Fibroblast Growth Factor 21 Research Articles

Взаимосвязь миокинов и саркопенического ожирения с неалкогольной жировой болезнью печени при конституционально-экзогенном ожирении у детей

Obesity in children is associated with high risk for development and progression of nonalcoholic fatty liver disease (NAFLD). NAFLD has common pathogenetic mechanisms with sarcopenic obesity (SO), in the development of which such myokines as fibroblast growth factor 21 (FGF-21) and irisin play an important role. The study of their secretion peculiarities is relevant to the prospects of using myokines as diagnostic markers or indicators for drug therapy and physical activity control as well as in the development of target therapy for NAFLD. The connection between NAFLD and SO and changes in myokine profile in children is an understudied issue. The purpose of this research was to determine differences between groups of pediatric patients with the presence v. those with the absence of NAFLD in constitutional-exogenous obesity in myokine and SO levels. Methods used: a single-stage comparative single-center uncontrolled study of 95 children aged 12 to 18 y/o with constitutional-exogenous obesity: body mass index (BMI) standard deviation score (SDS)≥+2.0. Results: NAFLD was detected in 48% (n=50/95) [95% CI (42; 63)] of whom steatohepatitis was detected in 40% (n=20/50) [95% CI (26; 55)]. SO was detected in 96% (n=48/50) [95% CI (86; 99)] with NAFLD including children with steatohepatitis (n=20). The combination of SO with elevated FRF-21 levels and decreased irisin was associated with NAFLD (AUC=0.761, [95% CI (0.65; 0.87)]). The SO frequency was statistically significantly higher in NAFLD than in the SO absence (p<0.001). The predictive ability of the SO presence in relation to the detection of NAFLD was found to be high (PCPR=96%, [95% CI (88; 99)]). FRF-21 values above 60 pg/mL (AUC=0.689, [95% CI (0.57; 0.81)]) and irisin values below 7.86 μg/mL (AUC=0.703, 95% CI (0.58; 0.82)]) were associated with the presence of NAFLD. When comparing operational characteristics, no differences were found for AUC value while the best performance was demonstrated by regression model and cut-off point of irisin equal to 7.86 μg/mL. Conclusion: SO combined with changes in myokine profile is associated with NAFLD. Identification of the main factors influencing the NAFLD development in childhood is crucial in preventing the progression of liver damage.

ADAM10-mediated β-klotho degradation: a key to FGF21 resistance in senescent vascular endothelial cells.

Fibroblast growth factor 21 (FGF21) is a key regulator of metabolism and cardiovascular health. However, its upregulation in aging and age-related disorders suggests the presence of FGF21 resistance. This study aimed to elucidate the mechanisms underlying senescence-associated FGF21 resistance in human umbilical vein endothelial cells (HUVECs) and to explore potential therapeutic interventions. Transcriptomic analysis revealed a significant reduction in the number of FGF21-regulated genes in senescent HUVECs compared to young cells, indicating the onset of FGF21 resistance. In young HUVECs, FGF21 inhibited inflammatory cytokines and upregulated mitochondrial ribosomal protein genes. Conversely, senescent HUVECs showed a downregulation of β-klotho, an essential co-receptor for FGF21, at the cell membrane, concomitant with an upregulation of ADAM10, a protease involved in β-klotho degradation. These changes were also observed in aged mouse aortas. ADAM10 was shown to bind directly to β-klotho and promote its degradation, contributing to FGF21 resistance. Inhibition of ADAM10 or overexpression of β-klotho restored FGF21 responsiveness in senescent HUVECs. Moreover, pharmacologically high concentrations of FGF21 were effective in overcoming resistance and restoring its regulatory effects on senescent cells. These findings suggest that ADAM10-mediated degradation of β-klotho is a central mechanism in the development of FGF21 resistance, and that targeting the ADAM10/β-klotho axis could represent a novel therapeutic approach to restore FGF21 sensitivity. Pharmacological administration of FGF21 may hold promise in treating vascular aging and its associated cardiovascular pathologies.

Beyond Metabolism; Fibroblast Growth Factor-21; A New Frontier in Women’s Health and Reproduction

Beyond Metabolism; Fibroblast Growth Factor-21; A New Frontier in Women’s Health and Reproduction

Maternal organokines throughout pregnancy as predictors of neonatal anthropometric characteristics and adiposity

AimsTo evaluate the relation between maternal concentrations of progranulin (PGRN), adipocyte fatty acid-binding protein (AFABP), brain-derived neurotrophic factor (BDNF), and fibroblast growth factor 21 (FGF21) throughout pregnancy with neonatal weight and length at birth and at one month of age, as well as with the percentage of fat mass at one month of age. Besides, we evaluated the association between maternal organokine concentrations with pregestational nutritional status and gestational weight gain (GWG).MethodsLongitudinal study of 100 healthy pregnant women and their neonates. Conventional biochemical tests were performed and maternal organokine concentrations were measured by ELISA. Neonatal percent fat mass was determined using the PEA POD system, and weight and length were measured using a soft tape measure and a baby scale. Multiple linear regression models were made to predict neonatal anthropometric measurements and adiposity.ResultsIn all women, PGRN concentrations significantly increased as pregnancy progressed, while AFABP concentrations increased until the third trimester and the highest BDNF concentrations were observed in the second trimester of pregnancy. In contrast, FGF21 concentrations did not change during pregnancy. Only maternal obesity was associated with some differences in AFABP and FGF21 concentrations. Gestational age at birth, maternal age and third-trimester PGRN concentrations predicted weight (gestational age at birth: β=0.11; maternal age: β=-0.033; PGRN: β=0.003, p<0.001) and, together with first-trimester BDNF concentrations, length (gestational age at birth: β=0.76; maternal age: β=-0.21; PGRN: β=0.24; BDNF: β=0.06, p<0.001) at birth. Maternal age and third-trimester BDNF concentrations predicted one-month-old neonate length (maternal age: β=-1.03; BDNF: β=0.45, p<0.001). Pregestational body mass index (pBMI), GWG, second-trimester FGF21 concentrations, and third-trimester AFABP concentrations predicted neonatal fat mass percentage (pBMI: β=-0.58; GWG: β=-0.32; FGF21: β=-0.004; AFABP: β=-1.27, p<0.001) at one month of age.ConclusionMaternal PGRN, AFABP, and BDNF concentrations, but not FGF21, vary throughout pregnancy. These organokines and maternal characteristics can be useful in the prediction of neonatal weight, length, and percentage fat mass.

The role of the glucagon-FGF21 axis in improving beta cell function during glucose intolerance and SGLT2 inhibition.

Although primarily secreted by the liver, Fibroblast Growth Factor 21 (FGF21) is also expressed in the pancreas, where its function remains unclear. This study aims to elucidate the role of the glucagon-FGF21 interaction in the metabolic benefits of SGLT2 inhibition (SGLT2i) and hypothesizes it is key to enhancing glucose and lipid metabolism in individuals with glucose intolerance or type 2 diabetes (T2D). FGF21, FGF1R, and β-klotho expression in human pancreas was analysed by RNAscope, qPCR and immunofluorescent techniques. Glucose-stimulated insulin secretion (GSIS) assay was used to investigate the effects of recombinant FGF21 (rFGF21) on islets from donors with glucose intolerance or T2D. To explore the role of the glucagon-FGF21 axis in the benefits of SGLT2i, we used WT and Sglt2 knockout (KO) mice fed a chow diet (CD) or a high-fat diet (HFD) and chronically treated with vehicle or dapagliflozin. Chronic rFGF21 treatment enhanced GSIS in islets from donors with glucose intolerance, with increased FGFR1 expression, suggesting FGF21's greater efficacy in the early stages of disease. In diet-induced insulin-resistant mice, dapagliflozin reduced postprandial glycaemia and elevated plasma glucagon and FGF21 levels. Sglt2 KO mice on a CD showed increased fasting plasma glucagon without changes in FGF21. In diet-induced insulin-resistant Sglt2 KO mice, elevated glucagon and FGF21 levels paralleled chronic dapagliflozin treatment, indicating similar metabolic adaptations in both models. Our findings indicate FGF21 as a crucial mediator in liver-pancreas crosstalk, improving lipid and glucose metabolism, enhancing pancreatic function, and potentiating the therapeutic efficacy of SGLT2i, thereby representing a target for prediabetes treatment.

Fibroblast growth factor 7 (FGF7) causes cartilage destruction, subchondral bone remodeling, and the premature growth plate closure in mice

ObjectiveFibroblast growth factor (FGF) signaling plays a significant role in osteoarthritis (OA) pathogenesis, though the OA-related functions of only a few FGFs have been fully elucidated. This study investigates the specific roles of FGF7 in OA development. MethodsFGF7 expression was analyzed in human (n=6) and mouse (n=10) cartilage. Experimental OA was induced by destabilization of the medial meniscus (DMM). The roles of FGF7 were explored using intra-articular (IA) injection of recombinant FGF7 (rFGF7) and whole-body Fgf7 knockout mice (Fgf7-/-). Subchondral bone remodeling and growth plate morphology were assessed microCT and histological analysis. ResultsFGF7 was upregulated in OA cartilage. IA injection of rFGF7 led to OA cartilage destruction (OARSI grade; 0.61 [95% CI 0.00–5.33]), while Fgf7-/- mice showed reduced DMM-induced cartilage erosion (OARSI grade; 1.89 [95% CI 1.08–3.00]) compared to WT mice (4.92 [95% CI 3.83–5.33]). These effects were associated with changes in matrix-degrading enzyme expression in chondrocytes. Mice receiving IA injection of rFGF7 (20 μg) exhibited increased subchondral bone thickness (68.01 μm [95% CI 61.55–74.46]) and decreased osteoclastogenesis (TRAP positivity; 1.94% [95% CI 1.41–2.47]) compared to controls (38.33 μm [95% CI 33.71–42.96]) and (4.23% [95% CI 3.28–5.19]), respectively. Additionally, rFGF7 treatment caused premature closure of growth plates, whereas Fgf7-/- mice exhibited significantly increased growth plate thickness. ConclusionsFGF7 exerts multiple functions in various joint tissues, including promoting cartilage destruction, inducing subchondral bone remodeling (SBP thickening), and triggering premature growth plate closure.

Plasma fibroblast growth factor 21 and risk of cognitive impairment among patients with ischemic stroke

Background and aimsPrevious study reported that plasma fibroblast growth factor 21 (FGF-21) was associated with poor prognosis in patients with ischemic stroke. The purpose of present study was to prospectively investigate the relationship between plasma FGF-21 and post-stroke cognitive impairment (PSCI). MethodsA total of 600 patients from 7 hospitals were included in this study and plasma FGF-21 levels were examined for all the participants. Cognitive impairment was evaluated using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA) at 3 months after ischemic stroke onset. Results323(53.8 %) or 419(69.8 %) participants had PSCI according to MMSE or MoCA at 3 months, respectively. After adjustment for age, National Institutes of Health stroke score, education, and other covariates, the odds ratio of PSCI defined by MMSE and MoCA for the highest vs lowest quartile of plasma FGF-21 was 1.77(1.05–2.98) and 2.40(1.35–4.29), respectively. Multiple-adjusted spline regression model showed a linear association between FGF-21 levels and PSCI (all P < 0.005 for linearity). Subgroup analyses further confirmed these results. ConclusionElevated plasma FGF-21 level was associated with PSCI at 3 months after stroke independently of established conventional risk factors, suggesting that plasma FGF-21 may have potential prognostic value in risk stratification of PSCI.

Endocrine adaptations to demanding physiological states in ruminants.

Highly productive ruminants rely on hormonally driven adaptations to prioritize the use of limiting nutrients during the demanding phases of the pregnancy-lactation cycle. Glucose, the predominant oxidative fuel of fetal life and the absolute precursor of mammary lactose synthesis, illustrates the need and benefit of such adaptations. Endocrine mechanisms such as insulin resistance and/or hypoinsulinemia favor the diversion of maternal glucose to the placenta or mammary gland where uptake is independent of insulin. Research in dairy cows in the 1980s and 1990s identified growth hormone as a peripherally acting signal opposing the effects of insulin. The following decades have seen the discovery of a new generation of signals secreted almost exclusively by adipose tissue, skeletal muscle or liver, dynamically regulated by metabolic challenges, and engaged in cross-organ communication. The understanding of these signals in the coordination of metabolism in ruminants has been limited by the availability of assays to measure their circulating concentrations and materials to perform functional studies. Nevertheless, emerging data point to their importance during demanding physiological states in ruminants, including early lactation in dairy cows and late pregnancy in sheep. Examples include modulation of insulin action by liver-derived fibroblast growth factor 21 (FGF21) and regulation of energy allocation among tissues by the action of the adipose-derived hormone leptin via its ability to control the hypothalamic-pituitary-thyroid axis. Recent studies investigating the regulation and action of FGF21 and leptin in dairy cows and sheep will be used to illustrate the potential of recently discovered signals to coordinate metabolism during physiologically demanding states such as early lactation.

Fenofibrate attenuates renal lipotoxicity in uninephrectomized mice with high-fat diet-induced obesity.

The objective of this study was to investigate the role of fenofibrate, a peroxisome proliferator-activated receptor-α agonist, in obesity-induced kidney damage (lipotoxicity) in mice with uninephrectomy. C57BL/6 mice underwent uninephrectomy and sham surgeries and were fed normocaloric or high-fat diets. After 10 weeks, obese mice were administered 0.02% fenofibrate for 10 weeks. Kidney function and morphology were evaluated, as well as levels of inflammatory and fibrotic mediators and lipid metabolism markers. High-fat diet-fed mice developed characteristic obesity and hyperlipidemia, with subsequent renal lipid accumulation and damage, including mesangial expansion, interstitial fibrosis, inflammation, and proteinuria. These changes were greater in obese uninephrectomy mice than in obese sham mice. Fenofibrate treatment prevented hyperlipidemia and glomerular lesions, lowered lipid accumulation, ameliorated renal dysfunction, and attenuated inflammation and renal fibrosis. Furthermore, fenofibrate treatment downregulated renal tissue expression of plasminogen activator inhibitor-1, monocyte chemoattractant protein-1, and local expression of fibroblast growth factor-21. Peroxisome proliferator-activated receptor-α activation by fenofibrate, with subsequent lipolysis, attenuated glomerular and tubulointerstitial lesions induced by renal lipotoxicity, thus protecting the kidneys of uninephrectomy mice from obesity-induced lesions. The study findings suggest a pathway in the pharmacological action of fenofibrate, providing insight into the mechanisms involved in kidney damage caused by obesity in kidney donors.

The dual GLP-1/glucagon receptor agonist G49 mimics bariatric surgery effects by inducing metabolic rewiring and inter-organ crosstalk

Bariatric surgery is effective for the treatment and remission of obesity and type 2 diabetes, but pharmacological approaches which exert similar metabolic adaptations are needed to avoid post-surgical complications. Here we show how G49, an oxyntomodulin (OXM) analog and dual glucagon/glucagon-like peptide-1 receptor (GCGR/GLP-1R) agonist, triggers an inter-organ crosstalk between adipose tissue, pancreas, and liver which is initiated by a rapid release of free fatty acids (FFAs) by white adipose tissue (WAT) in a GCGR-dependent manner. This interactome leads to elevations in adiponectin and fibroblast growth factor 21 (FGF21), causing WAT beiging, brown adipose tissue (BAT) activation, increased energy expenditure (EE) and weight loss. Elevation of OXM, under basal and postprandial conditions, and similar metabolic adaptations after G49 treatment were found in plasma from patients with obesity early after metabolic bariatric surgery. These results identify G49 as a potential pharmacological alternative sharing with bariatric surgery hormonal and metabolic pathways.

New insights into FGF21 alleviates diabetic cardiomyopathy by suppressing ferroptosis: a commentary.

Diabetic cardiomyopathy (DCM) is a severe cardiovascular complication of diabetes characterized by myocardial hypertrophy, fibrosis, and impaired cardiac function. Fibroblast growth factor 21 (FGF21) has emerged as a promising therapeutic target due to its antifibrotic, antioxidant, and anti-inflammatory properties. Our commentary summarizes and affirms the recent study by Wang et al., which demonstrates the significant role of ferroptosis in DCM pathogenesis. FGF21 has shown promise as a therapeutic target for DCM, potentially inhibiting ferroptosis, mitigating oxidative damage, and protecting cardiomyocyte function. Mechanistically, the study identified ATF4 as an upstream regulator of FGF21 in DCM, revealing that FGF21 directly interacts with ferritin and extends its half-life, thus inhibiting ferroptosis in DCM. These findings provide a theoretical basis for understanding the pathogenesis and treatment of DCM. Our commentary suggests that future studies should explore the role of non-cardiomyocyte cell types in DCM, verify findings with clinical samples, and address comprehensive methods for ferroptosis detection. Additionally, we discuss the clinical application and future potential of FGF21-based therapies for DCM. Such efforts may contribute to advancing DCM diagnosis and treatment, fostering the development of innovative therapeutic strategies.

Intestinal FXR deficiency induces dysregulation of xanthine oxidase and accounts for sex difference in hyperuricemia

Overproduction of uric acid caused by increased expression and/or enhanced activity of xanthine oxidase (XO) is one of the major etiologies of hyperuricemia, which had a significant sex differences. As an important enzyme involved in production of reactive oxygen species and uric acid, activity of XO is highly correlated with hyperuricemia and its complications. However, the mechanisms underlying XO dysregulation remain unclear, and sex difference in the prevalence of hyperuricemia has been well known. To explore the potential role of intestinal farnesoid X receptor (FXR) on XO regulation and production, and the mechanisms of sex differences in this pathological process. Two hundred and sixty-one dyslipidemia participants and intestine-specific FXR-knockout mice were used to study the relationship between the intestinal FXR and the serum uric acid level. Western blotting, quantitative real-time PCR, and dual-luciferase reporter assay, were applied to clarify the regulatory role of FXR deficiency on XO. Special inhibitors, agonists, siRNA, sex hormones were used to investigate the mechanism of sex difference in FXR deficiency induced hyperuricemia in cell and animal model. Serum fibroblast growth factor 19 (FGF19) levels were lower in hyperuricemia patients in a sex difference manner. Increased local TNFα level driven by intestinal FXR deficiency/inhibition induced overexpression and hyperactivity of intestinal XO, leading to elevated intestinal uric acid synthesis, and subsequently resulting in hyperuricemia. We found that estrogens inhibited XO expression and activity, whereas androgens enhanced XO activity, leading to the sex difference in FXR deficiency induced hyperuricemia. Infliximab treatment eliminated the sex difference in uric acid levels in intestinal FXR-knockout mice. This study demonstrated the role of intestinal FXR in the pathogenesis of hyperuricemia, and partially elucidated the mechanisms underlying the sex differences of hyperuricemia.

Branched-chain amino acids promote hepatic Cyp7a1 expression and bile acid synthesis via suppressing FGF21-ERK pathway.

Branched-chain amino acids (BCAAs) including leucine, isoleucine and valine have been linked with metabolic and cardiovascular diseases. BCAAs homeostasis is tightly controlled by their catabolic pathway. BCKA dehydrogenase (BCKD) complex is the rate-limiting step for BCAA catabolism. Mitochondrial phosphatase 2C (PP2Cm) dephosphorylates the BCKD E1alpha subunit and activates BCKD complex. Deficiency of PP2Cm impairs BCAA catabolism, leading to higher plasma BCAA concentrations. Emerging evidence shows that bile acids are key regulators of glucose, lipid and energy metabolism. In this study, we investigated whether a direct link existed between BCAAs and bile acids metabolism. Wild-type mice were fed with normal-BCAA or high-BCAA diet, while PP2Cm deficiency mice were fed with normal chow for 14 weeks. The mice were fasted for 6 h before tissue harvest to exclude metabolic changes due to immediate food intake. We showed that the bile acids in tissues and feces were significantly elevated in wild-type mice fed with high-BCAA diet as well as in PP2Cm deficiency mice fed with normal chow. These mice displayed significantly increased expression of cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of bile acid synthesis in liver, and 7α-hydroxy-4-cholesten-3-one (C4), a freely diffusible metabolite downstream of CYP7A1 in plasma. BCAAs induced Cyp7a1 expression in cultured hepatocytes. In mouse liver and cultured hepatocytes, we demonstrated that elevated BCAAs inhibited fibroblast growth factor 21 (FGF21) expression and ERK signaling pathway. Direct inhibition of ERK by U0126 (800 nM) markedly induced Cyp7a1 expression in cultured hepatocytes. Moreover, the induced Cyp7a1 expression and inhibitory effects of BCAAs on ERK signaling pathway were abolished by treatment with recombinant FGF21 protein in mouse liver and cultured hepatocytes. Collectively, this study demonstrates a direct link between BCAAs and bile acid synthesis. BCAAs promotes Cyp7a1 expression and bile acid synthesis in liver via inhibiting FGF21-ERK signaling pathway. BCAAs-regulated bile acid synthesis and homeostasis may contribute to developing novel therapeutic strategies for the treatment of metabolic disorders.

Gut microbiotas, inflammatory factors, and mental-behavioral disorders: A mendelian randomization study

BackgroundThe Mendelian randomization approach has emerged as a powerful tool, leveraging genetic variations as natural random experiments to minimize confounding and infer causality with unique advantages. Previous research has highlighted the crucial roles of gut microbiotas and inflammatory factors in mental-behavioral disorders, albeit to varying degrees. However, the precise causal relationship between gut microbiotas and mental-behavioral disorders remains elusive, and the potential role of inflammatory factors as mediators in this process is unclear. MethodsTo investigate the associations between gut microbiotas, inflammatory factors, and mental-behavioral disorders, we pooled data from large-scale genome-wide association studies (GWAS). Our study screened 27 diseases, encompassing nine subtypes of mental-behavioral disorders: neurodevelopmental disorders, eating disorders, sleep disorders, schizophrenia spectrum disorders, stress- and trauma-related disorders, mood and affective disorders, cognitive and executive function disorders, personality and somatization disorders, and addiction disorders. Mendelian randomization(MR) was employed to assess causal relationships between gut microbiotas, inflammatory factors, and these mental-behavioral disorders, with inverse variance weighting (IVW) as the primary statistical method. Furthermore, we explored whether inflammatory factors mediate the relationship between gut microbiotas and mental-behavioral disorders. ResultsHaving investigated the intricate interplay among gut microbiota, inflammatory factors, and mental-behavioral disorders, we have identified nine pivotal inflammatory factors that intricately regulate the progression of eight distinct disease subtypes. Noteworthy among these findings, levels of CC motif chemokine ligand 28 (CCL28) and CC motif chemokine ligand 25 (CCL25) are associated with the progression of attention-deficit/hyperactivity disorder (ADHD), interleukin-18 (IL-18) levels are linked to anorexia, IL-12β levels are related to schizophrenia (SZ) progression, IL-8 levels are associated with manic episodes, and IL-10 and monocyte chemoattractant protein-2 (MCP-2) levels are closely related to enduring personality changes(EPC). Additionally, fibroblast growth factor 19 (FGF19) levels are associated with cognitive disorders, while C-X-C motif chemokine ligand 1 (CXCL1) levels are related to executive functioning. ConclusionGut microbiotas and mental-behavioral disorders have causal relationships, with inflammatory factors mediating the pathway from gut microbiotas to these disorders.

FGF8 protects against polymicrobial sepsis by enhancing the host's anti-infective immunity.

Sepsis is characterized by a life-threatening syndrome caused by an unbalanced host response to infection. Fibroblast Growth Factor 8 (FGF8) has been newly identified to play important roles in inflammation and innate immunity, but its role in host response to sepsis is undefined. A cecal ligation and puncture (CLP) -induced mouse sepsis model was established to evaluate the immunomodulatory function of FGF8 during sepsis. The underlying molecular mechanisms were elucidated by cell models using relevant molecular biology experiments. The clinical value of FGF8 in the adjuvant diagnosis of sepsis was evaluated using clinical samples. FGF8 protein concentrations were elevated in CLP-induced septic mice compared to controls. In vivo, FGF8 blockade using anti-FGF8 antibody significantly increased mortality and bacterial burden and was paralleled by significantly aggravated tissue injury after CLP. Therapeutic administration of recombinant FGF8 (rFGF8) improved the bacterial clearance and mortality of septic mice in a FGFR1-dependent manner. In vitro, FGF8 directly enhanced bacterial phagocytosis and killing of macrophages by enhancing the phosphorylation of the ERK1/2 signaling pathway, which could be abrogated with the ERK1/2 pathway inhibitor U0126. Clinically, serum FGF8 levels in both adult and pediatric patients with sepsis from ICU were significantly higher than those in healthy controls. These results present a previously unrecognized role of FGF8 in improving survival of sepsis by enhancing host immune defense. Therefore, targeting FGF8 may provide new strategies for the diagnosis and immunotherapy of sepsis.

Genome Editing Tools for Improved and Sustainable Livestock Production Systems

Genome editing has great potential to improve production traits such as dairy and meat quality, as well as wool production in livestock species. Some notable examples include the production of the β-lactoglobulin (BLG) knockout resulting in hypoallergenic milk, disruption of the myostatin (MSTN) gene leading to increased muscle mass, longer wool achieved by mutating the fibroblast growth factor 5 (FGF5) gene, and the development of porcine reproductive and respiratory syndrome (PRRS)-resistant pigs through the editing of the CD163 receptor. These advancements demonstrated the immense potential for enhancing productivity, animal health, and welfare to significant impact the economic benefits for farmers and industries. The regulatory landscape for gene-edited animals varies globally; the countries like Argentina, Australia, Brazil, Colombia, and Japan have adopted progressive policies by treating gene- edited animals similarly to those produced by conventional breeding. In conclusion, genome editing technologies have the potential to transform agriculture, promoting sustainability and efficiency in livestock production systems.

Fibroblast growth factor 10 alleviates LPS-induced acute lung injury by promoting recruited macrophage M2 polarization.

Acute lung injury (ALI) is characterized by damage to the alveoli and an overabundance of inflammation. Representing a serious inflammatory condition, ALI lacks a precise treatment approach. Despite the recognized benefit impacts of Fibroblast growth factor-10 (FGF10) on ALI, the underlying mechanisms remain unelucidated. To study the role of FGF10 in ALI, C57BL/6J mice were intratracheally injected with 5mg/kg Lipopolysaccharide (LPS) with FGF10 (5mg/kg) or an equal volume of PBS. Inflammatory factors were quantified in bronchoalveolar lavage fluid (BALF) and plasma using ELISA. RNA sequencing of F4/80+Ly6G- macrophages in BALF explored changes in macrophage phenotype and potential mechanisms. Macrophage polarization in BALF was assessed using qRT-PCR, flow cytometry, and Western blot analysis. In vitro, a Transwell co-culture of mouse lung epithelial cells (MLE12) and bone marrow macrophages (BMDM) validated the role of FGF10 in modulating LPS-induced macrophage phenotypic changes. FGF10 ameliorated LPS-induced ALI by diminishing pro-inflammatory factors (IL-1β, TNF-α, and IL-6) and the neutrophil accumulation in BALF. FGF10 also increased the levels of anti-inflammatory factor IL-10. The FGF10 intervention group exhibited enhanced gene expression of macrophage arginine biosynthesis marker (ARG1), and expression of M2-type marker CD206 in monocytes and macrophages. In addition, phosphorylated STAT3 expression increased in isolated monocyte-derived macrophages. Experiments in vitro confirmed that FGF10 could elevate macrophage M2 marker ARG1 expression through the JAK2/STAT3 pathway. FGF10 ameliorates acute LPS-induced lung injury by modulating the polarization of monocyte-derived macrophages recruited in the alveolar space to the M2 type.

Maternal exercise represses FGF21 via SIRT1 to improve the phenotypic transformation of vascular smooth muscle in hypertensive offspring.

Maternal exercise during pregnancy is widely recognized as an effective means of promoting cardiovascular health in offspring. Few studies have explored how maternal exercise impacts vascular function and phenotypic switching in hypertensive offspring, despite the known involvement of vascular structural and functional remodeling in hypertension pathogenesis. Research indicates a significant relationship between elevated blood pressure and fibroblast growth factor 21 (FGF21) levels. It remains unclear whether maternal exercise during pregnancy can improve vascular function in hypertensive offspring by regulating FGF21 and its underlying mechanisms. In this study, pregnant spontaneously hypertensive rats and Wistar-Kyoto rats were randomly assigned to either a sedentary or exercise group. The exercise group underwent weightless swimming exercise from gestation day 1 (GD1) to GD20. The aim was to investigate the epigenetic modifications mediated by histone deacetylase sirtuin 1 (SIRT1) during the fetal period and the phenotypic changes in the mesenteric arteries (MAs) of hypertensive offspring. We found that maternal exercise significantly improved vascular remodeling in hypertensive offspring. Specifically, maternal exercise upregulated SIRT1 expression, which led to decreased H3K9ac (histone H3 lysine 9 acetylation) in the promoter region of the FGF21 gene. This epigenetic modification resulted in the transcriptional downregulation of FGF21 in the MAs of hypertensive fetuses. These results suggest that maternal exercise may lower blood pressure in hypertensive offspring by regulating deacetylation of the FGF21 gene promoter region through SIRT1, thereby reversing phenotypic switching and vascular structural remodeling.

TMIC-32. INFIGRATINIB INHIBITION OF THE THBS1 PATHWAY IN MELANOMA BRAIN METASTASIS

Abstract INTRODUCTION Despite promising preclinical studies, BRAF/MEK inhibition with vemurafenib in melanoma brain metastases (MBM) has suboptimal durable response in humans. Thrombospondin 1 (THBS1), a matricellular protein, is upregulated in vemurafenib-resistant metastatic melanoma, and its inhibition reverses BRAF inhibitor chemoresistance. However, the characteristics of THBS1-mediated signaling pathways as well as methods of inhibition require further exploration in the context of MBM. OBJECTIVE To characterize THBS1-mediated signaling pathways in MBM and evaluate the therapeutic potential of targeting THBS1 pathways. METHODS We analyzed human parenchymal MBM samples using publicly available single-cell RNA sequencing (scRNA-seq) data. Protein-protein interaction networks were assessed using the STRING database. Syngeneic B16 melanoma cells were intracranially implanted in C57BL/6J mice and treated with intraperitoneal injection of FGF7/FGFR2 small-molecule inhibitor Infigratinib or PBS (sham). Mice were immunophenotyped using flow cytometry and monitored for survival. RESULTS THBS1 is highly upregulated in immunosuppressive MBM-associated cell populations such as S100A8+ Metastasis-Associated Macrophages and Mesenchymal Stromal Cell-like cells. Gene set enrichment analysis of THBS1-positive cells paradoxically revealed upregulation of inflammation-associated gene sets. Differential expression analysis identified Fibroblast Growth Factor 7 (FGF7) as strongly co-expressed in THBS1-positive MBM cells, and STRING-DB confirmed close protein-protein interactions between FGF7 and THBS1. In vivo inhibition using Infigratinib for FGF7’s receptor, FGFR2, decreased the proportion of monocytic myeloid-derived suppressor cells (M-MDSCs) (P=0.030), increased T-cell activation marker IFN-y (P=0.027) and proliferation marker CD69 (P=0.047), and resulted in improved overall survival (P=0.0001). CONCLUSION MBM scRNA-seq data suggests that THBS1 is associated with inflammation-induced immunosuppression. Inhibiting the FGF7/FGFR2-THBS1 axis with Infigratinib modulates the tumor microenvironment by reducing immunosuppressive M-MDSCs and increasing T cell activation and proliferation. This data supports THBS1 inhibition as a viable therapeutic option that in the future can also be combined with other current immunotherapeutic strategies.

Lipidation-dimerization platform unlocks treatment potential of fibroblast growth factor 21 for non-alcoholic steatohepatitis

Optimizing the druggability of both native and AI-designed bioactive proteins is crucial for realizing their therapeutic potential. A key focus in designing protein-based therapeutics is improving their pharmacokinetic properties. However, a significant challenge is to preserve biological activity while implementing long-acting strategies. Fibroblast growth factor 21 (FGF21), an endogenous hormone with potential as a treatment for non-alcoholic steatohepatitis (NASH), exemplifies this challenge. In this study, we present a novel lipidation-dimerization (LiDi) platform that integrates lipidation with a dimeric form of FGF21 connected by a hydrophilic linker. The lipidation enhances albumin binding, enabling sustained release, while the dimeric structure boosts biological activity. In vivo evaluations of the LiDi FGF21 analogs demonstrated that they offer excellent pharmacokinetic properties and superior efficacy compared to other treatments for NASH. This platform effectively extends the therapeutic half-life of proteins without compromising their activity, substantially broadening the application range of proteins as therapeutics.