Engineered Exosomes with Growth Differentiation Factor-15 Overexpression Enhance Cardiac Repair After Myocardial Injury.

Background: Cardiac repair remains a thorny issue for survivors of acute myocardial infarction (AMI), due to the regenerative inertia of myocardial cells. Cell-free therapies, such as exosome transplantation, have become a potential strategy for myocardial injury. The aim of this study was to investigate the role of engineered exosomes in overexpressing Growth Differentiation Factor-15 (GDF-15) (GDF15-EVs) after myocardial injury, and their molecular mechanisms in cardiac repair. Methods: H9C2 cells were transfected with GDF-15 lentivirus or negative control. The exosomes secreted from H9C2 cells were collected and identified. The cellular apoptosis and autophagy of H2O2-injured H9C2 cells were assessed by Western blotting, TUNEL assay, electron microscopy, CCK-8 and caspase 3/7 assay. A rat model of AMI was constructed by ligating the left anterior descending artery. The anti-apoptotic, pro-angiogenic effects of GDF15-EVs treatment, as well as ensuing functional and histological recovery were evaluated. Then, mRNA sequencing was performed to identify the differentially expressed mRNAs after GDF15-EVs treatment. Results: GDF15-EVs inhibited apoptosis and promoted autophagy in H2O2 injured H9C2 cells. GDF15-EVs effectively decreased the infarct area and enhanced the cardiac function in rats with AMI. Moreover, GDF15-EVs hindered inflammatory cell infiltration, inhibited cell apoptosis, and promoted cardiac angiogenesis in rats with AMI. RNA sequence showed that telomerase reverse transcriptase (TERT) mRNA was upregulated in GDF15-EVs-treated H9C2 cells. AMPK signaling was activated after GDF15-EVs. Silencing TERT impaired the protective effects of GDF15-EVs on H2O2-injured H9C2 cells. Conclusion: GDF15-EVs could fulfil their protective effects against myocardial injury by upregulating the expression of TERT and activating the AMPK signaling pathway. GDF15-EVs might be exploited to design new therapies for AMI.

GDF-15 Suppresses Puromycin Aminonucleoside-Induced Podocyte Injury by Reducing Endoplasmic Reticulum Stress and Glomerular Inflammation.

GDF15, also known as MIC1, is a member of the TGF-beta superfamily. Previous studies reported elevated serum levels of GDF15 in patients with kidney disorder, and its association with kidney disease progression, while other studies identified GDF15 to have protective effects. To investigate the potential protective role of GDF15 on podocytes, we first performed in vitro studies using a Gdf15-deficient podocyte cell line. The lack of GDF15 intensified puromycin aminonucleoside (PAN)-triggered endoplasmic reticulum stress and induced cell death in cultivated podocytes. This was evidenced by elevated expressions of Xbp1 and ER-associated chaperones, alongside AnnexinV/PI staining and LDH release. Additionally, we subjected mice to nephrotoxic PAN treatment. Our observations revealed a noteworthy increase in both GDF15 expression and secretion subsequent to PAN administration. Gdf15 knockout mice displayed a moderate loss of WT1+ cells (podocytes) in the glomeruli compared to wild-type controls. However, this finding could not be substantiated through digital evaluation. The parameters of kidney function, including serum BUN, creatinine, and albumin-creatinine ratio (ACR), were increased in Gdf15 knockout mice as compared to wild-type mice upon PAN treatment. This was associated with an increase in the number of glomerular macrophages, neutrophils, inflammatory cytokines, and chemokines in Gdf15-deficient mice. In summary, our findings unveil a novel renoprotective effect of GDF15 during kidney injury and inflammation by promoting podocyte survival and regulating endoplasmic reticulum stress in podocytes, and, subsequently, the infiltration of inflammatory cells via paracrine effects on surrounding glomerular cells.

[Expression and diagnostic value of growth differentiation factor 15 in patients with septic cardiomyopathy].

OBJECTIVE: To explore the expression of growth differentiation factor 15 (GDF15) in patients with septic cardiomyopathy and its value in the diagnosis of septic cardiomyopathy. METHODS: A observational study was conducted. Fifty patients with septic cardiomyopathy admitted to Shanxi Bethune Hospital from May 2022 to March 2023 were selected as the experimental group. Forty-six patients with acute coronary syndrome (ACS) in the same period were selected as the case control group. Forty-nine healthy adults were selected as the healthy control group, who underwent physical examination in the physical examination center during the same period. The demographic data and clinical indicators of the subjects were recorded, and the serum GDF15 level was detected by double sandwich enzyme-linked immunosorbent assay (ELISA). And the 28-day outcome of patients with septic cardiomyopathy was followed up, and they were divided into survival group and death group. The serum GDF15 level of subjects in each group and its correlation with clinical indicators were analyzed and compared. Binary Logistic regression was used to analyze the risk factors of septic cardiomyopathy. Receiver operator characteristic curve (ROC curve) was used to evaluate the value of GDF15 in the diagnosis of septic cardiomyopathy. RESULTS: The serum GDF15 level of experimental group was significantly higher than that in the case control group and healthy control group [ng/L: 314.14 (221.96, 469.56) vs. 39.08 (26.27, 76.85), 6.39 (3.35, 14.42), both P < 0.01]. Correlation analysis showed that serum GDF15 level in patients with septic cardiomyopathy were correlated with cardiac troponin I (cTnI, r = 0.295, P = 0.038), brain natriuretic peptide (BNP, r = 0.464, P = 0.009), sequential organ failure assessment (SOFA, r = 0.363, P = 0.010) and acute physiology and chronic health evaluation II (APACHE II, r = 0.316, P = 0.025). However, there was no significant correlation with white blood cell count, neutrophil count, lymphocyte count, procalcitonin, C-reactive protein, lactic acid, albumin and other clinical indicators (r values were 0.086, 0.123, -0.051, 0.055, 0.119, 0.199, -0.234, all P > 0.05). Serum GDF15 level, SOFA score and APACHE II score in the death group (30 cases) were significantly higher than those in the survival group [20 cases; GDF15 (ng/L): 382.93±159.61 vs. 289.66±158.46, SOFA: 10.00 (7.00, 12.00) vs. 6.00 (5.00, 9.50), APACHE II: 21.70±6.07 vs. 14.85±7.57, all P < 0.05]. Binary Logistic regression analysis showed that serum GDF15 was an independent risk factor for the onset of septic cardiomyopathy [odds ratio (OR) = 1.062, 95% confidence interval (95%CI) was 1.011-1.115, P = 0.016]. ROC curve showed that the area under the curve (AUC) of GDF15 for predicting septic cardiomyopathy was 0.971, the specificity was 100%, and the sensitivity was 90.3%. CONCLUSIONS: The serum GDF15 level of patients with septic cardiomyopathy is significantly increased, and GDF15 may be used as an effective biomarker for the early diagnosis of septic cardiomyopathy.

Direct comparison of the diagnostic performance of growth differentiation factor 8 in pediatric versus adult heart failure.

INTRODUCTION: Growth differentiation factor 8 (GDF-8, myostatin) has been proposed for the management of adult heart failure (HF). Its potential role in pediatric HF patients is unknown. We sought to investigate its diagnostic performance in adult versus pediatric HF. METHODS: GDF-8 was measured prospectively in pediatric and adult HF patients and in matching controls. HF was defined as the combination of typical symptoms and impaired left ventricular systolic function. Diagnostic performance for the detection of HF was evaluated by receiver operating characteristic (ROC) analysis. RESULTS: We enrolled 137 patients with HF (85 pediatric) and 67 healthy controls (47 pediatric). Neither pediatric nor adult HF patients had significantly different GDF-8 levels compared to the reference groups (3.53 vs 3.46 ng/mL, p = 0.334, and 6.87 vs 8.15 ng/mL, p = 0.063, respectively), but pediatric HF patients had significantly lower GDF-8 levels compared to adult patients (p < 0.001). ROC analysis showed no significant improvement adding GDF-8 to NT-proBNP, age and sex (area under the curve (AUC): 0.870 vs 0.868, p = 0.614) in children and neither in addition to age nor sex in adult HF patients (AUC: 0.74 vs 0.62, p = 0.110). CONCLUSION: GDF-8 did not accurately differentiate between HF patients and normal comparators in neither adults nor in children.

GDF-15: a novel biomarker of heart failure predicts short-term and long-term heart-failure rehospitalization and short-term mortality in patients with acute heart failure syndrome.

BACKGROUND: Acute heart failure (AHF) is a potentially life-threatening clinical syndrome, usually requiring hospital admission. Growth Differentiation Factor-15 (GDF-15) is a distant member of the transforming growth factor-ß. The increased expression of GDF-15 has been observed during heart failure (HF) and is associated with worse outcomes. However, the relationship between GDF-15 and AHF is not well understood with limited evidence among Thai patients. PURPOSE: Investigate the correlation between biomarker levels (measured upon admission and discharge) and short- and long-term adverse outcomes, encompassing all-cause mortality and heart-failure (HF) rehospitalization (at 30, 90, and 180 days, as well as throughout the entire follow-up duration) in individuals experiencing acute HF. METHODS: This is a prospective single-center investigation involving patients admitted for AHF. Biomarkers, including GDF-15, high-sensitivity troponin T (hsTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP), were assessed upon admission and discharge. Outcomes, including all-cause mortality and HF rehospitalization, were examined. Logarithmic transformations were applied to the biomarker variables for subsequent analysis. Univariate and multivariate analyses of cause-specific hazards were conducted using the Cox proportional hazards regression model, while subdistribution hazards were assessed using the Fine-Gray regression model to evaluate outcomes. RESULTS: A total of 84 patients were enrolled (mean age of 69 years, 52% females). The GDF-15 level significantly decreased during admission (median at the time of admission 6,346 pg/mL, median at the time of discharge 5,711 pg/mL; p < 0.01). All-cause mortality at 30 days and 180 days were 6.0% and 16.7%, respectively. HF rehospitalization at 30 days and 180 days were 15.5% and 28.6%, respectively. Univariate analysis showed that total orthoedema congestion score (p = 0.02) and admission GDF-15 level (p = 0.01) were associated with 30-day all-cause mortality, whereas hsTnT or NT-proBNP levels did not show significant associations. However, higher levels of NT-proBNP upon admission were associated with all-cause mortality when considering the entire follow-up period (p < 0.01). Both univariate and multivariate analyses demonstrated that lower discharge GDF-15 levels and a greater reduction in GDF-15 levels from admission to discharge were associated with a lower risk of 30-day rehospitalization. Similarly, univariate analysis revealed that a greater reduction in NT-proBNP levels from admission to discharge was associated with lower 30-day rehospitalization rates. At 180 days, a greater reduction in GDF-15 levels remained associated with lower hazards and incidence of rehospitalization. CONCLUSION: The significant decrease in Growth Differentiation Factor-15 (GDF-15) levels during hospitalization suggests its potential as a dynamic marker reflecting the course of AHF. Importantly, higher GDF-15 levels at admission were associated with an increased risk of 30-day all-cause mortality, highlighting its prognostic value in this patient population. Moreover, lower discharge GDF-15 levels, reductions in GDF-15 from admission to discharge, and decreases in NT-proBNP from admission to discharge were associated with a reduced risk of 30-day rehospitalization.

Exposure to green spaces, cardiovascular risk biomarkers and incident cardiovascular disease in older adults: The Seniors-Enrica II cohort.

INTRODUCTION: The impact of residential green spaces on cardiovascular health in older adults remains uncertain. METHODS: Cohort study involving 2114 adults aged ≥ 65 years without cardiovascular disease (CVD), residing in five dense municipalities (Prince et al., 2015) of the Madrid region and with detailed characterization of their socioeconomic background, health behaviors, CVD biological risk factors, and mental, physical, and cognitive health. Greenness exposure was measured using the Normalized Difference Vegetation Index (NDVI) at varying distances from participants' homes. Traffic exposure, neighborhood environment, neighborhood walkability, and socioeconomic deprivation at the census level were also assessed. Serum N-terminal pro-B-type natriuretic peptide (NT-ProBNP), high-sensitivity troponin T (hs-TnT), interleukin 6 (IL-6), and Growth Differentiation Factor 15 (GDF-15) were measured at baseline, and incident CVD events identified through electronic medical records (International Classification of Primary Care-2 codes K74, K75, K77, K90, and K92). RESULTS: After adjusting for sex, age, educational attainment, financial hardship and socioeconomic deprivation at the census level, an interquartile range (IQR) increase in NDVI at 250, 500, 750, and 1000 m around participants' homes was associated with mean differences in ProBNP of -5.56 % (95 %CI: -9.77; -1.35), -5.05 % (-9.58; -0.53), -4.24 % (-8.19, -0.19), and -4.16 % (-7.59; -0.74), respectively; and mean differences in hs-TnT among diabetic participants of -8.03 % (95 %CI: -13.30; -2.77), -9.52 % (-16.08; -2.96), -8.05 % (-13.94, -2.16) and -5.56 % (-10.75; -0.54), respectively. Of similar magnitude, although only statistically significant at 250 and 500 m, were the observed lower IL-6 levels with increasing greenness. GDF-15 levels were independent of NDVI. In prospective analyses (median follow-up 6.29 years), an IQR increase in residential greenness at 500, 750, and 1000 m was associated with a lower risk of incident CVD. The variables that contributed most to the apparent beneficial effects of greenness on CVD were lower exposure to traffic, improved cardiovascular risk factors, and enhanced physical performance. Additionally, neighborhood walkability and increased physical activity were notable contributors among individuals with diabetes. CONCLUSION: Increased exposure to residential green space was associated with a moderate reduction in CVD risk in older adults residing in densely populated areas.

Global longitudinal strain and plasma biomarkers for prognosis in heart failure complicated by diabetes: a prospective observational study.

BACKGROUND: Heart failure (HF) and diabetes are associated with increased incidence and worse prognosis of each other. The prognostic value of global longitudinal strain (GLS) measured by cardiovascular magnetic resonance (CMR) has not been established in HF patients with diabetes. METHODS: In this prospective, observational study, consecutive patients (n = 315) with HF underwent CMR at 3T, including GLS, late gadolinium enhancement (LGE), native T1, and extracellular volume fraction (ECV) mapping. Plasma biomarker concentrations were measured including: N-terminal pro B-type natriuretic peptide(NT-proBNP), high-sensitivity troponin T(hs-TnT), growth differentiation factor 15(GDF-15), soluble ST2(sST2), and galectin 3(Gal-3). The primary outcome was a composite of all-cause mortality or HF hospitalisation. RESULTS: Compared to those without diabetes (n = 156), the diabetes group (n = 159) had a higher LGE prevalence (76 vs. 60%, p < 0.05), higher T1 (1285±42 vs. 1269±42ms, p < 0.001), and higher ECV (30.5±3.5 vs. 28.8±4.1%, p < 0.001). The diabetes group had higher NT-pro-BNP, hs-TnT, GDF-15, sST2, and Gal-3. Diabetes conferred worse prognosis (hazard ratio (HR) 2.33 [95% confidence interval (CI) 1.43-3.79], p < 0.001). In multivariable Cox regression analysis including clinical markers and plasma biomarkers, sST2 alone remained independently associated with the primary outcome (HR per 1 ng/mL 1.04 [95% CI 1.02-1.07], p = 0.001). In multivariable Cox regression models in the diabetes group, both GLS and sST2 remained prognostic (GLS: HR 1.12 [95% CI 1.03-1.21], p = 0.01; sST2: HR per 1 ng/mL 1.03 [95% CI 1.00-1.06], p = 0.02). CONCLUSIONS: Compared to HF patients without diabetes, those with diabetes have worse plasma and CMR markers of fibrosis and a more adverse prognosis. GLS by CMR is a powerful and independent prognostic marker in HF patients with diabetes.

[Biomarkers of Inflammation in Predicting the Outcomes of Heart Failure of Ischemic Etiology: the Results of Factor Analysis].

AIM: To study the prognostic significance of inflammatory biomarkers in patients with chronic heart failure (CHF) and stenotic multivessel coronary atherosclerosis, with determination of the biomarker separate set that reflects subclinical inflammation and is associated with the development of cardiovascular complications during prospective observation. MATERIAL AND METHODS: A prospective observational study was conducted that included 80 patients with CHF and ischemic heart disease who were scheduled for coronary artery bypass grafting (CABG) during their current hospitalization. In addition to routine clinical laboratory tests, coagulation parameters were evaluated and the following inflammatory biomarkers were determined: neutrophil gelatinase-associated lipocalin (NGAL), growth/differentiation factor 15 (GDF-15), fibroblast growth factor 23 (FGF-23), transforming growth factor beta-1 (TGF-ß1), and high-sensitivity C-reactive protein. Also, the calculated neutrophil-to-lymphocyte ratio (N LR) was included in the analysis. Follow-up duration was at least 12 months (median 16 [13, 22] months). Statistical analysis of the data was performed with the IBM SPSS Statistics 21 software. RESULTS: The study presented results of a factor analysis of 10 inflammatory biomarkers in patients who were scheduled for CABG. One of the factors identified by the analysis included the levels of NGAL and GDF-15, N LR, and the level of fibrinogen in the blood in CHF patients with stenotic coronary atherosclerosis and was significantly associated with the death rate during prospective observation. Furthermore, this association remained significant even after adjustments for age, glomerular filtration rate, severity of heart and coronary insufficiency, and the presence of diabetes mellitus. CONCLUSION: In patients with CHF and stenotic coronary atherosclerosis, a set of inflammatory markers, including blood NGAL, GDF-15, N LR, and fibrinogen, can be combined into one factor reflecting subclinical inflammation. The value of this factor can be used to predict cardiovascular death in the long term after surgical myocardial revascularization.

Association of Cardiac Biomarkers in Combination With Cognitive Impairment After Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment is a severe and common clinical complication that constitutes a substantial global health burden. We aimed to evaluate the association of 3 cardiac biomarkers in combination with poststroke cognitive impairment and their prognostic significance. METHODS AND RESULTS: This prospective study included 566 patients with ischemic stroke. Cardiac biomarkers, including sST2 (soluble suppression of tumorigenicity-2 receptor), GDF-15 (growth differentiation factor-15), and NT-proBNP (N-terminal pro-B-type natriuretic peptide), were measured. Cognitive impairment was defined as a Mini-Mental State Examination score of <27 or a Montreal Cognitive Assessment score of <25 at 3 months after ischemic stroke. Odds of cognitive impairment 3 months after ischemic stroke increased with the number of elevated cardiac biomarkers (sST2, GDF-15, and NT-proBNP; Ptrend<0.001). The multivariable adjusted odds ratios (95% CIs) of cognitive impairment defined by the Mini-Mental State Examination and Montreal Cognitive Assessment were 2.45 (1.48-4.07) and 1.86 (1.10-3.14) for the participants with ≥2 elevated cardiac biomarkers, respectively, compared with those without any elevated cardiac biomarker. Additionally, higher cardiac biomarker scores were associated with an increased risk of cognitive impairment (Ptrend<0.05). Simultaneously adding all 3 cardiac biomarkers to the basic model with traditional risk factors significantly improved the risk prediction of Mini-Mental State Examination-defined cognitive impairment (net reclassification improvement=34.99%, P<0.001; integrated discrimination index=2.67%, P<0.001). Similar findings were observed using the Montreal Cognitive Assessment scores. CONCLUSIONS: An increased number of elevated novel cardiac biomarkers were associated with an increased odds of poststroke cognitive impairment, suggesting that a combination of these cardiac biomarkers may improve the risk prediction of cognitive impairment. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01840072.

Incremental values of AOPP, IL-6, and GDF15 for identifying arteriosclerosis in patients with obstructive sleep apnea.

BACKGROUND: The objective of this study was to determine the independent and incremental values of advanced oxidative protein product (AOPP), interleukin 6 (IL-6), and growth differentiation factor 15 (GDF15) in identifying arteriosclerosis in patients with obstructive sleep apnea (OSA). METHODS: A total of 104 individuals diagnosed with OSA by polysomnography were recruited in our study. Arteriosclerosis was defined by measuring the ultrafast pulse wave velocity of the carotid artery. Peripheral venous blood samples were collected to analyze the levels of AOPP, IL-6, and GDF15 utilizing commercially available enzyme-linked immunosorbent assays. RESULTS: Compared to OSA patients without arteriosclerosis, those with arteriosclerosis exhibited significantly higher levels of AOPP, IL-6, and GDF15. GDF15 remained significantly associated with arteriosclerosis even after accounting for clinical factors such as age, gender, body mass index, systolic blood pressure, fasting blood glucose, smoking, and the apnea-hypoxia index (AHI). GDF15 demonstrated the largest area under the curve (AUC) for identifying arteriosclerosis in OSA patients (AUC, 0.85 [0.77-0.94]). The logistic regression model, combining clinical factors and AHI, was enhanced by the inclusion of AOPP and IL-6 (Chi-square = 25.06), and even further improved when GDF15 was added (Chi-square = 50.74). The integrated discrimination index increased by 0.06 to 0.16 when GDF15 was added to the models including clinical factors, AOPP, and IL-6. CONCLUSIONS: This study verified the independent and incremental value of GDF15 in identifying arteriosclerosis in OSA patients, surpassing clinical risk factors and other serum biomarkers such as AOPP and IL-6.

Mitochondrial dysfunction and cisplatin sensitivity in gastric cancer: GDF15 as a master player.

Gastric cancer, a major global health concern, poses challenges in effective treatment, notably due to chemoresistance. This study investigates the role of growth/differentiation factor-15 (GDF-15) in mitochondrial dysfunction and its impact on cisplatin sensitivity in gastric cancer cells. In this issue of The FEBS Journal, Wang et al. demonstrate that GDF15 upregulation is associated with cisplatin insensitivity, mediated by the ATF4-CHOP pathway and reactive oxygen species-activated general control nonderepressible 2 [Wang S-F et al. (2023) FEBS J, https://doi.org/10.1111/febs.16992]. Connecting these insights, we explore the broader implications of GDF15 expression in the aging-cancer axis, particularly its involvement in cellular senescence and the senescence-associated secretory phenotype (SASP). This study suggests that GDF15 released by senescent cells could contribute to tumor progression, indicating potential avenues for therapeutic intervention by targeting senescent cells and their SASP. While the study provides valuable insights into mitigating cisplatin resistance, further research is crucial to fully understand the role of GDF15 in the tumor microenvironment and its potential feedback loops promoting tumorigenesis.

Fibroblasts in the Aged Pancreas Drive Pancreatic Cancer Progression.

Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging. SIGNIFICANCE: Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.

Preventing obesity, insulin resistance and type 2 diabetes by targeting MT1-MMP.

Obesity is one of the predominant risk factors for type 2 diabetes. Despite all the modern advances in medicine, an effective drug treatment for obesity without overt side effects has not yet been found. The discovery of growth and differentiation factor 15 (GDF15), an appetite-regulating hormone, created hopes for the treatment of obesity. However, an insufficient understanding of the physiological regulation of GDF15 has been a major obstacle to mitigating GDF15-centric treatment of obesity. Our recent studies revealed how a series of proteolytic events predominantly mediated by membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP14), a key cell-surface metalloproteinase involved in extracellular remodeling, contribute to the pathogenesis of metabolic disorders, including obesity and diabetes. The MT1-MMP-mediated cleavage of the GDNF family receptor-α-like (GFRAL), a key neuronal receptor of GDF15, controls the satiety center in the hindbrain, thereby regulating non-homeostatic appetite and bodyweight changes. Furthermore, increased activation of MT1-MMP does not only lead to increased risk of obesity, but also causes age-associated insulin resistance by cleaving Insulin Receptor in major metabolic tissues. Importantly, inhibition of MT1-MMP effectively protects against obesity and diabetes, revealing the therapeutic potential of targeting MT1-MMP for the management of metabolic disorders.

TGF-ß Isoforms and GDF-15 in the Development and Progression of Atherosclerosis.

The effect of oxidised lipoproteins on the endothelium, monocytes, platelets, and macrophages is a key factor in the initiation and development of atherosclerosis. Antioxidant action, lipoprotein metabolism, and chronic inflammation are the fields of research interest for better understanding the development of the disease. All the fields are related to inflammation and hence to the secretion of cytokines, which are being investigated as potential diagnostic markers for the onset of atherosclerosis. Pathways of vascular damage are crucial for the development of new laboratory readouts. The very early detection of endothelial cell damage associated with the onset of atherosclerosis, allowing the initiation of therapy, remains a major research goal. This article summarises the latest results on the relationship of tumour growth factor beta (TGF-ß) isoforms and growth differentiation factor 15 (GDF-15) to the pathogenesis of atherosclerosis: which cells involved in atherosclerosis produce them, which effectors stimulate their synthesis and secretion, how they influence atherosclerosis development, and the relationship between the levels of TGF-ß and GDF-15 in the blood and the development and extent of atherosclerosis.

Artesunate treats obesity in male mice and non-human primates through GDF15/GFRAL signalling axis.

Obesity, a global health challenge, is a major risk factor for multiple life-threatening diseases, including diabetes, fatty liver, and cancer. There is an ongoing need to identify safe and tolerable therapeutics for obesity management. Herein, we show that treatment with artesunate, an artemisinin derivative approved by the FDA for the treatment of severe malaria, effectively reduces body weight and improves metabolic profiles in preclinical models of obesity, including male mice with overnutrition-induced obesity and male cynomolgus macaques with spontaneous obesity, without inducing nausea and malaise. Artesunate promotes weight loss and reduces food intake in obese mice and cynomolgus macaques by increasing circulating levels of Growth Differentiation Factor 15 (GDF15), an appetite-regulating hormone with a brainstem-restricted receptor, the GDNF family receptor α-like (GFRAL). Mechanistically, artesunate induces the expression of GDF15 in multiple organs, especially the liver, in mice through a C/EBP homologous protein (CHOP)-directed integrated stress response. Inhibition of GDF15/GFRAL signalling by genetic ablation of GFRAL or tissue-specific knockdown of GDF15 abrogates the anti-obesity effect of artesunate in mice with diet-induced obesity, suggesting that artesunate controls bodyweight and appetite in a GDF15/GFRAL signalling-dependent manner. These data highlight the therapeutic benefits of artesunate in the treatment of obesity and related comorbidities.

Candesartan protects from cisplatin-induced kidney damage via the GDF-15 pathway.

OBJECTIVE: The aim of this study was to explore the protective effect of candesartan against cisplatin-induced kidney damage, with a specific focus on the growth differentiation factor 15 (GDF-15) pathway. MATERIALS AND METHODS: 24 adult female Wistar rats, with a weight range of 200-210 grams, were enrolled in the study. Eight rats were included as a normal control group and did not receive any medication. 16 rats were administered cisplatin at a dosage of 2.5 mg/kg/day twice a week for 4 weeks (total dose 20 mg/kg). Then, they were randomly divided into two groups and treated with 1 ml/kg/day tap water or 8 mg/kg/day candesartan via oral gavage daily for 4 weeks. At the end of the treatment period, animals were sacrificed, and their kidneys were assessed histologically. In addition, plasma malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), creatinine, and GDF-15 levels were assessed. RESULTS: Treatment with candesartan resulted in a significant rise in serum GDF-15 levels and a significant reduction in levels of serum MDA, TNF-α, IL-6, and creatinine compared to the cisplatin and saline group. Candesartan treatment effectively protected the kidney injury, and histopathological examinations of the kidneys confirmed these results. CONCLUSIONS: This study demonstrates that candesartan alleviates cisplatin-induced renal toxicity by further increasing GDF-15, downregulating inflammatory markers, and reducing oxidative stress.

Growth differentiation factor-15 may be a novel biomarker in pancreatic cancer: A review.

Pancreatic cancer is a highly malignant and invasive gastrointestinal tumor that is often diagnosed at an advanced stage with a poor prognosis and high mortality. Currently, carbohydrate antigen199(CA199) is the only biomarker approved by the FDA for the diagnosis of pancreatic cancer, but it has great limitations. Growth differentiation factor-15 (GDF-15) is expected to be a novel biomarker for the diagnosis, efficacy prediction, and prognosis assessment of pancreatic cancer patients. In this paper, we searched the keywords GDF-15, macrophage inhibitory cytokine-1 (MIC-1), CA199, pancreatic cancer, and tumor markers in PubMed and Web of Science, searched related articles, and read and analyzed the retrieved papers. Finally, we systematically described the characteristics, mechanism of action, and clinical value of GDF-15, aiming to provide help for the detection and treatment of pancreatic cancer.

Growth Differentiation Factor-15 Orchestrates Inflammation-Related Diseases via Macrophage Polarization.

Macrophage polarization is a critical determinant of disease progression and regression. Studies on macrophage plasticity and polarization can provide a theoretical basis for the tactics of diagnosis and treatment for macrophage-related diseases. These include inflammation-related diseases, such as sepsis, tumors, and metabolic disorders. Growth differentiation factor-15 (GDF-15) or macrophage inhibitory cytokine-1, a 25 kDa secreted homodimeric protein, is a member of the transforming growth factor-ß (TGF-ß) superfamily that is released in response to external stressors. GDF-15 regulates biological effects such as tumor occurrence, inflammatory response, tissue damage, angiogenesis, and bone metabolism. It has been shown to exert anti-inflammatory and pro-inflammatory effects in inflammation-related diseases. Moreover, inflammatory stimuli can induce GDF-15 expression in immune and parenchymal cells. GDF-15 exhibits a feedback inhibitory effect by inhibiting tumor necrosis factor-α secretion during the macrophage activation anaphase, suggesting that there may be a close association between the two. GDF-15 directly induces CD14+ monocytes to produce the M2-like macrophage phenotype, inhibits monocyte-derived macrophage for M1-like polarization, and induces monocyte-derived Mφ for M2-like polarization. This review summarizes the macrophage polarization mechanism of GDF-15 under the conditions of sepsis, colon cancer, atherosclerosis, and obesity. An improved understanding of the role and molecular mechanisms of action of GDF-15 could greatly elucidate the mechanism of disease occurrence and development and provide new ideas for targeted disease prevention and treatment. An advanced understanding of the function and molecular mechanisms of action of GDF-15 may be helpful in the assessment of its potential value as a therapeutic and diagnostic target.

Identification of molecular markers for predicting the severity of heart failure after AMI: An Olink precision proteomic study.

BACKGROUND: Acute myocardial infarction (AMI) still has a high incidence of varying degrees of heart failure (HF). The aim of this study is to identify new molecular markers for predicting the severity of HF after AMI. METHODS: We analyzed demographic indicators, past medical history, clinical indicators, major adverse cardiac events (MACEs) and molecular markers in patients with different Killip classifications after AMI. Olink proteomics was used to explore new molecular markers for predicting different severity of HF after AMI. RESULTS: Neutrophil count was the independent risk factors for in-hospital MACEs. Nineteen differentially expressed proteins (DEPs) increased significantly with increasing Killip classification. Five DEPs were also found to have an AUC (95 % CI) value greater than 0.8: GDF-15, NT-pro BNP, TNF-R2, TNF-R1 and TFF3. CONCLUSIONS: Neutrophil count, GDF-15, TNF-R2, TNF-R1 and TFF3 were closely related to the Killip classification of HF after AMI, which suggests that the inflammatory response plays an important role in the severity of HF after AMI and that regulating inflammation might become a new target for controlling HF.

GDF15 is a dynamic biomarker of the integrated stress response in the central nervous system.

AIM: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). METHODS: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. RESULTS: GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. CONCLUSIONS: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.