer is shown for the first time in our study. This study, which showed a significant relationship between the presence of metastasis and serum hepatocyte growth factor level, suggests that serum hepatocyte growth factor level may be a prognostic biomarker in patients who are diagnosed with pancreatobiliary cancer.

Improvement of physical activity significantly reduced serum hepatocyte growth factor levels in a general population: 10year prospective study.

Hepatocyte growth factor (HGF) is an adipocytokineelevated in obese subjects. We have previously reported that serum HGF levels were significantly associated with insulin resistance or components of the metabolic syndrome. However, it has been unknown how physical activity (PA) affects HGF levels after a long-term follow-up. Our aim was to clarify the association between PA changes and HGF levels as well as cerebro-cardiovascular disease (CVD) development, during a 10year follow-up period in a Japanese general population. Of 1320 subjects who received a health check-up examination in Tanushimaru town in 1999, 903 subjects (341 males and 562 females), who received the examination both in 1999 and 2009 were enrolled. We evaluated their PA levels by Baecke questionnaire in 1999 and by a simple questionnaire in 2009. We measured the HGF levels by ELISA method in 1999 and 2009. We divided the subjects into four PA groups, stable low PA, increased PA, decreased PA, and stable high PA. Using these questionnaires, we compared their PA and HGF levels after an interval of 10years. A significant inverse association was found between PA changes and HGF levels at 10years, after adjustment for age and sex. The HGF levels of the increased PA group were significantly lower than stable low PA (p = 0.038), and the increased PA group showed reduced CVD development compared to the stable low PA group after adjustment for age and sex (p = 0.012). Our data demonstrated that improvement of PA levels was associated with reduced HGF levels and CVD development.

Donor and Recipient Adipose-Derived Mesenchymal Stem Cell Therapy for Rat Lung Transplantation

Mesenchymal stem cells (MSCs) are beginning to be proven as immunosuppressant in the field of organ transplantation. However, the effects of MSC origin (donor or recipient) on immunosuppression are not clear. Hence, we investigated the effects of recipient and donor adipose-derived MSCs (ADMSCs) on immunosuppression in a rat lung transplantation model. Subjects were divided into no treatment, tacrolimus administration, recipient ADMSC administration, donor ADMSC administration, and mixed donor and recipient ADMSC administration groups. ADMSC-administered groups were also treated with tacrolimus. Histologic study, immunofluorescence, immunohistochemistry, enzyme-linked immunosorbent assay, and polymerase chain reaction were used for various analyses. Fluorescently labeled ADMSCs were predominant in the grafted donor lung, but not in the recipient lung, on day 5. On day 7, the pathologic rejection grades of the grafted donor lung were significantly lower in the ADMSC-administered groups (P < .05) and did not differ among these groups. Although serum hepatocyte growth factor and vascular endothelial growth factor levels did not differ among the groups, interleukin 10 level was slightly higher in the ADMSC-administered groups. The numbers of infiltrating regulatory T cells in the grafted lung were significantly higher in the ADMSC-administered groups (P < .05) but did not differ with cell origin. Transcriptional analysis suggested interleukin 6 suppression to be the main overlapping immunosuppressive mechanism, regardless of origin. Therefore, a donor or recipient origin may not influence the immunosuppressive efficacy of ADMSCs in our rat lung transplantation model. Collectively, the results indicate that allogenic ADMSCs, regardless of their origin, may exert similar immunosuppressive effects in clinical organ transplantation.

Effect of hepatocyte growth factor on mice with hypoxic pulmonary arterial hypertension: a preliminary study.

To study the association between hepatocyte growth factor (HGF) and treatment response in mice with hypoxic pulmonary arterial hypertension (HPAH) and the possibility of HGF as a new targeted drug for HPAH. After successful modeling, the HPAH model mice were randomly divided into two groups: HPAH group and HGF treatment group (tail vein injection of recombinant mouse HGF 1 mg/kg), with 10 mice in each group. Ten normal mice were used as the control group. After 5 weeks, echocardiography was used to measure tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio; the Griess method was used to measure the content of nitric oxide in serum; ELISA was used to measure the serum level of endothelin-1; transmission electron microscopy was used to observe changes in the ultrastructure of pulmonary artery. Compared with the HGF treatment and normal control groups, the HPAH group had significantly higher tricuspid peak velocity, right ventricular systolic pressure, right ventricular hypertrophy index, and right ventricular/body weight ratio (P<0.05). The transmission electron microscopy showed that the HPAH group had massive destruction of vascular endothelial cells and disordered arrangement of the elastic membrane of arteriolar intima with rupture and loss. The structure of vascular endothelial cells was almost complete and the structure of arterial intima elastic membrane was almost normal in the HGF treatment group. Compared with the normal control and HGF treatment groups, the HPAH group had significantly higher serum levels of nitric oxide and endothelin-1 (P<0.05). Increasing serum HGF level can alleviate the impact of HPAH on the cardiovascular system of mice, possibly by repairing endothelial cell injury, improving vascular remodeling, and restoring the normal vasomotor function of pulmonary vessels.

Abstract 5138: Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancer

Abstract Background: Recent evidence has highlighted the role of hepatocyte growth factor (HGF) as a putative biomarker to predict EGFR inhibitor resistance. This study investigated the impact of plasma HGF levels on EGFR inhibition and the therapeutic implications of MET inhibition in KRAS, NRAS, and BRAF (RAS/RAF) wild-type colorectal cancer (CRC). Methods: Clinical outcomes were analyzed according to the plasma HGF levels in patients with metastatic CRC (mCRC) receiving palliative first-line cetuximab or bevacizumab + FOLFIRI chemotherapy. Then, in vitro experiments were conducted to validate the clinical findings and to establish pre-clinical evidence of MET inhibition in the HGF-high population. Results: From March 2015 to September 2019, a total of 80 patients were enrolled. The median age was 63 (range, 24-85) years. Of these, 45 patients (56.2%) were treated with bevacizumab + FOLFIRI and 35 patients (43.8%) were treated with cetuximab + FOLFIRI. Among patients with evaluable disease (43 patients (95.6%) in the bevacizumab group and 34 patients (97.1%) in the cetuximab group), the objective response rate was 60.0% and 37.8%, respectively (p=0.162). The median serum HGF level was 374.75 (range, 9.43-30,644.44) pg/mL, and the optimal cut-off value of HGF levels was 12.70 pg/mL by the maximal chi-square method. During a median follow-up of 29.3 (range, 1.2-71.3) months, both progression-free survival (PFS) and overall survival (OS) were significantly shorter in the high HGF group compared with the low HGF group: median 11.8 (95% confidence interval [CI], 10.5-13.1) months vs. 24.7 (95% CI, 23.4-25.9) months for PFS (p=0.009), and median 21.1 (95% CI, 17.9-24.3) months vs. not reached for OS (p=0.018). The difference in PFS and OS was statistically significant in the cetuximab group (p=0.003 for PFS and p=0.035 for OS), but not in the bevacizumab group. In five RAS/RAF wild-type CRC cell lines (Caco-2, COLO 320DM, KM12C, SNU-C1, and SNU-C4), the addition of HGF activated ERK1/2 and AKT via MET phosphorylation. In the cytotoxicity assays, Caco-2 and SNU-C4 were relatively sensitive to cetuximab compared with the others and, in the presence of HGF, cetuximab sensitivity was significantly decreased in the two cells. Moreover, capmatinib, a MET inhibitor, abrogated the effect of HGF on common downstream signaling pathways of EGFR and MET and thus the cetuximab resistance was significantly overcome in vitro. Conclusions: Among patients with mCRC receiving cetuximab + FOLFIRI, those with high plasma HGF levels had significantly worse PFS and OS. HGF induced cetuximab resistance by AKT and ERK activation while capmatinib, a MET inhibitor, significantly increased the anti-tumor effects of cetuximab in the presence of HGF in vitro. Our data may provide evidence of future clinical trials of dual EGFR and MET targeting strategies in patients with HGF-high, RAS/RAF wild-type mCRC. Citation Format: Sang-A Kim, Hyejoo Park, Kui-Jin Kim, Ji-Won Kim, Ji Hea Sung, Milang Nam, Ju Hyun Lee, Eun Hee Jung, Koung Jin Suh, Ji Yun Lee, Se Hyun Kim, Jeong-Ok Lee, Jin Won Kim, Yu Jung Kim, Jee Hyun Kim, Soo-Mee Bang, Jong Seok Lee, Keun-Wook Lee. Cetuximab resistance induced by hepatocyte growth factor is overcome by MET inhibition in KRAS, NRAS, and BRAF wild-type colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5138.

Favorable Cardiovascular Health Is Associated With Lower Hepatocyte Growth Factor Levels in the Multi-Ethnic Study of Atherosclerosis

Introduction: Hepatocyte growth factor (HGF) is a cytokine released in response to endothelial injury and a potential biomarker of cardiovascular disease (CVD) risk. We examined the association between cardiovascular health (CVH) and HGF in a multi-ethnic cohort of adults free from CVD at baseline.Methods: This cross-sectional study conducted between 2020 and 2021 used MESA baseline examination data (2000–2002) from 6,490 US adults aged 45–84 years. The independent variable was CVH measured by the CVH score and number of ideal metrics. The score was derived from seven metrics: smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose. Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0 to 14. An inadequate score was 0–8, average, 9–10 and optimal, 11–14. The dependent variable was logarithmically transformed HGF. We used regression analyses to estimate associations between CVH and HGF adjusting for sociodemographic factors.Results: Participants' mean (SD) age was 62 (10) years. Fifty-three percent were female. A one-unit increment in the CVH score was significantly associated with 3% lower HGF levels. Average and optimal CVH scores were significantly associated with 8% and 12% lower HGF levels, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF levels.Conclusion: Favorable CVH was significantly associated with lower HGF levels in this ethnically diverse cohort. Interventions aimed at promoting and preserving favorable CVH may reduce the risk of endothelial injury as indicated by lower serum HGF levels.

Analysis of Soluble Mesenchymal-Epithelial Transition Factor and Hepatocyte Growth Factor Serum Levels in Children With Autism Spectrum Disorder

Background: Hepatocyte Growth Factor (HGF) and its receptor, Mesothelial-Epithelial Transition (cMet) factor signaling, play an essential role in controlling synaptogenesis. Objectives: Because of the vital role of HGF and Met signaling in synaptogenesis and spatial learning function of the brain’s hippocampal region, we aimed to study the HGF and soluble cMet (s-cMet) serum levels in children with different stages of Autism Spectrum Disorders (ASD). Materials &amp; Methods: A total of 189 ASD patients (mild; n=69, moderate; n=63 and severe; n=57) and 82 control were enrolled in this project. Blood samples were collected from ASD patients referred to Pediatric Neurology Clinic, 17 Shahrivar Hospital, Rasht City, Iran, and serum concentrations of s-cMet and HGF were measured by ELISA. The control children with no clinical characteristics of ASD attended routine blood tests. Results: HGF Mean±SD serum concentration in ASD patients was 239±52.02 pg/mL compared to controls which was 360.04±71.15 pg/mL (P=0.004). Also, the Mean±SD serum concentrations of HGF in mild, moderate, and severe ASD patients were 297.54±69.82, 232.81±56.41, and 189±33.25 ng/mL, respectively, compared to control, which was 360.18±57.40. Besides, the s-cMet Mean±SD serum concentrations in ASD and controls were 143.54±32.50 and 200.25±31.16 pg/mL, respectively (P=0.005). The Mean±SD serum concentrations of s-cMet in the mild, moderate, and severe ASD patients were 172.81±37.69, 129.81±45.55, and 85.18±22.95 ng/mL, respectively, as compared to the control, which was 214.54±34.17 ng/mL. Conclusion: Serum HGF and s-cMet concentration decreased in ASD patients corresponding to disease severity. Also, detecting serum HGF and s-cMet may help classify ASD.

Overexpression of Hepatocyte growth factor and its soluble receptor (s-cMet) in the serum of patients with different grades of meningioma

ObjectivesMeningiomas are the most common primary intracranial tumor. Hepatocyte growth factor (HGF) and its receptor, cMet, were shown to be involved in meningioma. This study was aimed to determine the concentration of HGF and soluble cMet (s-cMet) in the serum of patients with different grades of meningioma. MethodsNinety serum samples from different grades of meningioma patients (42 cases of grade I, 28 grade II, 20 grade III) and 51 controls were included in this study. The serum total protein concentration (TPC) was measured by a Bio-Rad protein assay and serum concentration of HGF and s-cMet by enzyme linked immunosorbent assay (ELISA). ResultsNo significant change in the serum TPC of patients was seen as compared to controls. We also showed that serum HGF and s-cMet concentration in meningioma patients was higher than in controls. The results showed that starting from grades I to III meningioma, a significant increase in HGF and s-cMet serum concentration was observed (HGF; 380 ± 57.69, 430.27 ± 48.72, 596.36 ± 104.49 pg/ml, respectively, as compared to controls which was 327.72 ± 49.68 pg/ml and for s-cMet was 274.45 ± 45.05, 314.81 ± 38.71, 433.54 ± 51.81 ng/ml, respectively, as compared to controls which was 213.72 ± 29.13 ng/ml). The results showed that a high concentration of HGF and s-cMet is associated with advanced grades of meningioma. ConclusionIt is concluded that HGF and s-cMet serum levels increased in meningioma patients and their concentration was significantly higher in more advanced grades of the disease. It is also suggested that HGF/s-cMet might be involved in the progression of meningioma.

Serum hepatocyte growth factor as a predictor of disease severity and future exacerbations in patients with non-cystic fibrosis bronchiectasis

BackgroundSerum biomarkers associated with the severity of non-cystic fibrosis (CF) bronchiectasis are insufficient. This study determined the association of serum hepatocyte growth factor (HGF), osteopontin, and pentraxin-3 levels with disease severity and exacerbation in patients with non-CF bronchiectasis. MethodsSerum levels of HGF, osteopontin, and pentraxin-3 were measured in patients with clinically stable non-CF bronchiectasis (n = 61). The correlation between the biomarkers and bronchiectasis severity index (BSI) and FACED score was assessed using univariate and multivariate linear regression analyses. Predictive variables associated with exacerbation were analyzed using a Cox proportional hazards model and the time to first exacerbation in high and low HGF groups during the observation period was compared using Kaplan-Meier survival curves. ResultsThe BSI showed significant correlation with HGF (r = 0.423; p = 0.001) and pentraxin-3 (r = 0.316; p = 0.013). The FACED score was significantly correlated with HGF (r = 0.406; p = 0.001). Univariate and multivariate linear regression analysis revealed that serum level of HGF was independently associated with both scoring systems. The high HGF group showed a significantly shorter time to first exacerbation (Log-rank test, p = 0.014). Multivariate Cox proportional hazards regression analysis revealed that high serum HGF level and colonization with non-pseudomonas organisms were independent predictors of future exacerbations (HR 2.364; p = 0.024 and HR 2.438; p = 0.020, respectively). ConclusionSerum level of HGF is a potential biomarker that is closely associated with disease severity and future risk of exacerbations in patients with non-CF bronchiectasis.

Abstract P008: Ideal Cardiovascular Health And Hepatocyte Growth Factor In The Multi-ethnic Study Of Atherosclerosis

Background: Hepatocyte growth factor (HGF) is a cytokine released in response to vascular injury and a novel biomarker of cardiovascular disease (CVD) risk. However, the relationship between ideal cardiovascular health (CVH) and HGF is unknown. We examined whether ideal CVH is associated with lower HGF levels in a multi-ethnic cohort of adults free from clinical CVD at baseline. Methods: We analyzed data from the MESA study of 6,490 men and women aged 45-84 years. The independent variable was the CVH score derived from 7 metrics (smoking, body mass index, physical activity, diet, total cholesterol, blood pressure and blood glucose). Each metric was scored 0 points (poor), 1 point (intermediate) and 2 points (ideal). The total CVH score ranged from 0-14. An inadequate score was 0-8, average, 9-10 and optimal, 11-14. The number of ideal metrics was also counted. The dependent variable was logarithmically transformed HGF. We examined the association between the CVH score and HGF using linear regression models adjusted for age, sex, race/ethnicity, education, income, health insurance and study site. Results: The mean (SD) age of participants was 62 (10) years. Fifty-three percent were women. Participants with optimal CVH scores had the lowest HGF concentration [Median (IQR): 807 (678-962) pg/mL] compared to those with average [870 (740-1,036)] and inadequate scores [969 (821-1,159)]. A one-unit increment in the CVH score was significantly associated with a 3% lower HGF concentration (Table). Average and optimal CVH scores were also significantly associated with 8% and 12% lower HGF concentrations, respectively, compared to inadequate scores. Additionally, a greater number of ideal metrics was associated with lower HGF concentrations. Interactions by age, sex and race/ethnicity were not significant. Conclusion: In this ethnically diverse cohort, optimal CVH was significantly associated with lower HGF levels. Interventions aimed at promoting ideal CVH may reduce vascular injury as indicated by lower serum HGF levels.

Prognostic relevance of longitudinal HGF levels in serum of patients with ovarian cancer.

The pleiotropic protein hepatocyte growth factor (HGF) is the only known ligand of the tyrosine kinase mesenchymal–epithelial transition (cMET) receptor. The HGF/cMET pathway mediates invasion and migration of ovarian cancer cells, and upregulation of HGF/cMET pathway components has been associated with poor prognosis. This study investigated the clinical relevance of circulating HGF in serum of patients with ovarian cancer. Serum HGF (sHGF) was determined by enzyme‐linked immunosorbent assay in a total of 471 serum samples from 82 healthy controls and 113 patients with ovarian cancer (88.5% with ≥ FIGO III). Patient samples were collected at primary diagnosis and at four follow‐up time points throughout treatment and at disease recurrence. Patients with ovarian cancer showed elevated median sHGF levels at primary diagnosis, and sHGF levels transiently increased after surgery and normalized in the course of chemotherapy, even dropping below initial baseline. Higher levels of sHGF were an independent predictor for shorter overall survival (OS) (a) at primary diagnosis (HR = 0.41, 95% CI: 0.22–0.78, P = 0.006), (b) at longitudinal follow‐up time points (after surgery and before/during/after chemotherapy), (c) along the patients’ individual dynamics (HR = 0.21, 95% CI: 0.07–0.63, P = 0.005), and (d) among a subgroup analysis of patients with BRCA1/2 wild‐type ovarian cancer. This is the first study proposing sHGF as an independent prognostic biomarker for ovarian cancer at primary diagnosis and in the course of platinum‐based chemotherapy, irrespective of the postoperative residual disease after surgical debulking. sHGF could be implemented into clinical diagnostics as a CA125 auxiliary tumor marker for individualized prognosis stratification and sHGF‐guided therapy monitoring.

Association of Hepatocyte Growth Factor Genetic Variation (S3735520) and Its Concentration in Autism Spectrum Disorders: A Case-control Study

Background: Hepatocyte Growth Factor (HGF) was shown to play a key role in synaptogenesis, survival, maturation, and reconstruction of neuron cells and was shown to be implicated in Autism Spectrum Disorder (ASD). Objectives: Assessing the relationship between HGF (rs3735520) gene polymorphism and its circulating levels in ASD. Materials &amp; Methods: A total of 140 ASD patients and 120 children healthy controls referred to Shahid Rajaei Hospital, Mazandaran, Iran from September 2017 to January 2019 were enrolled in the study. Genomic DNA was extracted from blood samples, HGF polymorphism was determined by polymerase chain reaction-restriction fragment length polymorphism and HGF serum concentration was measured by enzyme-linked immunosorbent assay. Statistical analysis was done by ANOVA and the Chi-square test, using χ² in MedCalc statistical software ver. 12.1.4. Results: Genotype frequencies of CC, CT, and TT in the ASD group were 25.71%, 52.86%, and 21.43%, and in controls were 26.67%, 68.33%, and 5%, respectively (P=0003) and C and T alleles frequencies in patients were 53% and 47% and in controls were 61% and 39%, respectively (P=0.046). Moreover, the Mean±SD serum HGF levels in the controls and ASD patients were 363.33±118.44 and 219.95±73.61 pg/mL, respectively (P=0.009). Furthermore, ASD patients carrying TT genotype had lower serum HGF levels than CT and TT carriers (CC, CT, and TT Mean±SD serum levels were 271.88±30.47, 217.77±33.59 and 156.33±22.72 pg/mL, respectively). Conclusion: There was a significant relationship between HGF gene polymorphism and its serum levels with ASD in an Iranian population. We also suggest that TT genotype may be associated with a decrease in HGF circulation levels in ASD.

A Potential Mechanism of Tumor Progression during Systemic Infections Via the Hepatocyte Growth Factor (HGF)/c-Met Signaling Pathway.

Background: Increasing evidence has demonstrated that postoperative infectious complications (PICs) after digestive surgery are significantly associated with negative long-term outcomes; however, precise mechanisms of how PICs affect the poor long-term survival remain unclear. Here, we focused on the hepatocyte growth factor (HGF)/c-Met signaling pathway as one of those mechanisms. Methods: In the clinical setting, serum HGF levels were measured in the patients with sepsis and those with PICs after undergoing esophagectomy. Using a liver metastasis mouse model with cecal ligation and puncture (CLP), expressions of HGF and the roles of the HGF/c-Met pathway in the progression of tumor cells were examined. Results: Serum HGF levels were very high in the patients with intra-abdominal infection on postoperative days (PODs) 1, 3, and 5; similarly, compared to the patients without PICs, those with PICs had significantly higher serum HGF levels on 1, 3, and 5 days after esophagectomy. The patients with PICs showed poorer overall survival than those without PICs, and the patients with high serum HGF levels on POD 3 showed poorer prognosis than those with low HGF levels. Similarly, at 24 and 72 h after operation, serum levels of HGF in CLP mice were significantly higher than those in sham-operated mice. Intraperitoneal injection of mouse recombinant HGF significantly promoted liver metastases in sham-operated mice on 14 days after surgery. Knocking down c-Met expression on NL17 tumor cells by RNAi technology significantly inhibited the promotion of CLP-induced liver metastases. Conclusions: Infections after surgery increased serum HGF levels in the clinical as well as experimental settings. Induction of high serum HGF levels by CLP promoted liver metastases in a murine liver metastasis model, suggesting the involvement of the HGF/c-Met signaling pathway in tumor promotion mechanisms. Thus, targeting the HGF/c-Met signaling pathway may be a promising approach for malignant tumors, particularly in the patients with PICs.

Serum Hepatocyte Growth Factor Level as the Biomarker for Postoperative Intimal Hyperplasia

Postoperative intimal hyperplasia is still the major cause of the vein graft occlusion. It may be useful to find the biomarker for the progression of postoperative intimal hyperplasia. The endothelial injury is considered as the first step for postoperative intimal hyperplasia. Hepatocyte growth factor (HGF) is not only the organ specific growth actor, but also the vascular endothelial growth factor. Edaravone (Radicut, Mitsubishi Tanabe Pharma Co., Japan) is not only the first free radical scavenger commercially available, but also alleviates the endothelial injury in vivo. In this study, we evaluated whether serum HGF levels can be the biomarker for postoperative intimal hyperplasia in the rat model. Moreover, we estimated whether edaravone can suppress postoperative intimal hyperplasia. In the 17 male rats (mean weight 498 ± 53 g), we interposed the right epigastric vein graft into the common femoral artery with 10-0 interrupted sutures, as previously described. The rats were divided into two groups: the Edaravone group, which received preoperative administration of edaravone (3.0 mg/kg) into peritoneal cavity; and the control group, which received the same dose of saline. Vein grafts from each group were stained with hematoxylin and eosin and Elastica Verhoeff’s van Gieson’s. Three unoperated right epigastric veins were also examined a Shame. The initial areas of vein graft were measured using computerized planimetry (NIH Image Ver. 1.61). Serum HGF levels were also measured and compared (unpaired t-test). This study was approved by the Hyogo College of Medicine Animal Research Committee (No. 235). The average of intimal area in Group Control were gradually increased (30 ± 16 × 10-3 mm2 at 2 weeks and 434 ±111 × 10-3 mm2 at 4 weeks), which were significantly suppressed in the Edaravone group (53 ± 54 × 10-3 mm2 at 4 weeks; P < .01). Serum HGF levels were also gradually increased (4.94 ± 0.50 ng/mL at 2 weeks and 7.20 ±1.40 ng/mL at 4 weeks), comparing with that of Shame (3.96 ± 0.22 ng/mL; P < .05) (Figure). Serum HGF levels in the Edaravone group at 4 weeks seemed to be suppressed, but not be significantly when compared with the Control group (5.46 ± 0.55 ng/mL; P = .20) (Fig). Serum HGF levels might be the biomarker for postoperative intimal hyperplasia in the rat model, which can be suppressed with edaravone.

SO023HEPATOCYTE GROWTH FACTOR (HGF) PRECLUDE HIGH-FAT DIET-INDUCED OBESITY AND IMPROVED INSULIN RESISTANCE IN MICE

Abstract Background and Aims Obesity and its associated chronic inflammation in adipose tissue initiate insulin resistance, which is related to several pathologies including hypertension and atherosclerosis. Previous reports demonstrated that circulating hepatocyte growth factor (HGF) level was associated with obesity and type 2 diabetes. However, its precise role in obesity and related-pathology is unclear. Method In this experiment, cardiac-specific over-expression of human HGF in mice (HGF-Tg mice) which showed 4-5 times higher serum HGF levels than wild-type mice were used. We chose cardiac specific HGF overexpression, as other strain of HGF transgenic mice such as liver and kidney specific HGF overexpression mice develop cancer and cystic diseases, which are rare in the heart. In the present study, using HGF-Tg mice and anti-HGF neutralizing antibody (HGF-Ab), we explored the role of HGF in obese and insulin resistance induced by high fat diet (HFD) for 14 weeks (200 or 400ug/week). Results With normal chow diet (ND), there were no significant changes in body weight between WT and HGF-Tg mice. While body weight in wild-type mice fed with HFD for 14 weeks was significantly increased accompanied with insulin resistance, HGF-Tg mice prevented body weight gain and insulin resistance. Insulin resistance in obesity arises from the combination of altered functions of insulin target cells (e.g., liver, skeletal muscle, and adipose tissue) and the accumulation of macrophages that secrete pro-inflammatory mediators in adipose tissue. The accumulation of macrophages and elevated levels of inflammatory mediators in adipose tissue were significantly inhibited in HGF-Tg mice as compared to wild-type mice. In the gWAT, the mRNA levels of the mature macrophage marker F4/80, the chemoattractants, MCP-1 and CXCL2, and the inflammatory cytokines, such as TNF-α and iNOS, were significantly increased in WT mice fed with HFD. However, these levels were markedly reduced in HGF-Tg mice fed with HFD. Additionally, activation of Akt by insulin administration was significantly reduced in the gWAT SM, and liver by HFD; however, this activation was restored in HGF-Tg mice. Moreover, insulin-induced Akt signaling was decreased in HGF-Ab groups as compared to saline group under HFD condition. Importantly, HFD significantly increased the level of HGF mRNA by approximately 2 fold in gWAT, SM, and liver without changing cMet expression. All together, these data indicate that the HGF as one of the systemic gWAT, SM, and liver-derived growth factor plays a role in compensatory mechanism against insulin-resistance through the at least anti-inflammatory effect in adipose tissue. The HFD-induced obesity in wild-type mice treated with HGF-neutralizing antibody showed an exacerbated response to the glucose tolerance test. Conclusion HGF suppresses inflammation in adipose tissue induced by a high-fat diet, and as a result improves systemic insulin resistance. These gain-of-function and loss-of-function studies demonstrated that the elevated HGF level induced by HFD have protective role against obesity and insulin resistance.

Delayed recanalization after MCAO ameliorates ischemic stroke by inhibiting apoptosis via HGF/c-Met/STAT3/Bcl-2 pathway in rats

The activation of tyrosine kinase receptor c-Met by hepatocyte growth factor (HGF) showed an anti-apoptotic effect in numerous disease models. This study aimed to investigate the neuroprotective mechanism of the HGF/c-Met axis-mediated anti-apoptosis underlying the delayed recanalization in a rat model of middle cerebral artery occlusion (MCAO). Permanent MCAO model (pMCAO) was induced by intravascular filament insertion. Recanalization was induced by withdrawing the filament at 3 days after MCAO (rMCAO). HGF levels in the blood serum and brain tissue expressions of HGF, c-Met, phosphorylated-STAT3 (p-STAT3), STAT3, Bcl-2, Bax, cleaved caspase-3(CC3) were assessed using ELISA and western blot, respectively. To study the mechanism, HGF small interfering ribonucleic acid (siRNA) and c-Met inhibitor, su11274, were administered intracerebroventricularly (i.c.v.) or intranasally, respectively. The concentration of HGF in the serum was increased significantly after MCAO. Brain expression of HGF was increased after MCAO and peaked at 3 days after recanalization. HGF and c-Met were both co-localized with neurons. Compared to rats received permanent MCAO, delayed recanalization after MCAO decreased the infarction volume, inhibited neuronal apoptosis, and improved neurobehavioral function, increased expressions of p-STAT3 and its downstream Bcl-2. Mechanistic studies indicated that HGF siRNA and su11274 reversed the neuroprotection including anti-apoptotic effects provided by delayed recanalization. In conclusion, the delayed recanalization after MCAO increased the expression of HGF in the brain, and reduced the infarction and neuronal apoptosis after MCAO, partly via the activation of the HGF/c-Met/STAT3/Bcl-2 signaling pathway. The delayed recanalization may serve as a therapeutic alternative for a subset of ischemic stroke patients.