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Background/Objectives: HIV-associated neurocognitive impairment (NCI) remains a prevalent issue among people with HIV (PWH) despite advancements in antiretroviral therapy (ART). The pathogenesis of HIV-associated NCI is linked to chronic neuroinflammation caused by HIV, even in those with successful viral suppression. Growth Differentiation Factor 15 (GDF15), a protein involved in inflammatory and metabolic stress responses, has emerged as a key player and potential biomarker for various neurological conditions. This study investigates the relationship between GDF15 expression and HIV-associated NCI. Methods: PWH from the California NeuroAIDS Tissue Network (CNTN) underwent comprehensive neuropsychological exams within 12 months before death and were categorized based on cognitive performance. We examined GDF15 levels in their CSF (Cerebrospinal Fluid) and brain tissues using immunoblotting, immunohistochemistry, double immunolabeling, and ELISA. Results: The cohort was of a similar age across HIV-associated NCI statuses (mean = 40.5), with a predominance of males (77%). The mean plasma viral load was 3.56 log10 copies/mL for Neurocognitively Unimpaired (NUI) PWH and 5.38 log10 copies/mL for people with HIV-associated NCI. GDF15 protein levels were significantly elevated in the frontal cortices of PWH with NCI compared to NUI PWH. Conclusions: The findings indicate that GDF15 may play a role in the pathogenesis of HIV-associated NCI, possibly through neuroinflammatory mechanisms. The strong association between GDF15 levels and cognitive impairment severity suggests its potential as a biomarker for the early detection and monitoring of NCI in PWH.

Background: Sepsis-associated encephalopathy (SAE) is a severe neurological condition caused by sepsis, and presents with symptoms ranging from delirium and coma to long-term cognitive dysfunction. SAE is acknowledged as a widespread brain impairment characterized by the activation of microglia. However, the specific pathological mechanisms that drive this activation are still not clearly understood. Growth differentiation factor 15 (GDF15) levels have been noted to be considerably increased in patients with sepsis, where they are linked to disease severity and can independently predict short- and long-term mortality risk. Serum levels of GDF15 have also been negatively associated with gray matter volume and predict cognitive impairment in older individuals. However, the impact of GDF15 on sepsis-induced cognitive and memory impairments, as well as the mechanisms behind these effects, are poorly understood. Methods: To examine the role of GDF15 in SAE, a sepsis model was created in adult C57BL/6J mice using intraperitoneal administration of lipopolysaccharide (LPS). GDF15 levels in plasma and cerebrospinal fluid were measured by ELISA. The anti-GDF15 monoclonal antibody ponsegromab was injected intracerebroventricularly before modeling, and cognitive and memory functions of the septic mice were assessed using fear-conditioning and novel object recognition tests. Microglial activation and phagocytosis were evaluated using immunofluorescence and Golgi staining. Additionally, an in vitro investigation of LPS-stimulated microglia was conducted to evaluate the impacts of GDF15 on inflammatory cytokine productions and microglial phagocytic activity. Mechanisms were explored using RNA sequencing, qPCR, western blotting, flow cytometry, and immunofluorescence assays. Results: In the cerebrospinal fluid of septic mice, levels of GDF15 were notably elevated after intraperitoneal injection of LPS. Lateral ventricular injection of the anti-GDF15 antibody alleviated both cognitive and memory impairment in the septic mice, together with microglial activation and phagocytosis in the hippocampus, thereby protecting against synaptic loss. Conclusion: The levels of GDF15 were elevated in the brains of septic mice. Targeting GDF15 with an anti-GDF15 antibody was found to improve sepsis-induced cognitive and memory impairment by reducing the microglial inflammatory response and phagocytosis. These results indicate that GDF15 could serve as an important therapeutic target for treating SAE. [ABSTRACT FROM AUTHOR]

Background: Neuromuscular diseases (NMDs) and mitochondriopathies are rare and heterogeneous disorders. Diagnosis is often difficult and delayed, partly due to the lack of reliable biomarkers. Chitotriosidase (CHIT1) as a candidate marker for lysosomal storage diseases is elevated in Niemann pick disease type C as a prototype of this group of diseases. Most recently, a relevant role of the lysosomal pathway in mitochondriopathies has been discussed, but markers of lysosomal involvement have not been investigated. Therefore, the aim of this study was to evaluate CHIT1 concentrations in a broad spectrum of NMDs and mitochondriopathies. Methods: CHIT1 serum concentration of 151 patients with NMD or primary mitochondriopathy was determined by enzyme-linked immunosorbent assay, and compared to 38 healthy controls and 8 patients with Niemann pick disease type C. Results were controlled for age, sex, CRP and CHIT1 polymorphism, and compared to several established markers (CK, FGF21, GDF15). Results: CHIT1 levels were not altered in NMDs, but significantly increased in mitochondriopathies, within the range of Niemann-Pick patients. Compared to the established biomarkers, CHIT1 and FGF21 showed a similar diagnostic performance, while better results were found for GDF15. However, there was a tendency for higher CHIT1 concentrations in patients with central nervous system involvement (MELAS syndrome), while FGF21 and GDF15 were not relevantly altered in these patients. Consequently, a combination of biomarkers including CHIT1 provided the best overall diagnostic performance. Conclusions: Serum CHIT1 concentration is significantly elevated in mitochondriopathies compared to healthy controls and other NMD, identifying CHIT1 as potential complementary biomarker in mitochondriopathies. [ABSTRACT FROM AUTHOR]

Background: Charcot–Marie–Tooth disease (CMT), a slowly advancing hereditary nerve disorder, presents a significant challenge in the medical field. Effective drugs for treatment are lacking, and we struggle to find sensitive markers to track the disease's severity and progression. In this study, our objective was to investigate the levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) in individuals with CMT and to compare them to a control group. Our primary goal is to determine whether these biomarker levels are related to the severity of the disease. Methods: Initially, 44 patients with CMT and 44 controls participated in this study. CMT diagnosis was approved by genetic testing. Disease severity was assessed through clinical evaluations using the CMT Neuropathy Score version 2 (CMTNSv2). NfL and GFAP concentrations were measured using Single molecule array, while FGF-21 and GDF-15 concentrations were measured by enzyme-linked immunosorbent assays. Results: In the group of patients with CMT, the concentrations of GDF15, FGF21, NfL, and GFAP were significantly higher than in the control group (p < 0.05). NfL and GFAP levels were correlated with the CMTNSv2 score (rs = 0.46, p = 0.002; rs = 0.31, p = 0.04). Conclusion: Our study has provided confirmation that plasma concentrations of NfL, GFAP, GDF15, and FGF21 are significantly elevated in patients with CMT compared to controls. Furthermore, NfL and GFAP levels were correlated with the clinical severity of CMT. These findings suggest that NfL and GFAP can be reliable disease indicators in future research. [ABSTRACT FROM AUTHOR]

The Warburg effect, characterized by the shift toward aerobic glycolysis, is closely associated with the onset and advancement of tumors, including multiple myeloma (MM). Nevertheless, the specific regulatory mechanisms of glycolysis in MM and its functional role remain unclear. In this study, we identified that growth differentiation factor 15 (GDF15) is a glycolytic regulator, and GDF15 is highly expressed in MM cells and patient samples. Through gain-of-function and loss-of-function experiments, we demonstrated that GDF15 promotes MM cell proliferation and inhibits apoptosis. Moreover, GDF15 enhances Warburg-like metabolism in MM cells, as evidenced by increased glucose uptake, lactate production, and extracellular acidification rate, while reducing oxidative phosphorylation. Importantly, the tumor-promoting effects of GDF15 in MM cells are fermentation-dependent. Mechanistically, GDF15 was found to promote the expression of key glycolytic genes, particularly the glucose transporter GLUT1, through the activation of the TGFβ signaling pathway. Pharmacological inhibition of the TGFβ signaling pathway effectively abrogated the oncogenic activities of GDF15 in MM cells, including cell proliferation, apoptosis, and fermentation. In vivo experiments using a subcutaneous xenotransplanted tumor model confirmed that GDF15 knockdown led to a significant reduction in tumor growth, while GDF15 overexpression promoted tumor growth. Overall, our study provides insights into the molecular mechanisms underlying MM pathogenesis and highlights the potential of targeting GDF15-TGFβ signaling -glycolysis axis as a therapeutic approach for future therapeutic interventions in MM. [ABSTRACT FROM AUTHOR]

Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15−/− mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15−/− mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15−/− mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15−/− mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels. [ABSTRACT FROM AUTHOR]

Growth differentiation factor 15 (GDF15) is a member of the transforming growth factor beta (TGF-β) superfamily and is related to metabolism, injury, and aging. GDF15 has both tumor-promoting and tumor-suppressing effects. However, its role in colorectal cancer (CRC) with high microsatellite instability (MSI-H) must be further clarified. In our study, we found that GDF15 is generally elevated in pancarcinoma, particularly in colorectal cancer, and serves as an early indicator of the development of colorectal cancer. IHC and WB confirmed that GDF15 was elevated in MSI-H CRC clinical tissues and MSI-H CRC cell lines (HCT-116 and LoVo). Suppressing GDF15 by siRNA resulted in a substantial decrease in cell viability and proliferation. Furthermore, suppressing GDF15 can increase the sensitivity of MSI-H CRC cells to 5-fluorouracil (5-FU), which decreases cell viability and increases the apoptosis rate. In vivo experiments also demonstrated that mouse xenografts with suppressed GDF15 expression were more susceptible to 5-FU chemotherapy. We examined alterations in mitochondria via electron microscopy and changes in the mitochondrial membrane potential, ferroptosis-related signals (MDA, Fe2+), and SLC7A11/GSH/GPX4 protein pathway. Our research indicates that inhibiting GDF15 affects ferroptosis-related pathways, leading to ferroptosis and improving the MSI-H CRC response to 5-FU therapy. As a result, GDF15 could be a promising target for diagnosing and treating MSI-H CRC, potentially enhancing the overall effectiveness of therapy for patients with MSI-H CRC. [ABSTRACT FROM AUTHOR]

The mechanisms by which bariatric/metabolic surgery induces weight loss and the amelioration of obesity-associated complications are far from being fully elucidated. Variations in circulating hormones involved in the regulation of energy balance are usually considered to explain the effects of surgery beyond the restrictive mechanism. Recent studies have shown that gastric bypass modulates the plasma levels of GDF15, a molecule with anorectic action potentially contributing to the body weight reduction observed after surgery. Here, we report that sleeve gastrectomy has different effects on GDF15 plasma levels in patients with obesity depending on the presence of metabolic syndrome (MetS). Patients with MetS showed higher GDF15 plasma levels at baseline, but they had no increase in hormone concentrations compared to patients without MetS. Furthermore, at baseline, a correlation between blood glucose and GDF15 was observed in patients with MetS, and between plasma insulin and GDF15 in patients without MetS. Considering this data, GDF15 seems a molecule reflecting the severity of metabolic derangements not directly involved in mechanisms of surgical weight loss, and its role in obesity physiopathology and treatment needs to be further investigated. [ABSTRACT FROM AUTHOR]

Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15. [ABSTRACT FROM AUTHOR]

Growth differentiation factor 15 (GDF15) is a stress‐induced cytokine that suppresses food intake and causes weight loss. GDF15 also reduces voluntary physical activity and, thus, it is not clear whether combining GDF15 with exercise will be beneficial or if reductions in food intake would be offset by decreases in physical activity. We investigated how GDF15 treatment combined with voluntary wheel running (VWR) would impact weight gain, food intake, adiposity and indices of metabolic health in mice. High‐fat fed male and female mice underwent daily GDF15 treatments and were given access to voluntary running wheels, or not, for 11 days. In both sexes, VWR prevented weight gain. In males, GDF15 reduced food intake, as well as attenuated weight gain and the accumulation of adipose tissue, with no additional effect of VWR. In female mice, GDF15 did not impact body weight gain or body composition. GDF15 acutely reduced food intake in female mice but this was followed by a period of rebound hyperphagia and consequently GDF15 did not reduce total food intake in female mice. GDF15 treatment reduced wheel running distance in both sexes. There were main effects of VWR to improve glucose tolerance in female but not male mice. These findings show that GDF15 has sex‐specific effects on food intake and consequently weight gain and adiposity. There is no added benefit of combining GDF15 and voluntary physical activity for weight loss. Adaptive responses to acute caloric restriction induced by GDF15 might limit its effectiveness as a weight loss tool in females. Key points: GDF15 is a stress‐induced signalling factor that reduces food intake and voluntary physical activity.It is not known whether combining GDF15 treatment with voluntary wheel running would impart beneficial combined effects in attenuating weight gain and the accumulation of adipose tissue.In the present study, we demonstrate that GDF15 reduces food intake and prevents weight gain in male but not female mice consuming a high‐fat diet and also that combining GDF15 with voluntary wheel running (VWR) does not lead to a greater dampening of weight gain.In female mice, GDF15 acutely reduced food intake, but this was followed by a period of rebound hyperphagia resulting in no differences in total food intake.In both sexes, VWR was equivalent, or superior to GDF15 in preventing weight gain. [ABSTRACT FROM AUTHOR]

The growth differentiation factor 15 (GDF15)–glial cell‐derived neurotrophic factor family receptor alpha‐like (GFRAL) pathway plays a crucial role in the regulation of metabolism, appetite and body weight control. Obesity is an increasingly prevalent chronic disease worldwide, necessitating effective treatment strategies. Recent preclinical and clinical studies have highlighted that targeting the GDF15‐GFRAL signalling pathway is a promising approach for treating obesity, particularly because it has minimal impact on skeletal muscle mass, which is essential to preserve during weight loss. Given its distinctive mechanisms, the GDF15‐GFRAL axis represents an attractive target for addressing various metabolic disorders, especially obesity. In this review, we will explore how the GDF15‐GFRAL axis is regulated, its distribution in the body and its role in the regulation of metabolism, appetite and obesity. Additionally, we will discuss recent advances and potential challenges in targeting the GDF15‐GFRAL axis for obesity treatment. [ABSTRACT FROM AUTHOR]

Aim: Gamma‐glutamyltransferase (GGT) is known as an oxidative stress marker, induced by alcohol consumption and metabolic disorders, and is reported as a predictor of hepatocellular carcinoma (HCC) development after hepatitis C virus (HCV) elimination. However, it is not clear whether GGT serves simply as a surrogate marker for overlapping metabolic diseases or reflects HCV‐specific carcinogenicity. We investigated the association between GGT and hepatocarcinogenesis after achieving a sustained viral response (SVR), accounting for drinking habits or diabetes, and examined predisposing factors associated with GGT levels after SVR. Methods: This is a prospective, multicenter, and observational study using the database of 1001 patients after HCV eradication with direct‐acting antiviral agents. The association of GGT at SVR with cumulative HCC development was examined in a multivariate analysis using Cox proportional hazard models after adjustment for covariates including alcohol and diabetes. The association between oxidative stress markers or genetic factors and GGT levels was analyzed. Results: High GGT levels at SVR were associated with HCC development (HR] 2.38, 95% CI 1.10–5.17). This association was also significant when restricted to patients without alcohol consumption or diabetes (HR 8.38, 95% CI 2.87–24.47). GGT levels were correlated with serum growth differentiation factor 15 levels, a marker of mitochondrial dysfunction. Single‐nucleotide polymorphisms of ZNF827 and GDF15 were associated with high GGT levels. Conclusions: High GGT levels at SVR were associated with HCC development after accounting for alcohol consumption and diabetes. GGT levels are influenced by genetic predisposition and may reflect mitochondrial dysfunction after HCV eradication. [ABSTRACT FROM AUTHOR]

Growth differentiation factor (GDF15) has been considered a biomarker and recently a hormonal driver for diseases in different populations. However, the role of GDF15 as a biomarker of health outcomes in obese men from different racial/ethnic background has not been evaluated. The objective of this study was to investigate the racial/ethnic differences on the relationship between GDF15 and markers of glucometabolic status, hormonal profile, body composition and bone mineral density (BMD) in obese men. One hundred ninety‐three obese men from diverse racial/ethnic backgrounds were enrolled. BMD and body composition were measured by dual energy X‐ray absorptiometry. Serum GDF15, osteocalcin, C‐terminal telopeptide, sclerostin, adiponectin, leptin, estradiol, testosterone, follicle‐stimulating hormone, luteinizing hormone, 25‐hydroxyvitamin D, lipid profile, and hemoglobin A1C (A1C) were measured. Non‐African Americans (NAA) had significantly higher GDF15 level than African Americans (AA). Level was also higher in patients with type 2 diabetes (T2DM). In both the groups GDF15 correlated with A1C and lean mass. However. GDF15 correlated with body fat, LDL total cholesterol and femoral neck BMD only in NAA and with appendicular lean mass only in AA. Ethnicity, total cholesterol and T2DM were found to be independent predictors of GDF15. We conclude that GDF15 may influence glucometabolic status, body composition and bone parameters which may affect cardiovascular risk and osteoporosis between races. [ABSTRACT FROM AUTHOR]

Aims Heart failure and associated cachexia is an unresolved and important problem. This study aimed to determine the factors that contribute to cardiac cachexia in a new model of heart failure in mice that lack the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A. Methods and results Mice were irradiated and reconstituted with bone marrow cells. Mice lacking functional PPP1R15A, exhibited dilated cardiomyopathy and severe weight loss following irradiation, whilst wild-type mice were unaffected. This was associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in circulation. We provide evidence that the blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. We also show the relevance of GDF15 to lean mass and protein intake in patients with heart failure. Conclusion Our data suggest that cardiac stress mediates a GDF15-dependent pathway that drives weight loss and worsens cardiac function. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure. [ABSTRACT FROM AUTHOR]

Growth Differentiation Factor 15 (GDF15) is an emerging biomarker that significantly increases during acute stress responses, such as infections, and is moderately elevated in chronic and inflammation-driven conditions. While evidence suggests that high levels of GDF15 in cardiac surgery are associated with worse outcomes, its utility as an evaluator of early postoperative complications remains unclear. This study aims to characterize the postoperative profile of GDF15 in patients undergoing isolated surgical aortic valve replacement, evaluating its association with short-term outcomes. Serum samples from patients undergoing cardiac surgery were collected preoperatively and at defined postoperative time points (1 h, 6 h, 12 h, 24 h, and 48 h) to measure GDF15 levels. GDF15 levels significantly increased after surgery, peaking at 6 h. A positive correlation was observed between GDF15 levels and both cardiopulmonary bypass and aortic cross-clamp times. Notably, patients who developed postoperative acute kidney injury (AKI) or required prolonged hemodynamic support had significantly higher GDF15 levels, with increased mechanical ventilation time and extended intensive care unit length of stay. Furthermore, GDF15 levels correlated with postoperative SOFA scores at 24 h after surgery. GDF15 may be a valuable biomarker for risk stratification and guiding therapeutic decisions in cardiac surgery patients. Higher GDF15 levels were significantly associated with prolonged hemodynamic support, postoperative AKI, and measures of illness severity. [ABSTRACT FROM AUTHOR]

Background and Objectives: In this study, the effects of an eight-week exercise and nutrition program on blood lipids, glucose, insulin, insulin resistance (HOMA-IR), leptin, ghrelin, irisin, malondialdehyde (MDA), and Growth Differentiation Factor 15 (GDF15) in overweight women were investigated. Materials and Methods: A total of 48 women volunteers participated in this study. The participants were randomly divided into four groups: control (C), exercise (E), nutrition (N), exercise + nutrition (E + N). While no intervention was applied to group C, the other groups participated in the predetermined programs for 8 weeks. At the beginning and end of this study, body composition was measured and blood samples were taken. Results: It was determined that the body composition components, lipid profile indicators, insulin, glucose, insulin resistance, leptin, ghrelin, irisin, and MDA parameters examined in this study showed positive changes in the intervention groups. Group E had a greater effect on body muscle percentage, MDA, and irisin levels, while group N had a greater effect on blood lipids and ghrelin levels. Conclusions: As a result, it is thought that lifestyle changes are important to improve cardiovascular health and combat obesity, and that maintaining a healthy diet together with exercise may be more effective. [ABSTRACT FROM AUTHOR]

Growth differentiation factor-15 (GDF15) increases in circulation during pregnancy and has been implicated in food intake, weight loss, complications of pregnancy, and metabolic illness. We used a Gdf15 knockout mouse model (Gdf15−/−) to assess the role of GDF15 in body weight regulation and food intake during pregnancy. We found that Gdf15−/− dams consumed a similar amount of food and gained comparable weight during the course of pregnancy compared with Gdf15+/+ dams. Insulin sensitivity on gestational day 16.5 was also similar between genotypes. In the postnatal period, litter size and survival rates were similar between genotypes. There was a modest reduction in birth weight of Gdf15−/− pups, but this difference was no longer evident from postnatal day 3.5 to 14.5. We observed no detectable differences in milk volume production or milk fat percentage. These data suggest that GDF15 is dispensable for changes in food intake, and body weight as well as insulin sensitivity during pregnancy in a mouse model. [ABSTRACT FROM AUTHOR]

Abstract Background Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC. Methods We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed. Results A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16). Conclusions GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC.

Abstract Introduction Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials. Methods Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. Results Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p

Abstract GDF15 and FGF21, stress-responsive cytokines primarily secreted from the liver, are promising therapeutic targets for metabolic dysfunction-associated steatotic liver disease (MASLD). However, the interaction between GDF15 and FGF21 remains unclear. We examined the effects of hepatocyte-specific GDF15 or FGF21 overexpression in high-fat diet (HFD)-fed mice for 8 weeks. Hydrodynamic injection of GDF15 or FGF21 sustained high circulating levels of GDF15 or FGF21, respectively, resulting in marked reductions in body weight, epididymal fat mass, insulin resistance, and hepatic steatosis. In addition, GDF15 treatment led to early reduction in body weight despite no change in food intake, indicating the role of GDF15 other than appetite loss. GDF15 treatment increased liver-derived serum FGF21 levels, whereas FGF21 treatment did not affect GDF15 expression. GDF15 promoted eIF2α phosphorylation and XBP1 splicing, leading to FGF21 induction. In murine AML12 hepatocytes treated with free fatty acids (FFAs), GDF15 overexpression upregulated Fgf21 mRNA levels and promoted eIF2α phosphorylation and XBP1 splicing. Overall, continuous exposure to excess FFAs resulted in a gradual increase of β-oxidation-derived reactive oxygen species and endoplasmic reticulum stress, suggesting that GDF15 enhanced this pathway and induced FGF21 expression. GDF15- and FGF21-related crosstalk is an important pathway for the treatment of MASLD.

Abstract Background Cardiovascular toxicity represents a significant adverse consequence of cancer therapies, yet there remains a paucity of effective biomarkers for its timely monitoring and diagnosis. To give a first evidence able to elucidate the role of Growth Differentiation Factor 15 (GDF15) in the context of cancer diagnosis and its specific association with cardiac indicators in cancer patients, thereby testing its potential in predicting the risk of CTRCD (cancer therapy related cardiac dysfunction). Methods Analysis of differentially expressed genes (DEGs), including GDF15, was performed by utilizing data from the public repositories of the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Cardiomyopathy is the most common heart disease and its main clinical manifestations, such as heart failure and arrhythmia, are similar to those of CTRCD. Examination of GDF15 expression was conducted in various normal and cancerous tissues or sera, using available database and serum samples. The study further explored the correlation between GDF15 expression and the combined detection of cardiac troponin-T (c-TnT) and N-terminal prohormone of brain natriuretic peptide (NT-proBNP), assessing the combined diagnostic utility of these markers in predicting risk of CTRCD through longitudinal electrocardiograms (ECG). Results GDF15 emerged as a significant DEG in both cancer and cardiomyopathy disease models, demonstrating good diagnostic efficacy across multiple cancer types compared to healthy controls. GDF15 levels in cancer patients correlated with the established cardiac biomarkers c-TnT and NT-proBNP. Moreover, higher GDF15 levels correlated with an increased risk of ECG changes in the cancer cohort. Conclusion GDF15 demonstrated promising diagnostic potential in cancer identification; higher GDF15, combined with elevated cardiac markers, may play a role in the monitoring and prediction of CTRCD risk.

Abstract Background Plasma growth differentiation factor 15 (GDF15) and N‐terminal proB‐type natriuretic peptide (NT‐proBNP) are cardiovascular biomarkers that associate with a range of diseases. Epigenetic scores (EpiScores) for GDF15 and NT-proBNP may provide new routes for risk stratification. Results In the Generation Scotland cohort (N ≥ 16,963), GDF15 levels were associated with incident dementia, ischaemic stroke and type 2 diabetes, whereas NT-proBNP levels were associated with incident ischaemic heart disease, ischaemic stroke and type 2 diabetes (all PFDR 95%) with levels of GDF15 and NT-proBNP, respectively. EpiScores for GDF15 and NT-proBNP were trained in a subset of the population. The GDF15 EpiScore replicated protein associations with incident dementia, type 2 diabetes and ischaemic stroke in the Generation Scotland test set (hazard ratios (HR) range 1.36–1.41, PFDR

Background: Bone metastasis (BM) is a common and fatal condition in patients with castration-resistant prostate cancer (CRPC). However, there are no useful blood biomarkers for CRPC with BM, and the mechanism underlying BM is unclear. In this study, we investigated precise blood biomarkers for evaluating BM that can improve the prognosis of patients with CRPC. Methods: We comprehensively examined culture supernatants from four prostate cancer (PCa) cell lines using Orbitrap mass spectrometry to identify specific proteins secreted abundantly by PCa cells. The effects of this protein to PCa cells, osteoblasts, osteoclasts were examined, and BM mouse model. In addition, we measured the plasma concentration of this protein in CRPC patients for whom bone scan index (BSI) by bone scintigraphy was performed. Results: A total of 2,787 proteins were identified by secretome analysis. We focused on GDF15 propeptide (GDPP), which is secreted by osteoblasts, osteoclasts, and PCa cells. GDPP promoted the proliferation, invasion, and migration of PC3 and DU145 CRPC cells, and GDPP aggravated BM in a mouse model. Importantly, GDPP accelerated bone formation and absorption in the bone microenvironment by enhancing the proliferation of osteoblasts and osteoclasts by upregulating individual transcription factors such as RUNX2, OSX, ATF4, NFATc1, and DC-STAMP. In clinical settings, including a total of 416 patients, GDPP was more diagnostic of BM than prostate-specific antigen (PSA) (AUC = 0.92 and 0.78) and the seven other blood biomarkers (alkaline phosphatase, lactate dehydrogenase, bone alkaline phosphatase, tartrate-resistant acid phosphatase 5b, osteocalcin, procollagen I N-terminal propeptide and mature GDF15) in patients with CRPC. The changes in BSI over time with systemic treatment were correlated with that of GDPP (r = 0.63) but not with that of PSA (r = -0.16). Conclusions: GDPP augments the tumor microenvironment of BM and is a novel blood biomarker of BM in CRPC, which could lead to early treatment interventions in patients with CRPC. [ABSTRACT FROM AUTHOR]

Growth differentiation factor 15 (GDF15) is a stress-response cytokine related to a wide variety of metabolic diseases. However, the impact of GDF15-specific genetic variants on the abovementioned conditions is poorly known. The aim of this study was to assess the impact of selected GDF15 single-nucleotide polymorphisms (SNPs) on metabolic disturbances and subclinical atherosclerosis. A cross-sectional study involving 153 participants of a metabolic patient-based cohort was performed. Three selected SNPs (rs888663, rs1054564 and rs1059369) in a locus on chromosome 19 including the GDF15 gene were genotyped by Polymerase Chain Reaction (PCR), and its relationship with the serum GDF15 levels, health status and clinical variables were analyzed. Of the three SNPs analyzed, only rs1054564 showed different distributions between the healthy volunteers and patients suffering lipid alterations and associated disorders. Accordingly, just the rs1054564 variant carriers showed a significant increase in GDF15 serum levels compared to the wild-type carriers. The group of variant carriers showed a higher frequency of individuals with diabetes, compared to the wild-type carrier group, without showing differences in other metabolic conditions. Additionally, the frequency of individuals with atherosclerotic carotid plaque was higher in the rs1054564 variant carriers than in the wild-type carriers. Logistic regression models identified that the presence of the rs1054564 variant carriers increase the likelihood for both diabetes and carotid plaque independently of confounding factors. Overall, the findings of this study identify the rs1054564 variant as a potential indicator for the likelihood of diabetes and subclinical atherosclerosis. [ABSTRACT FROM AUTHOR]

Introduction: Growth differentiation factor 15 (GDF15) is a cytokine of the TGFβ family. Here, we analyzed GDF15 levels in patients with locally advanced non-small cell lung cancer (LA-NSCLC) who participated in OCOG-ALMERA (NCT02115464), a phase II randomized clinical trial, that investigated metformin in combination with standard of care concurrent chemoradiotherapy (cCRT). OCOG-ALMERA was not able to demonstrate benefit in the metformin arm. Therefore, biomarker studies are needed to better define stratification parameters for future trials. Methods: Patients were randomized to treatment with platinum-based chemotherapy and concurrent chest radiotherapy (60–66 Gy), with or without metformin (2000 mg/d). The trial collected tumor volume parameters, survival outcomes, and patient blood plasma at baseline, during (weeks 1 and 6) and 6 months after cCRT. Plasma GDF15 levels were assayed with the ELISA method. Statistical analyses explored associations between GDF15, survival outcomes, and radiotherapy tumor volumes. Results: Baseline plasma levels of GDF15 were elevated in study patients, they increased during cCRT (p < 0.001), and the addition of metformin was associated with a further increase (week 6, p = 0.033). Baseline GDF15 levels correlated with the radiotherapy gross target volume (GTV, p < 0.01), while week 1 of radiotherapy levels correlated with radiotherapy planned target volume (PTV, p < 0.006). In multivariate analysis, baseline plasma GDF15 was prognostic for poor relapse-free (RFS) and overall survival (OS) (p = 0.005 and p = 0.002, respectively). Conclusions: GDF15 is a plasma marker that responds to the treatment of unresected LA-NSCLC with cCRT and metformin. GDF15 levels correspond with tumor volume and increased GDF15 levels predict for poor RFS and OS. These results require validation in larger clinical trial datasets. Highlights: Analysis of plasma specimens of OCOG-ALMERA, a phase II clinical trial that investigated metformin in combination with standard of care concurrent chemoradiotherapy, suggests that the cytokine growth differentiation factor 15 (GDF15) may be a promising biomarker in unresected locally advanced non-small cell lung cancer (LA-NSCLC). GDF15 levels increased during chemoradiotherapy, did more so in metformin-treated patients and corresponded with the radiotherapy clinical target volumes. Baseline plasma levels of GDF15 predicted overall and relapse-free survival. Validation of these results within larger clinical trials could lead to the establishment of an easily assessable plasma biomarker that could guide LA-NSCLC treatment in the future. [ABSTRACT FROM AUTHOR]

Background: Achieving first complete remission with induction chemotherapy (ICT) for acute myeloid leukemia (AML) correlates with patient's prognosis. This study aimed to determine the correlation between oxidative stress and the outcome of ICT in AML patients. Methods: A total of 195 AML patients underwent initial ICT at the Longyan First Affiliated Hospital of Fujian Medical University from 06-11-2018 to 12-30-2023. Three weeks after ICT, patients were divided into two groups, CR (complete remission) and PR (partial remission), by detecting blood parameters and bone marrow cells. Serum oxidative stress-related factors, malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), and growth/differentiation factor-15 (GDF15) activities or levels were measured to assess the diagnostic value of these factors as a means of diagnosing the efficacy of ICT in patients. Factors affecting PR after initial ICT were analyzed. Results: Patients in the PR group had higher levels of oxidative stress three weeks after initial ICT. Compared with the CR group, patients in the PR group had elevated levels of MDA and GDF15 and reduced activities of SOD, GSH-Px, and T-AOC. Serum MDA levels (AUC 0.709; 95% CI. 0.618 - 0.781) and the combination of multiple indicators (AUC 0.791; 95% CI. 704 - 0.851) had diagnostic value for the efficacy of AML patients undergoing ICT. Serum MDA and GDF15 exceeding cutoff values were risk factors for PR in AML patients undergoing ICT, as were serum SOD and T-AOC below cutoff values. Preoperative malnutrition was associated with PR in patients. Conclusions: Serum oxidative stress-related factors in AML patients are helpful in detecting the efficacy of ICT. Oxidative stress in response to ICT is useful for characterizing the efficacy in AML patients after ICT. [ABSTRACT FROM AUTHOR]

Type 1 diabetes (T1D) is a chronic metabolic disease resulting from an autoimmune destruction of pancreatic beta cells. Beta cells activate various stress responses during the development of T1D, including senescence, which involves cell cycle arrest, prosurvival signaling, and a proinflammatory secretome termed the senescence-associated secretory phenotype (SASP). We previously identified growth and differentiation factor 15 (GDF15) as a major SASP factor in human islets and human EndoC-βH5 beta cells in a model of DNA damage-mediated senescence that recapitulates features of senescent beta cells in T1D. Soluble GDF15 has been shown to exert protective effects on human and mouse beta cells during various forms of stress relevant to T1D; therefore, we hypothesized that secreted GDF15 may play a prosurvival role during DNA damage-mediated senescence in human beta cells. We found that elevated GDF15 secretion was associated with endogenous senescent beta cells in an islet preparation from a T1D donor, supporting the validity of our DNA damage model. Using antibody-based neutralization, we found that secreted endogenous GDF15 was not required for senescent human islet or EndoC cell viability. Rather, neutralization of GDF15 led to reduced expression of specific senescence-associated genes, including GDF15 itself and the prosurvival gene BCL2-like protein 1 (BCL2L1). Taken together, these data suggest that SASP factor GDF15 is not required to sustain senescent human islet viability, but it is required to maintain senescence-associated transcriptional responses. NEW & NOTEWORTHY: Beta cell senescence is an emerging contributor to the pathogenesis of type 1 diabetes, but candidate therapeutic targets have not been identified in human beta cells. In this study, we examined the role of a secreted factor, GDF15, and found that although it is not required to maintain viability during senescence, it is required to fine-tune gene expression programs involved in the senescence response during DNA damage in human beta cells. [ABSTRACT FROM AUTHOR]

Introduction and aim. Growth differentiation factor 15 (GDF15), a member of the TGF-β superfamily, plays crucial roles in various physiological and pathological processes including inflammation, apoptosis, angiogenesis, cell repair, growth, metabolic regulation, and immune response. This review aims to discuss the biological roles and clinical significance of GDF15 and to analyze its impact across different medical fields such as cardiology, oncology, neurology, gynecology, and areas related to aging and metabolic disorders. Material and methods. A review was constructed through a literature search on PubMed and Google Scholar databases, focusing on studies from 2014 to 2024, using relevant keywords. Analysis of the literature. Recent research highlights GDF15's potential as a biomarker in cardiovascular diseases, its role in cancer progression and resistance to therapies, and its significance in metabolic regulation affecting conditions like obesity, diabetes, and cachexia. Emerging research also points to its role in aging, mitochondrial diseases, and systemic conditions such as sepsis, liver, and lung disorders. Conclusion. GDF15's involvement in multiple pathological states and its broad impact across various medical disciplines underline its potential for future clinical applications. Understanding GDF15's complex roles could lead to novel therapeutic strategies and enhance prognostic assessments in diverse medical fields. [ABSTRACT FROM AUTHOR]

Uveitis is a vision-threatening disease primarily driven by a dysregulated immune response, with retinal microglia playing a pivotal role in its progression. Although the transcription factor EGR2 is known to be closely associated with uveitis, including Vogt-Koyanagi-Harada disease and Behcet's disease, and is essential for maintaining the dynamic homeostasis of autoimmunity, its exact role in uveitis remains unclear. In this study, diminished EGR2 expression was observed in both retinal microglia from experimental autoimmune uveitis (EAU) mice and inflammation-induced human microglia cell line (HMC3). We constructed a mice model with conditional knockout of EGR2 in microglia and found that EGR2 deficiency resulted in increased intraocular inflammation. Meanwhile, EGR2 overexpression downregulated the expression of inflammatory cytokines as well as cell migration and proliferation in HMC3 cells. Next, RNA sequencing and ChIP-PCR results indicated that EGR2 directly bound to its downstream target growth differentiation factor 15 (GDF15) and further regulated GDF15 transcription. Furthermore, intravitreal injection of GDF15 recombinant protein was shown to ameliorate EAU progression in vivo. Meanwhile, knockdown of GDF15 reversed the phenotype of EGR2 overexpression-induced microglial inflammation in vitro. In summary, this study highlighted the protective role of the transcription factor EGR2 in AU by modulating the microglial phenotype. GFD15 was identified as a downstream target of EGR2, providing a unique target for uveitis treatment. [ABSTRACT FROM AUTHOR]

Noise-induced hidden hearing loss (HHL) is a newly uncovered form of hearing impairment that causes hidden damage to the cochlea. Patients with HHL do not have significant abnormalities in their hearing thresholds, but they experience impaired speech recognition in noisy environments. However, the mechanisms underlying HHL remain unclear. In this study, we developed single-cell transcriptome profiles of the cochlea of mice with HHL, detailing changes in individual cell types. Our study revealed a transient threshold shift, reduced auditory brainstem response wave I amplitude, and decreased number of ribbon synapses in HHL mice. Our findings suggest elevated oxidative stress and GDF15 expression in cochlear hair cells of HHL mice. Notably, the upregulation of GDF15 attenuated oxidative stress and auditory impairment in the cochlea of HHL mice. This suggests that a therapeutic strategy targeting GDF15 may be efficacious against HHL. HHL mice had a transient threshold shift, reduced ABR wave I amplitude, and decreased number of ribbon synapses. HHL mice's cochlear hair cells exhibited increased oxidative stress and elevated GDF15 expression. Upregulation of GDF15 attenuated oxidative stress and auditory damage in the cochlea of HHL mice, implying that GDF15-targeted treatment techniques may be useful for HHL. [ABSTRACT FROM AUTHOR]

Nausea and vomiting during pregnancy (NVP), particularly its severe form, Hyperemesis gravidarum (HG), affects up to 70% of pregnancies and significantly impacts the quality of life for those with the condition as well as generates a great economic burden, with annual costs exceeding $1.7 billion in the United States. Despite the available treatments targeting neurotransmitters like serotonin and dopamine, many patients experience inadequate relief and suffer from severe side effects, including headaches and dizziness. Recent research has underscored the role of GDF15, a protein mainly produced by the placenta and linked to NVP symptoms. This protein, part of the TGF-β superfamily, has been implicated in appetite and weight regulation and is altered in those with HG due to specific genetic mutations. Addressing the challenges of delivering effective treatments, current innovations focus on targeting GDF15 to reduce symptoms while ensuring fetal safety. Promising therapeutic strategies include non-IgG immunotherapies, small peptide and molecule antagonists, and novel administration methods such as transdermal patches. These approaches aim to optimize dosage and reduce adverse effects. The effective development and testing of these treatments necessitate advanced animal models that closely resemble human pregnancy physiology, highlighting the need for further research and funding. This ongoing research holds significant potential to improve the clinical outcomes for HG patients and decrease the economic impact on healthcare systems, urging a dedicated response from the scientific and medical communities to advance these promising treatments. [ABSTRACT FROM AUTHOR]

Numerous studies have shown that exosomes play a regulatory role in a variety of biological processes as well as in disease development and progression. However, exosome-mediated intercellular communication between brain microvascular endothelial cells (BMECs) and astrocytes during meningitic Escherichia coli (E. coli)–induced neuroinflammation remains largely unknown. Here, by using in vivo and in vitro models, we demonstrate that exosomes derived from meningitic E. coli–infected BMECs can activate the inflammatory response of astrocytes. A label-free quantitation approach coupled with LC-MS/MS was used to compare the exosome proteomic profiles of human BMECs (hBMECs) in response to meningitic E. coli infection. A total of 57 proteins exhibited significant differences in BMEC-derived exosomes during the infection. Among these proteins, growth differentiation factor 15 (GDF15) was significantly increased in BMEC-derived exosomes during the infection, which triggered the Erk1/2 signaling pathway and promoted the activation of astrocytes. The identification and characterization of exosome protein profiles in BMECs during meningitic E. coli infection will contribute to the understanding of the underlying pathogenic mechanisms from the perspective of intercellular communication between BMECs and astrocytes, and provide new insights for future prevention and treatment of E. coli meningitis. [ABSTRACT FROM AUTHOR]

Abnormal functions of trophoblast cells are associated with the pathogenesis of preeclampsia (PE). Nuclear receptor subfamily 2 group F member 1 (NR2F1) acts as a transcriptionally regulator in many diseases, but its role in PE remains unknown. Hypoxia/reoxygenation (H/R)-stimulated HTR-8/SVneo cells were used to mimic PE injury in vitro. NR2F1 overexpression alleviated trophoblast apoptosis, as evidenced by the decreased number of TUNEL-positive cells and the downregulation of caspase 3 and caspase 9 expression in cells. NR2F1 overexpression increased the invasion and migration ability of HTR-8/SVneo cells, accompanied by increased protein levels of matrix metalloproteinase (MMP)-2 and MMP-9. mRNA-seq was applied to explore the underlying mechanism of NR2F1, identifying growth differentiation factor 15 (GDF15) as the possible downstream effector. Dual-luciferase reporter, ChIP-qPCR, and DNA pull-down assays confirmed that NR2F1 bound to the promoter of GDF15 and transcriptionally inhibited its expression. GDF15 overexpression increased apoptosis and decreased the ability of invasion and migration in HTR-8/SVneo cells expressing NR2F1. MAPK pathway was involved in the regulation of PE. Administration of p38 inhibitor, ERK inhibitor, and JNK inhibitor reversed the effect of simultaneous overexpression NR2F1 and GDF15 on trophoblast apoptosis, invasion, and migration. Our findings demonstrated that NR2F1 overexpression inhibited trophoblast apoptosis and promoted trophoblast invasion and migration. NR2F1 might negatively regulate GDF15 expression by binding to its promoter region, which further inhibited MAPK signaling pathway in PE. Our study highlights that NR2F1 might sever as a potential target in PE. [ABSTRACT FROM AUTHOR]

Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases. Synopsis: The MondoA dependent relationship between TXNIP and GDF15 in response to oxaliplatin-induced ROS can be used to predict aggression and treatment sensitivity in colorectal adenocarcinoma. Non-lethal oxaliplatin treatment increases glucose update, oxidative phosphorylation and ROS in CRC models. The increase in the above drives MondoA to translocate to the nucleus and promote TXNIP expression which, amongst other impacts, inhibits GDF15 expression. GDF15 binds to CD48 on naïve CD4 T cells to induce Tregs which inhibit CD8 T cell activation. In aggressive or oxaliplatin-resistant cases, the inter-relationship between TXNIP and GDF15, and control of local Treg induction, is lost. The GDF15/TXNIP ratio can be used to predict aggression, sensitivity to oxaliplatin and highlight a population suitable for GDF15 targeting therapies. The MondoA dependent relationship between TXNIP and GDF15 in response to oxaliplatin-induced ROS can be used to predict aggression and treatment sensitivity in colorectal adenocarcinoma. [ABSTRACT FROM AUTHOR]

BackgroundCharcot–Marie–Tooth disease (CMT), a slowly advancing hereditary nerve disorder, presents a significant challenge in the medical field. Effective drugs for treatment are lacking, and we struggle to find sensitive markers to track the disease’s severity and progression. In this study, our objective was to investigate the levels of neurofilament light chain (NfL), glial fibrillary acid protein (GFAP), fibroblast growth factor 21 (FGF-21) and growth differentiation factor 15 (GDF-15) in individuals with CMT and to compare them to a control group. Our primary goal is to determine whether these biomarker levels are related to the severity of the disease.MethodsInitially, 44 patients with CMT and 44 controls participated in this study. CMT diagnosis was approved by genetic testing. Disease severity was assessed through clinical evaluations using the CMT Neuropathy Score version 2 (CMTNSv2). NfL and GFAP concentrations were measured using Single molecule array, while FGF-21 and GDF-15 concentrations were measured by enzyme-linked immunosorbent assays.ResultsIn the group of patients with CMT, the concentrations of GDF15, FGF21, NfL, and GFAP were significantly higher than in the control group (p

Neurodegeneration is characteristically multifaceted, with limited therapeutic options. One of the chief pathophysiological mechanisms driving these conditions is neuroinflammation, prompting increasing clinical interest in immunomodulatory agents. Growth differentiation factor 15 (GDF15; previously also called macrophage inhibitory cytokine-1 or MIC-1), an anti-inflammatory cytokine with established neurotrophic properties, has emerged as a promising therapeutic agent in recent decades. However, methodological challenges and the delayed identification of its specific receptor GFRAL have hindered research progress. This review systematically examines literature about GDF15 in neurodegenerative diseases and neurotrauma. The evidence collated in this review indicates that GDF15 expression is upregulated in response to neurodegenerative pathophysiology and increasing its levels in preclinical models typically improves outcomes. Key knowledge gaps are addressed for future investigations to foster a more comprehensive understanding of the neuroprotective effects elicited by GDF15.

Cachexia is a complicated metabolic syndrome mainly associated with cancers, characterized by extreme weight loss and muscle wasting. It is a debilitating condition that negatively affects prognosis and survival. However, there is currently no effective pharmacological intervention that can reverse body weight loss and improve physical performance in patients with cachexia. Growth differentiation factor 15 (GDF15) can suppress appetite and regulate energy balance through binding to glial cell-derived neurotrophic factor receptor alpha-like (GFRAL). In order to develop a novel, effective treatment for cachexia, we generated a GDF15-targeting VHH nanobody, GB18–06, that was able to bind GDF15 with high affinity. In vitro, GB18–06 potently inhibited the GDF15-GFRAL signaling pathway, leading to a reduction of downstream ERK and AKT phosphorylation levels; in vivo, GB18–06 alleviated weight loss (>20%) in cancer and chemotherapy-induced cachexia models in mice. Compared with the control (phosphate-buffered saline) group, the ambulatory activity of mice in the GB18–06-treated group also increased 77%. Furthermore, GB18–06 exhibited desirable pharmacokinetic properties and an excellent developability profile. Our study has demonstrated a means of developing targeted treatment for cachexia with high efficacy, potentially leading to improved clinical outcomes and quality of life for patients with cachexia.

Background: The prognosis of pancreatic ductal adenocarcinomas (PDAC) remains very poor, emphasizing the critical importance of early detection, where biomarkers offer unique potential. Although growth differentiation factor 15 (GDF15) and Lipocalin 2 (LCN2) have been linked to PDAC, their precise roles as biomarkers are uncertain. Methods: Circulating levels of GDF15 and LCN2 were examined in human PDAC patients, heathy controls, and individuals with benign pancreatic diseases. Circulating levels of IL-6, CA19-9, and neutrophil-to-lymphocyte ratio (NLR) were measured for comparisons. Correlations between PDAC progression and overall survival were assessed. A mouse PDAC model was employed for comprehensive analyses, complementing the human studies by exploring associations with various metabolic and inflammatory parameters. Sensitivity and specificity of the biomarkers were evaluated. Findings: Our results demonstrated elevated levels of circulating GDF15 and LCN2 in PDAC patients compared to both healthy controls and individuals with benign pancreatic diseases, with higher GDF15 levels associated with disease progression and increased mortality. In PDAC mice, circulating GDF15 and LCN2 progressively increased, correlating with tumor growth, behavioral manifestations, tissue and molecular pathology, and cachexia development. GDF15 exhibited highly sensitive and specific for PDAC patients compared to CA19-9, IL-6, or NLR, while LCN2 showed even greater sensitivity and specificity in PDAC mice. Combining GDF15 and LCN2, or GDF15 and CA19-9, enhanced sensitivity and specificity. Interpretation: Our findings indicate that GDF15 holds promise as a biomarker for early detection and prognosis of PDAC, while LCN2 could strengthen diagnostic panels.

The central nervous system regulates feeding, weight and glucose homeostasis in rodents and humans, but the site-specific mechanisms remain unclear. The dorsal vagal complex in the brainstem that contains the nucleus of the solitary tract (NTS) and area postrema (AP) emerges as a regulatory center that impacts energy and glucose balance by monitoring hormonal and nutrient changes. However, the specific mechanistic metabolic roles of the NTS and AP remain elusive. This mini-review highlights methods to study their distinct roles and recent findings on their metabolic differences and similarities of growth differentiation factor 15 (GDF15) action and glucose sensing in the NTS and AP. In summary, future research aims to characterize hormonal and glucose sensing mechanisms in the AP and/or NTS carries potential to unveil novel targets that lower weight and glucose levels in obesity and diabetes.

Abstract Chemotherapy, the standard of care treatment for cancer patients with advanced disease, has been increasingly recognized to activate host immune responses to produce durable outcomes. Here, in colorectal adenocarcinoma (CRC) we identify oxaliplatin-induced Thioredoxin-Interacting Protein (TXNIP), a MondoA-dependent tumor suppressor gene, as a negative regulator of Growth/Differentiation Factor 15 (GDF15). GDF15 is a negative prognostic factor in CRC and promotes the differentiation of regulatory T cells (Tregs), which inhibit CD8 T-cell activation. Intriguingly, multiple models including patient-derived tumor organoids demonstrate that the loss of TXNIP and GDF15 responsiveness to oxaliplatin is associated with advanced disease or chemotherapeutic resistance, with transcriptomic or proteomic GDF15/TXNIP ratios showing potential as a prognostic biomarker. These findings illustrate a potentially common pathway where chemotherapy-induced epithelial oxidative stress drives local immune remodeling for patient benefit, with disruption of this pathway seen in refractory or advanced cases.

Yi-Ning Du,1 Jin-Wei Zhao2 1Department of Medical Sciences, Li Ka-shing School of Medicine, University of Hong Kong, Hong Kong, People’s Republic of China; 2Department of Hepatopancreatobiliary Surgery, Second Hospital of Jilin University, Jilin University, Changchun, Jilin Province, People’s Republic of ChinaCorrespondence: Jin-Wei Zhao, Department of Hepatopancreatobiliary Surgery, Second Hospital of Jilin University, Jilin University, No. 218, Ziqiang Road, Changchun, 130000, Jilin Province, People’s Republic of China, Tel +8615844089385, Email zhaojinweizjwei@126.comAbstract: Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths globally and the sixth most common cancer worldwide. Evidence shows that growth differentiation factor 15 (GDF15) contributes to hepatocarcinogenesis through various mechanisms. This paper reviews the latest insights into the role of GDF15 in the development of HCC, its role in the immune microenvironment of HCC, and its molecular mechanisms in metabolic dysfunction associated steatohepatitis (MASH) and metabolic associated fatty liver disease (MAFLD)-related HCC. Additionally, as a serum biomarker for HCC, diagnostic and prognostic value of GDF15 for HCC is summarized. The article elaborates on the immunological effects of GDF15, elucidating its effects on hepatic stellate cells (HSCs), liver fibrosis, as well as its role in HCC metastasis and tumor angiogenesis, and its interactions with anticancer drugs. Based on the impact of GDF15 on the immune response in HCC, future research should identify its signaling pathways, affected immune cells, and tumor microenvironment interactions. Clinical studies correlating GDF15 levels with patient outcomes can aid personalized treatment. Additionally, exploring GDF15-targeted therapies with immunotherapies could improve anti-tumor responses and patient outcomes.Keywords: growth differentiation factor 15, GDF15, hepatocellular carcinoma, HCC, immune suppression, immunotherapy

Background Purpose Nausea and emesis are ubiquitously reported medical conditions and often present as treatment side effects along with polymorbidities contributing to detrimental life‐threatening outcomes, such as poor nutrition, lower quality of life, and unfavorable patient prognosis. Growth differentiation factor 15 (GDF15) is a stress response cytokine secreted by a wide variety of cell types in response to a broad range of stressors. Circulating GDF15 levels are elevated in a range of medical conditions characterized by cachexia and malaise. In recent years, GDF15 has gained scientific and translational prominence with the discovery that its receptor, GDNF family receptor α‐like (GFRAL), is expressed exclusively in the hindbrain. GFRAL activation may results in profound anorexia and body weight loss, effects which have attracted interest for the pharmacological treatment of obesity.This review highlights compelling emerging evidence indicating that GDF15 causes anorexia through the induction of nausea, emesis, and food aversions, which encourage a perspective on GDF15 system function in physiology and behavior beyond homeostatic energy regulation contexts. This highlights the potential role of GDF15 in the central mediation of nausea and emesis following a variety of physiological, and pathophysiological conditions such as chemotherapy‐induced emesis, hyperemesis gravidarum, and cyclic vomiting syndrome. [ABSTRACT FROM AUTHOR]