Growth Differentiation Factor Research Articles

GDF15 Analogues Acting as GFRAL Ligands.

Growth differentiation factor 15 (GDF15) is a TGF-β superfamily member involved in diverse physiological and pathological processes. It is expressed in various tissues and its circulating levels rise during exercise, aging, pregnancy, and conditions such as cancer, cardiovascular disease, and infections. The biological activities of GDF15, including anorexia and cachexia, are primarily mediated through the GFRAL receptor, localized in the brainstem and functioning via RET co-receptor recruitment. This signaling is crucial for energy homeostasis and nausea induction. Recent studies suggest a broader GFRAL distribution, potentially explaining GDF15's distinct roles. These findings sparked interest in leveraging GDF15-GFRAL pathways for therapeutic development. Two primary strategies include GDF15 analogues as GFRAL agonists for obesity treatment and GDF15-derived peptides as antagonists to counteract cancer-induced cachexia and related disorders. This review highlights advancements in understanding GDF15-GFRAL signaling and its implications, summarizing bioactive GDF15-derived molecules, their pharmacological applications, and offering insights into novel treatment avenues for GDF15-associated conditions.

Recombinant GDF11 Promotes Recovery in a Rat Permanent Ischemia Model of Subacute Stroke.

Background: Stroke remains a leading cause of death and disability, underscoring the urgent need for treatments that enhance recovery. Growth Differentiation Factor 11 (GDF11), a member of the TGF-β superfamily, is a circulating protein involved in cellular development and tissue repair. GDF11 has gained attention for its potential regenerative properties in aging and disease contexts, making it a candidate for stroke recovery therapies. Methods: The therapeutic benefits of recombinant GDF11 (rGDF11) were evaluated using a rat ischemic stroke model, in which focal cerebral infarcts were induced in 8 -10 week-old young adult male Sprague-Dawley rats by permanently occluding the proximal right middle cerebral artery. Rats received single or multiple doses of rGDF11 (0.1-4 mg/kg) or vehicle 24-72 hours post-injury. Sensorimotor functions were evaluated, and brain and serum samples were examined to determine mechanism of action and identify biomarkers, using immunofluorescence, target-specific ELISAs, and an aptamer-based proteomics platform. Results: We confirmed rGDF11 activity in vitro and in established in vivo mouse models of cardiac hypertrophy and glucose metabolism and assessed the efficacy of rGDF11 treatment in six preclinical stroke studies, using independent Contract Research Organizations with all study animals and treatment groups blinded. All six studies revealed consistent improvement of sensorimotor outcomes with rGDF11. rGDF11-treated rats showed increased cortical vascularization and radial glia in the ventricular zone. Serum analysis revealed rGDF11 dose-dependent decreases in C-reactive protein and identified novel pharmacodynamic biomarkers and pathways associated with potential mechanisms of action of rGDF11. Conclusion: These results demonstrate that systemically delivered rGDF11 enhances neovascularization, reduces inflammation, promotes neurogenesis, and improves sensorimotor function post-injury in a rat model of ischemic stroke. More importantly, these data define an optimized and clinically-feasible rGDF11 dosing regimen for therapeutic development in ischemic stroke and identify a panel of candidate pharmacodynamic and mechanistic biomarkers to support clinical translation.

Identification of growth differentiation factor 15 as an early predictive biomarker for metabolic dysfunction-associated steatohepatitis: A nested case-control study of UK Biobank proteomic data.

This study aims to determine the predictive capability for metabolic dysfunction-associated steatohepatitis (MASH) long before its diagnosis by using six previously identified diagnostic biomarkers for metabolic dysfunction-associated steatotic liver disease (MASLD) with proteomic data from the UK Biobank. A nested case-control study comprising a MASH group and three age- and sex-matched control groups (metabolic dysfunction-associated steatosis, viral hepatitis and normal liver controls) was conducted. Olink proteomics, anthropometric and biochemical data at baseline levels were obtained from the UK Biobank. The baseline levels of CDCP1, FABP4, FGF21, GDF15, IL-6 and THBS2 were analysed prospectively to determine their predictive accuracy for subsequent diagnosis with a mean lag time of over 10 years. At baseline, GDF15 demonstrated the best performance for predicting MASH occurrence at 5 and 10 years later, with AUCs of 0.90 at 5 years and 0.86 at 10 years. A predictive model based on four biomarkers (GDF15, FGF21, IL-6 and THBS2) showed AUCs of 0.88 at both 5 and 10 years. Furthermore, a protein-clinical model that included these four circulating protein biomarkers along with three clinical factors (BMI, ALT and TC) yielded AUCs of 0.92 at 5 years and 0.89 at 10 years. GDF15 at baseline levels outperformed other individual circulating protein biomarkers for the early prediction of MASH. Our data suggest that GDF15 and the GDF15-based model may be used as easy-to-implement tools to identify patients with high risks of developing MASH at a mean lag time of over 10 years.

Growth differentiation factor-15 and N-terminal pro-BNP in acute heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) continues to be an increasingly common health problem associated with a high mortality rate. Elevated levels of Growth differentiation factor-15 (GDF15) and N-terminal pro-brain natriuretic peptide (NT-proBNP) are reportedly associated with poor clinical outcomes in a broad range of cardiovascular diseases. The aim of the present study was to examine the effect of the combined assessment of these markers on clinical outcomes in patients with HFpEF. This study is the prospective observational study. We measured the serum levels of GDF15 and NT-proBNP in 643 patients (mean age 73±12, 42% females). All patients were prospectively followed up for a median period of 1998days. Total 132 HF-related events and 88 all-cause deaths occurred during the follow-up period. Multivariate Cox proportional hazards regression analysis demonstrated that both serum GDF15 and NT-proBNP levels were independently associated with HF-related events after adjustment for confounding risk factors (GDF15: hazard ratio, 1.72; 95% confidence interval, 1.35-2.19; P<0.0001 and NT-proBNP: hazard ratio, 1.63; 95% confidence interval, 1.25-2.13; P=0.0003). Serum GDF15 levels improved the prediction capacity for HF-related events (0.7405 vs. 0.7190; P=0.0422), with a significant net reclassification index (0.2724) and integrated discrimination improvement (0.0246). The C indices of GDF15 for HF-related events and all-cause deaths were significantly larger than those of NT-proBNP in men (HF-related events: 0.7389 vs. 0.6721; P=0.0393, and all-cause deaths: 0.6922 vs.0.6109; P=0.0262) but not in women. The combination of GDF15 and NT-proBNP levels stratified patients with HFpEF, identifying those at a high risk for HF-related events and all-cause deaths. Serum GDF15 could be an additional prognostic information to NT-proBNP in patients with HFpEF. The prognostic abilities of serum GDF15 and NT-proBNP differed according to sex. These markers were the feasible markers for patients with HFpEF, identifying those at a high risk for HF-related events and all-cause deaths.

CircMETTL6 Suppresses Ovarian Cancer Cell Growth and Metastasis Through Inhibition of GDF15 Transcription by Disrupting the NONO-POLR2A Complex.

Circular RNAs (circRNAs) are a distinctive class of non-coding RNAs with covalent closed-loop structure, lacking 5' caps and 3' poly(A) tails. These molecules are prevalent in eukaryotes and play keyroles in cancer. Here, the function of a new circRNA, circMETTL6, in ovarian cancer is identified and investigated. The prognostic significance of circMETTL6 is assessed using RNA in situ hybridization. Functional studies involving circMETTL6 overexpression are performed both in vitro and in vivo. Mechanistic investigations are performed using RNA-seq, RNA pull-down, RNA immunoprecipitation, co-immunoprecipitation, chromatin immunoprecipitation, protein degradation assay and dual-luciferase reporter assays. circMETTL6 is significantly downregulated in ovarian cancer, and its lower expression correlates with worse prognosis. Overexpression of circMETTL6 significantly inhibited proliferation, migration, and invasion of ovarian cancer cell in vitro, as well as tumor growth and metastasis in vivo. Mechanistically, circMETTL6 recruited the non-POU domain containing octamer binding protein (NONO) by binding to its Coiled-coil domain and disrupted its binding with RNA polymerase II subunit A (POLR2A), and consequently inhibiting growth differentiation factor 15 (GDF15) transcription, thereby suppressing ovarian cancer progression. These findings establish circMETTL6 as a novel tumor suppressor in ovarian cancer. Targeting the circMETTL6/NONO/GDF15 axis presents a potential therapeutic avenue for ovarian cancer treatment.

Patients with chronic heart failure and predominant left atrial versus left ventricular myopathy

BackgroundLeft atrial (LA) and ventricular (LV) functional impairment often co-exist in patients with heart failure (HF). However, some patients with HF have a disproportionate LA or LV dysfunction. We aimed to characterize patients with predominant LA and LV myopathy in a cohort of patients with chronic HF across the spectrum of LV ejection fraction (LVEF).MethodsFrom a nationwide, prospective, multi-center, observational HF cohort, transthoracic echocardiographic examination was performed on each patient. LA reservoir strain and LV global longitudinal strain (LVGLS) were measured using dedicated software of the two-dimensional speckle tracking analysis to evaluate LA and LV function and to define the myopathy.ResultsA total of 374 patients with chronic HF (mean age 58.9±11.5 years, 20% female, mean LVEF 39±17%) were included. By calculating the residuals from the linear regression between LA reservoir and LVGLS, we identified 47 patients with predominant LA myopathy, 271 patients with balanced LA/LV and 56 patients with predominant LV myopathy. Patients with predominant LA myopathy were older, had a higher prevalence of atrial fibrillation (AF), diabetes, higher plasma concentrations of N-terminal pro-B-type natriuretic peptide (NT-proBNP), Growth differential factor 15(GDF15), high sensitivity Troponin T (hs-TNT) as well as more dilated left and right atria, and worse right atrial function compared to other groups (all p-values < 0.05). Using multivariable logistic regression adjusted for LVEF and LA size, independent predictors of predominant LA myopathy were the presence of AF, diabetes, and higher GDF15, whereas absence of diabetes independently predicted predominant LV myopathy. Patients with predominant LA myopathy group had a lower probability of survival than the other groups (Log rank p-value = 0.01).ConclusionWhile most patients with HF have balanced LA/LV myopathy, those with predominant LA myopathy are characterized by older age, more AF, more diabetes, higher circulating biomarkers of cardiac stress and injury, and worse outcomes.

The effect of cachexia and anti-cancer therapies on GDF-15 levels in patients with pancreatic adenocarcinoma.

778 Background: Growth differentiation factor 15 (GDF15) is a novel biomarker in the setting of pancreatic adenocarcinoma (PDAC). Preliminary studies have found that downstream effects of GDF-15 promote the progression of pancreatic cancer. PDAC has a high prevalence of cachexia which is commonly treated with enzyme supplementation and nutritional support. Platinum-based therapies often used to treat PDAC increase the likelihood of patients experiencing cachexia. The purpose of this study was to observe the GDF-15 levels in respect to weight change of PDAC patients being treated with cachexia and anti-cancer therapies. Methods: Serum and Plasma samples were collected from locally advanced and advanced PDAC patients on 5 IRB approved studies from 2014-2024. Samples were analyzed using the R-PLEX Human GDF-15 Antibody Set. The study objective was compared using two-sample paired t-tests and Pearson correlation matrices. Elevated GDF-15 was determined as &gt;1500 pg/mL. Results: Samples from 73 patients were utilized for this study (63% female; median age: 69; BMI: 23.31±4.96 kg/m 2 ). At baseline 71.8% (46/64) had elevated GDF-15, at Cycle 3 76% (25/33), and at Cycle 5 86% (25/29). In the total sample set, there was a slight negative correlation in the change of weight (-1.75 kg, p = 0.013) and GDF-15 (577.5 pg/mL, p = 0.278) from C1 to C3 (r = -0.185, p = 0.366). There was a slight negative correlation (r = -0.44, p = 0.076) in the difference of weight and GDF-15 from C1 to C3 in patients receiving chemotherapy. A strong negative correlation was observed in the change of GDF15 and weight from C1D1 to C1D8 in patients treated with platinum-based therapy (r = -0.530, p = 0.212) and a weak negative correlation (r = -0.421, p = 0.065) for patients with non-platinum-based therapy. There was a strong positive association (r = 0.993, p &lt; 0.01) between the change in weight and GDF-15 from C1 to C5 in patients not receiving chemotherapy. There was no significant decrease in GDF-15 levels across the patients at all time points. Conclusions: Despite cachexia and anti-cancer treatment, the GDF-15 levels of PDAC patients continue to remain elevated in consecutive blood draws. Further research in GDF-15 kinetics is warranted. Clinical trial information: NCT02400398 , NCT03207724 , NCT04098237 , NCT05336266 , NCT04634539 . Weight and GDF-15 levels across different chemotherapy regimens. Baseline Cycle 1 Cycle 3 Cycle 5 BMI (kg/m2) Weight (kg) GDF15 (pg/mL) Weight (kg) GDF15 (pg/mL) Weight (kg) GDF15 (pg/mL) Chemotherapy 23.21 63.83 3243.25 63.44 3498.76 60.14 3201.33 No Chemotherapy 23.77 65.85 3113.73 62.32 2949.56 71.05 2944.54 Platinum Based 20.88 59.89 6527.78 51.7 3600.87 58.1 5152.50 Non-platinum-based chemotherapy 23.86 64.89 2442.14 64.67 3487.41 60.39 2957.43

Effect of ketorolac on serum GDF-15 and IL-8 in patients with pancreatic cancer with cachexia.

713 Background: Cancer cachexia deteriorates the quality of life, chemotherapy tolerance and survivability of pancreatic cancer (PC) patients. Although a prevalent condition affecting PC patients, there are no approved therapies for cachexia and its mechanism of action is poorly understood. Elevated growth differentiation factor 15 (GDF-15), a stress-induced cytokine, has been associated with the pathogenesis of cachexia. Similarly, prior studies have displayed positive correlations between the proinflammatory factor interleukin-8 (IL-8) and PC cachexia. This abstract focuses on the exploratory endpoints (serum GDF-15 and IL-8 levels) of a feasibility trial on ketorolac as a treatment for PC cachexia. Methods: Patients took ketorolac 10 mg PO QID for 5 consecutive days, with weights measured on Day 1 (D1) and Day 6 (D6). Serum cytokines were drawn on D1 and D6. IL-8 was measured using a HDF15 assay (Eve Technologies). GDF-15 was measured using a human R-plex GDF-15 assay. Activity (e.g., number of steps) was measured via Fitbit. Differences in weight, activity, GDF-15, and IL-8 were analyzed using two-sample paired t-tests. Results: Twenty-nine patients were enrolled, of which 19 were evaluable. Median age was 70, 47.4% (9/19) were female, and 94.7% (18/19) were adherent with ketorolac. Statistically significant increases in both weight per baseline BMI and activity were observed from D1 to D6 (0.0716±0.1079 kg/BMI, p=0.012; 1423±2477 steps, p=0.0221). Of the 19 evaluable patients, 16 patients provided complete D1 and D6 pairs of serum cytokines. From D1 to D6, the mean GDF-15 level decreased by 277.5 pg/mL (p=0.529) and mean IL-8 decreased by 65.13 pg/mL (p=0.103). In all patients who gained weight (n=14), a trend toward reduced IL-8 from D1 to D6 was observed (79.57±39.57 pg/mL, p=0.065). Similarly, for patients who gained ≥ 1-kg from D1 to D6 (n=10), a trend toward reduced GDF-15 was observed (951.2±482.3 pg/mL, p=0.080). Patients with increased activity from D1 to D6 (n=12) had mean reductions of 157.7 pg/mL (p=0.643) and 70.17 pg/mL (p=0.179) in GDF-15 and IL-8, respectively. Conclusions: Given the growing literature suggesting associations between inflammatory cytokines and cancer cachexia, it is critical to investigate treatments that may possibly alter cytokine levels. Although our findings suggest that ketorolac aids in weight gain and increased activity, larger sample sizes are needed to determine whether these differences are related to reductions of specific serum cytokines. However, given reductions that trended towards significance for both GDF-15 and IL-8 serum levels within subsets of patients that gained weight on ketorolac, further studies investigating these cytokines are warranted to hopefully provide insight on the mechanistic action of ketorolac in cachexia. Clinical trial information: NCT05336266 .

Lower circulating mitochondrial DNA and increased mitokines suggest significant mitochondrial dysfunction in systemic lupus erythematosus with renal involvement

BackgroundSLE is associated with significant morbidity, especially in the case of renal involvement. Mitochondrial dysfunction plays a significant role in SLE and may be assessed by measuring mitochondrial DNA (mtDNA)...

Associations Between Growth Differentiation Factor 15 and Anxiety and Depression in the General Population: The Akershus Cardiac Examination 1950 Study.

Several studies suggest a bidirectional association between inflammation, and anxiety and depression. Elevated inflammatory cytokines generate and aggravate neuroinflammation, which may play a part in developing psychological symptoms. Growth differentiation factor 15 (GDF-15) is a novel biomarker possibly reflecting fibrosis and inflammation. The aim of the current study was to investigate the associations between levels of GDF-15 and symptoms of anxiety and depression in the general population. We measured GDF-15 in middle-aged persons participating in the Akershus Cardiac Examination 1950 Study. Symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS), with HADS ≥8 denoting significant symptoms. We used multivariable regression analysis to assess the associations between GDF-15 and HADS, adjusting for levels of C-reactive protein (CRP), demographics, and comorbidities. A total of 3638 participants had valid assessment of HADS and measurements of GDF-15 and CRP. The mean age was 63.9 (SD 0.65) years, and 48.8% were women. In adjusted models, levels of GDF-15 were associated with the continuous HADS-D score (β = 0.27, 95% confidence interval [CI] = 0.12 to 0.43) and HADS-D score ≥8 (odds ratio = 1.41, 95% CI = 1.12 to 1.78), but not with the continuous HADS-A score (β = 0.06, 95% CI = -0.12 to 0.24) or HADS-A score ≥8 (odds ratio = 1.06, 95% CI = 0.88 to 1.27). Levels of GDF-15 are independently associated with symptoms of depression in the general population. Our results reinforce the notion that inflammation may be a contributing factor for the development of clinical depression. ClinicalTrials.gov identifier NCT01555411 (Akershus Cardiac Examination [ACE] 1950 Study), https://clinicaltrials.gov/study/NCT01555411.

GDF-15 improves the predictive capacity of Steatotic liver disease non-invasive tests for incident morbidity and mortality risk for cardio-renal-metabolic diseases and malignancies

Background & aimsNoninvasive tools (NITs) are currently used to stratify the risk of having or developing hepatic steatosis or fibrosis. Their performance and a proteomic-enabled improvement in forecasting long-term cardio-renal-metabolic morbidity, malignancies, as well as cause-specific and all-cause mortality, are lacking. Therefore, the performance of established NITs needs to be investigated in identifying cardio-renal-metabolic morbidity, malignancies, cause-specific and overall mortality and improve their performance with novel, proteomic-enabled NITs, including growth differentiation factor 15 (GDF-15), allowing multipurpose utilization. Methods502,359 UK Biobank participants free of the study outcomes at baseline with a 14-year median follow-up were grouped into three categories: a) general population, b) potentially metabolic dysfunction-associated steatotic liver disease (MASLD) population, c) individuals with type 2 diabetes mellitus. The investigated NITs include Aspartate aminotransferase to Platelet Ratio Index (APRI), Fibrosis 4 Index (FIB-4), Fatty Liver Index (FLI), Hepatic Steatosis Index (HSI), Lipid Accumulation Product (LAP), and metabolic dysfunction–associated fibrosis (MAF-5) score. ResultsAdding GDF-15 to the existing NITs led to significantly increased prognostic performance compared to the traditional NITs in almost all instances, reaching substantially high C-indices, ranging between 0.601 and 0.808, with an overall >0.2 improvement in C-index. Overall, with the GDF-15 enhanced NITs, up to more than seven times fewer individuals need to be screened to identify more incident cases of adverse outcomes compared to the traditional NITs. The cumulative incidence of all outcomes, based on the continuous value percentiles of NITs, is increasing exponentially in the upper quintile of the GDF-15 enhanced NITs. ConclusionsThe herein-developed GDF-15 enhanced indices demonstrate higher screening effectiveness and significantly improved prognostic abilities, which are reduced to practice through an easy-to-use web-based calculator tool (https://clinicalpredictor.shinyapps.io/multimorbidity-mortality-risk/).

GDF15-GFRAL signaling drives weight loss and lipid metabolism in mouse model of amyotrophic lateral sclerosis.

Weight loss is a common early sign in amyotrophic lateral sclerosis (ALS) patients and negatively correlates with survival. In different cancers and metabolic disorders, high levels of serum growth differentiation factor 15 (GDF15) contribute to a decrease of food intake and body weight, acting through GDNF family receptor alpha-like (GFRAL). Here we report that GDF15 is highly expressed in the peripheral blood of ALS patients and in the hSOD1G93A mouse model and that GFRAL is upregulated in the brainstem of hSOD1G93A mice. We demonstrate that the localized GFRAL silencing by shRNA in the area postrema/nucleus tractus solitarius of hSOD1G93A mice induces weight gain, reduces adipose tissue wasting, ameliorates the motor function and muscle atrophy and prolongs the survival time. We report that microglial cells could be involved in mediating these effects because their depletion with PLX5622 reduces brainstem GDF15 expression, weight loss and the expression of lipolytic genes in adipose tissue. Altogether these results reveal a key role of GDF15-GFRAL signaling in regulating weight loss and the alteration of and lipid metabolism in the early phases of ALS.

Sex-specific associations of neurodegeneration and inflammatory biomarkers with intrinsic capacity in older adults: Findings from the 4-year longitudinal Multidomain Alzheimer's Prevention Trial (MAPT).

This four-year longitudinal study investigated whether the cross-sectional and longitudinal associations of inflammation-related and neurodegenerative-related blood biomarkers with intrinsic capacity differ according to sex. The sample comprised 1117 older adults (<70years, 63.8% females) from the Multidomain Alzheimer's Prevention Trial (MAPT). The domains of intrinsic capacity were operationalized as cognition (Mini-Mental State Examination), locomotion (Short Physical Performance Battery), vitality (Handgrip Strength), and psychological well-being (Geriatric Depression Scale), each scaled from 0 (worst intrinsic capacity possible) to 100 (best intrinsic capacity possible). Plasma biomarkers included interleukin 6 (picograms per milliliter), growth differentiation factor-15 (picograms per milliliter), tumor necrosis factor receptor 1 (picograms per milliliter), neurofilament light chain (picograms per milliliter), progranulin (nanograms per milliliter), and amyloid-beta ratio. Linear mixed models were analyzed to examine whether sex modified the cross-sectional and longitudinal association between biomarkers and intrinsic capacity. No significant interaction effect was observed at baseline. Longitudinal analyses revealed a significant interaction between sex and interleukin 6 (p=.005), such that higher levels of interleukin 6 tended to be associated with a faster decline in intrinsic capacity for males (B=-0.385; p=.055; 95% CI=-0.778; 0.008) but not for females (B=0.287; p=.041; 95% CI=0.011; 0.563). The other biomarkers had no sex-dependent associations with intrinsic capacity. A potential sex-dependent effect of the inflammatory status on intrinsic capacity must be further investigated. Clinical trial registration with ClinicalTrials.govNCT00672685.

GDF10 promotes rodent cardiomyocyte maturation during the postnatal period.

Cardiomyocytes and cardiac fibroblasts undergo coordinated maturation after birth, and cardiac fibroblasts are required for postnatal cardiomyocyte maturation in mice. Here, we investigate the role of cardiac fibroblast-expressed Growth Differentiation Factor 10 (GDF10) in postnatal heart development. In neonatal mice, Gdf10 is expressed specifically in cardiac fibroblasts, with its highest expression coincident with the onset of cardiomyocyte cell cycle arrest and transition to hypertrophic growth. In neonatal rat ventricular myocyte (NRVM) cultures, GDF10 treatment promotes cardiomyocyte maturation indicated by increased binucleation, downregulation of cell cycle progression genes, and upregulation of cell cycle inhibitor genes. GDF10 treatment leads to an increase in cardiomyocyte cell size, together with increased expression of mature sarcomeric protein isoforms and decreased expression of fetal cardiac genes. RNAsequencing of GDF10-treated NRVM shows an increase in the expression of genes related to myocardial maturation, including upregulation of sodium and potassium channel genes. In vivo, loss of Gdf10 leads to a delay in myocardial maturation indicated by decreased cardiomyocyte cell size and binucleation, as well as increased mitotic activity, at postnatal (P) day 7. Further, induction of mature sarcomeric protein isoform gene expression is delayed, and expression of cell cycle progression genes is prolonged. However, by P10, indicators of cardiomyocyte maturation and mitotic activity are normalized in Gdf10-null hearts relative to controls. Together, these results implicate GDF10 as a novel crosstalk mediator between cardiomyocytes and cardiac fibroblasts, which is required for appropriate timing of cardiomyocyte maturation steps including binucleation, hypertrophy, mature sarcomeric isoform gene expression, and cell cycle arrest in the postnatal period.

The role and molecular mechanism of GDF5 in regulating cell migration and angiogenesis via the Hippo-YAP signaling pathway in colorectal cancer.

292 Background: Distant metastasis is a leading cause of poor prognosis and mortality in colorectal cancer (CRC) patients, with angiogenesis playing a crucial role in tumor progression. The TGF-β superfamily has been shown to significantly influence tumor angiogenesis, yet the biological function and molecular mechanism of Growth Differentiation Factor 5 (GDF5), a member of this superfamily, remain unexplored in CRC. Given that the efficacy of current anti-angiogenic therapies is limited to a subset of patients, identifying new therapeutic targets involved in tumor angiogenesis is of great clinical importance. GDF5, with its potential role in angiogenesis regulation, presents a promising candidate to bridge this therapeutic gap. Methods: In this study, we analyzed GDF5 expression in CRC tissue samples using both the TCGA dataset and samples from our center, revealing significantly lower GDF5 expression in tumors compared to adjacent normal tissues. Moreover, GDF5 downregulation correlated with lymph node metastasis and disease recurrence. Functional assays in vitro demonstrated that GDF5 overexpression reduced tumor cell migration and invasion, while its knockdown produced the opposite effect. Co-culture assays showed that GDF5 knockdown significantly enhanced endothelial cell migration and angiogenesis, whereas overexpression diminished these effects. Additionally, F-actin cytoskeletal staining indicated that GDF5 overexpression led to cytoskeletal remodeling in endothelial cells. Mechanistically, we found that GDF5 overexpression in tumor cells downregulated the epithelial-mesenchymal transition (EMT) marker Slug and upregulated E-cadherin, while downregulating N-cadherin. In endothelial cells, GDF5 inhibited the Hippo-YAP signaling pathway, increasing YAP phosphorylation and reducing nuclear YAP levels. Conversely, GDF5 knockdown suppressed YAP phosphorylation and promoted its nuclear translocation. Results: Our findings demonstrate that GDF5 functions as a tumor suppressor in CRC by regulating cell migration and angiogenesis. This study reveals that GDF5 exerts its anti-cancer effects by modulating both EMT in tumor cells and cytoskeletal changes in endothelial cells, leading to the inhibition of the Hippo-YAP signaling pathway and reduced angiogenic potential. These results identify GDF5 as a promising new target for anti-angiogenic therapy in CRC, offering potential avenues for improving treatment strategies in patients resistant to current therapies. Conclusions: GDF5 acts as a tumor suppressor in colorectal cancer by inhibiting cell migration and angiogenesis through modulation of the Hippo-YAP signaling pathway, making it a promising therapeutic target for anti-angiogenic treatment in patients resistant to current therapies.

Mechanisms and pharmacotherapy of cancer cachexia-associated anorexia.

Cachexia is a multifactorial metabolic syndrome characterized by weight and skeletal muscle loss caused by underlying illnesses such as cancer, heart failure, and renal failure. Inflammation, insulin resistance, increased muscle protein degradation, decreased food intake, and anorexia are the primary pathophysiological drivers of cachexia. Cachexia causes physical deterioration and functional impairment, loss of quality of life, lower response to active treatment, and ultimately morbidity and mortality, while the difficulties in tackling cachexia in its advanced phases and the heterogeneity of the syndrome among patients require an individualized and multidisciplinary approach from an early stage. Specifically, strategies combining nutritional and exercise interventions as well as pharmacotherapy that directly affect the pathogenesis of cachexia, such as anti-inflammatory, metabolism-improving, and appetite-stimulating agents, have been proposed, but none of which have demonstrated sufficient evidence to date. Nevertheless, several agents have recently emerged, including anamorelin, a ghrelin receptor agonist, growth differentiation factor 15 neutralization therapy, and melanocortin receptor antagonist, as candidates for ameliorating anorexia associated with cancer cachexia. Therefore, in this review, we outline cancer cachexia-associated anorexia and its pharmacotherapy, including corticosteroids, progesterone analogs, cannabinoids, anti-psychotics, and thalidomide which have been previously explored for their efficacy, in addition to the aforementioned novel agents, along with their mechanisms.

Prospective Investigation Unravels Plasma Proteomic Links to Dementia.

Investigating plasma proteomic signatures of dementia offers insights into its pathology, aids biomarker discovery, supports disease monitoring, and informs drug development. Here, we analyzed data from 48,367 UK Biobank participants with proteomic profiling. Using Cox and generalized linear models, we examined the longitudinal associations between proteomic signatures and dementia-related phenotypes. Mendelian randomization analysis was employed to identify causal associations, and machine learning algorithms were applied to develop protein-based models for dementia prediction. We identified 74 proteins significantly associated with the risk of various types of dementia and cognitive functions after Bonferroni correction. Among these, strong associations were observed for growth/differentiation factor 15 (GDF15), glial fibrillary acidic protein (GFAP), and neurofilament light polypeptide (NEFL), across all types of dementia. Additionally, 15 proteins demonstrated significant associations with neuroimaging-defined dementia endophenotypes. Two-sample Mendelian randomization analyses further substantiated causal relationships between dementia-associated proteins and Alzheimer's disease, particularly involving GDF15, proto-oncogene tyrosine-protein kinase receptor Ret (RET), and GFAP. Moreover, we identified three protein modules associated with dementia, primarily linked to immune system processes, angiogenesis, and energy metabolism, providing insights into potential biological pathways underlying the disease. Furthermore, we proposed a ten-protein panel capable of forecasting dementia over a median follow-up period of 8.6 years, achieving an area under the curve (AUC) of 0.857 (95% confidence interval (CI), 0.837-0.876). Our results revealed dementia-associated plasma proteomic signatures, and their causal relationships, notably GDF15-RET signaling with Alzheimer's disease, and proposed a promising protein panel for high-risk dementia screening.

Growth differentiation factor-15 as a biomarker for intensive care unit-acquired weakness: a meta-analysis

Growth differentiation factor-15 as a biomarker for intensive care unit-acquired weakness: a meta-analysis

The Effect of Anti-Activin Receptor Type IIA and Type IIB Antibody on Muscle, Bone and Blood in Healthy and Osteosarcopenic Mice.

Anti-Activin Receptor Type IIA and Type IIB antibody (αActRIIA/IIB ab) is a recently developed drug class that targets the activin receptor signalling pathway. Inhibition of receptor ligands (activins, myostatin, growth differentiation factor 11, etc.) can lead to skeletal muscle hypertrophy, bone formation, and increased haematopoiesis. Despite the αActRIIA/IIB ab, bimagrumab, having progressed to clinical trials, two crucial questions about αActRIIA/IIB ab therapy remain: Does αActRIIA/IIB ab influence bone metabolism and bone strength similarly to its generic classmates (activin receptor-based ligand traps)? Does αActRIIA/IIB ab affect red blood cell parameters, thereby increasing the risk of thromboembolism, similar to its generic classmates? Therefore, the aim of the present study was to investigate the therapeutic potential of αActRIIA/IIB ab in a mouse model of concurrent sarcopenia and osteopenia and to investigate the effect on bone and haematopoiesis in more detail. In C57BL/6JRj mice, combined sarcopenia and osteopenia were induced locally by injecting botulinum toxin A into the right hindlimb, resulting in acute muscle paresis. Immediately after immobilization, mice received twice-weekly intraperitoneal injections with αActRIIA/IIB ab (10 mg/kg) for 21 days, after which they were sacrificed. Muscle mass, skeletal muscle fibre size and Smad2 expression were analysed in the rectus femoris and gastrocnemius muscles. Bone mass and bone microstructure were analysed in the trabecular bone at the distal femoral metaphysis, while the cortical bone was analysed at the femoral mid-diaphysis. In a substudy, the effect on haematopoiesis was explored 2 and 7 days after a single αActRIIA/IIB ab (30 mg/kg) injection in C57BL/6JRj mice. αActRIIA/IIB ab caused a large increase in muscle mass in both healthy (+21%) and immobilized (sarcopenic and osteopenic) (+12%) mice. Furthermore, αActRIIA/IIB ab increased trabecular bone (bone volume fraction) for both healthy (+65%) and immobilized (+44%) mice. For cortical bone, αActRIIA/IIB ab caused a small, but significant, increase in bone area (+6%) for immobilized mice, but not for healthy mice. Treatment with αActRIIA/IIB ab did not change red blood cell count, haemoglobin concentration or mean cell volume after either 2 or 7 days. Treatment with αActRIIA/IIB ab caused a significant increase in both skeletal muscle mass and bone parameters in both healthy and immobilized mice, suggesting a potential in the treatment of concurrent osteopenia and sarcopenia. Interestingly, the bone anabolic effect of the treatment was much more pronounced on trabecular bone than on cortical bone. There was no pronounced effect of short-term treatment on haematopoiesis.

Biomarkers associated with progression of infantile hemangioma: Exploratory study.

To identify patients with infantile hemangioma (IH) in need of early-stage treatment in this multicenter, prospective, observational study, we investigated the potential of plasma cytokines as a clinically useful marker. Plasma samples were collected at three time points from 41 patients with infantile hemangioma: baseline (days 14-60 after delivery), visit 1 (days 61-150, the proliferative phase), and visit 2 (days 151-395, the involuting phase). With a twofold or more increase in tumor volume during the baseline-visit 1 period regarded as progression, progression was seen in 15 cases (36.6%). In the first step, cytokine arrays were performed using plasma samples in five progressive and five non-progressive cases. Plasma levels of six cytokines at baseline were selected for a prediction marker of change in tumor volume during baseline-visit 1. Validation enzyme-linked immunosorbent assay indicated that the baseline growth differentiation factor 1 (GDF1) concentration tended to correlate with the proliferation ratio of total lesions or target lesion during baseline-visit 1, although without statistical significance. However, the plasma GDF1 concentrations were significantly lower in patients with a fourfold or more increase in total volume (p = 0.013). Furthermore, changes in plasma interleukin (IL)-7Rα levels showed a statistically significant inverse correlation between volume change of the target lesion during baseline-visit 1 (p = 0.0069). Our results suggest that plasma GDF1 measurement after birth is a useful marker for progression of IH. Additionally, the downregulation of IL-7Rα that begins several months after birth may also contribute to tumor growth. (UMIN-CTR: UMIN000038574).