Search Results (1,552)

Background: Fibroblast growth factor 21 (FGF21), a secreted protein, plays a crucial role in regulating metabolism and energy homeostasis. Nevertheless, the expression pattern of Fgf21 across diverse tissues and its responsiveness to various dietary regimens remain incompletely understood. Methods: In this study, we developed a Fgf21-enhanced green fluorescent protein (EGFP) reporter mouse model to explore the expression of endogenous Fgf21 in different tissues under four dietary conditions: normal chow, low-protein diet, fasting, and fasting-refeeding. Results: A low-protein diet was found to induce Fgf21 expression in both the liver and skeletal muscle. Notably, Fgf21 was predominantly expressed in the periportal region of the liver. In the pancreas, Fgf21 exhibited a patchy expression pattern in the exocrine portion, but was absent in the endocrine part, regardless of the dietary regimens. Regarding the spleen, fasting triggered the expression of Fgf21, which was mainly localized in the red pulp area. Moreover, under fasting conditions, Fgf21 showed a scattered expression pattern in the small intestine. Conclusions: The Fgf21-EGFP reporter mouse model serves as a valuable tool for dissecting the expression of endogenous Fgf21 in different tissues under various dietary and stress conditions. Further investigations using this model may contribute to uncovering the hitherto unrecognized functions of locally produced FGF21. Full article

Androgenetic alopecia is the most common cause of hair loss for women and men. Current treatments for androgenetic alopecia, such as those based on drugs like Minoxidil, Finasteride, or Dutasteride, have been associated with a variety of side effects, such as irritation, contact dermatitis, scalp pruritus, burning, etc. In this regard, plant extracts have emerged as promising alternatives to available chemical-based treatments for androgenetic alopecia given their efficacy, customer acceptability, and potentially minimized side effects. In this study, we evaluated the efficacy of Kyoh^®, an extract from rocket leaves, as a treatment to improve the signs of androgenetic alopecia. We found that Kyoh^® contained 2.1% total flavonoids, with kaempferol, quercetin, and isorhamnetin diglucosides being the most abundant. Additionally, Kyoh^® showed a stimulating effect on the growth of human dermal follicle papilla cells in laboratory conditions. Most importantly, Kyoh^® enhanced the gene expression of the hair growth-associated growth factors VEGF (Vascular Endothelial Growth Factor) and FGF7 (Fibroblast Growth Factor 7). Specifically, VEGF expression increased by 60.7% after 4 h and 267.3% after 24 h, while FGF7 expression increased by 50.3% after 4 h and 244.3% after 24 h, indicating both a rapid induction of gene expression and a sustained effect lasting at least one day. Moreover, Kyoh^® increased the gene expression of NRF2 (Nuclear factor erythroid 2-related factor 2) by 71.2%, which encodes for a protein participating in the antioxidant response. Overall, our study shows that flavonol-rich rocket extract (Kyoh^®) is a promising treatment for promoting hair growth, demonstrated by its proliferation-promoting effect, potential antioxidant priming, and induction of the expression of growth factors associated with hair growth and health. Full article

Background: Fibroblast growth factor (FGF) signaling plays a crucial role in several cellular functions in cancer cells. Tasurgratinib, formerly known as E7090, is an orally available FGF receptor (FGFR)1–3 selective inhibitor. Here, we present the effects of tasurgratinib on the resistance to CDK4/6 inhibitors and endocrine therapy (ET) in a preclinical model. Methods: Estrogen receptor (ER)⁺ breast cancer (BC) patient-derived xenograft (PDX) models harboring ESR1 wild-type or ESR1 mutation were used as animal models. An in vitro cell proliferation assay of ER⁺ BC cell lines treated with fulvestrant or palbociclib + fulvestrant was conducted in the presence of FGF2 and FGF10, with or without tasurgratinib. Results: Among five ER⁺ BC PDX models, OD-BRE-0438 and OD-BRE-0704 showed higher sensitivities to tasurgratinib with prior palbociclib + fulvestrant than without it. In these models, palbociclib + fulvestrant treatment upregulated the expression of several FGF ligand mRNAs. In vitro, FGF2 and FGF10 decreased the sensitivity to both fulvestrant and palbociclib + fulvestrant, which was restored by co-treatment with tasurgratinib. Consistently, fulvestrant + tasurgratinib and elacestrant + tasurgratinib showed antitumor activity in ER⁺ BC PDX models harboring ESR1 wild-type and ESR1 mutation, respectively. In these models, fulvestrant or elacestrant upregulated the expression of several FGF ligand mRNAs. Conclusions: FGF signaling plays a role in resistance to CDK4/6 inhibitors and ET in ER⁺ BC. Tasurgratinib has the potential to exhibit significant antitumor activity in combination with ET against ER⁺ BC via FGF signaling inhibition. These findings indicate the therapeutic potential of tasurgratinib in treating ER⁺ BC. Full article

Huntingtin-interacting protein 1-related (HIP1R) shares some function similarities with HIP1, and HIP1 regulates arthritis and RA fibroblast-like synoviocytes (FLS) invasiveness. Therefore, we hypothesized that HIP1R might be involved in the regulation of FLS phenotypes and molecular processes relevant to RA. siRNA was used to knockdown HIP1R, HIP1 or control in RA FLS, followed by cell studies for invasion in Matrigel, migration, proliferation, and adhesion. RNA was sequenced and analyzed. HIP1R knockdown significantly reduced RA FLS invasiveness and migration (p < 0.05). The DEGs in siRNA HIP1R had an enrichment for GO processes “astrocyte and glial cell projection”, “small GTPase signaling”, and “PDGFR signaling”. The most significantly DEGs had decreased expression in siRNA HIP1R and included AKT1S1, GABBR2, GPR56, and TXNDC12. siRNA HIP1 RA FLS had an enrichment for the “Rap1 signaling pathway” and “Growth factor receptor binding”. The most significantly DEGs in HIP1 siRNA included FGF2, PGF, and SLC39A8. HIP1R and HIP1 DEG lists had a greater than expected number of similar genes (p = 0.0015), suggesting that, despite the major differences detected, both have partially overlapping functions in RA FLS. The most significantly DEGs in both HIP1R and HIP1 analyses are involved in cancer cell behaviors and outcomes. HIP1R is a new gene implicated in RA FLS invasiveness and migration, and regulates unique pathways and cell processes relevant to both RA as well as cancer biology. Our study provides new insight into processes implicated in FLS invasiveness, which is relevant for joint damage in RA, and identify new potential gene targets for FLS-specific treatments. Full article

While whole-genome sequencing (WGS) using short-read technology has become a standard diagnostic test, this technology has limitations in analyzing certain genomic regions, particularly short tandem repeats (STRs). These repetitive sequences are associated with over 50 diseases, primarily affecting neurological function, including Huntington disease, frontotemporal dementia, and Friedreich’s ataxia. We analyzed 2689 cases with movement disorders and dementia-related phenotypes processed at Variantyx in 2023–2024 using a two-tiered approach, with an initial short-read WGS followed by ONT long-read sequencing (when necessary) for variant characterization. Of the 2038 cases (75.8%) with clinically relevant genetic variants, 327 (16.0%) required additional long-read analysis. STR variants were reported in 338 cases (16.6% of positive cases), with approximately half requiring long-read sequencing for definitive classification. The combined approach enabled the precise determination of repeat length, composition, somatic mosaicism, and methylation status. Notable advantages included the detection of complex repeat structures in several genes such as RFC1, FGF14, and FXN, where long-read sequencing allowed to determine somatic repeat unit variations and accurate allele phasing. Further studies are needed to establish technology-specific guidelines for the standardized interpretation of long-read sequencing data for the clinical diagnostics of repeat expansion disorders. Full article

Fibroblast growth factor 21 (FGF21), a hormone-like protein, plays a crucial role in enhancing glucose and lipid metabolism, offering promising therapeutic avenues for conditions such as nonalcoholic steatohepatitis and severe hypertriglyceridemia. Despite its potential, this protein’s limited stability and brief half-life pose significant challenges for its use in clinical settings. In this study, we created an FGF21 analog (named FGF21-164) that is a mutant of FGF21 and fused it with the tandem repeat sequence of human CD164. FGF21-164, characterized by extensive glycosylation and sialylation, exhibits enhanced pharmacokinetic properties, particularly in terms of its significantly longer half-life compared to its native form. The in vitro efficacy of FGF21-164 was evaluated using 3T3-L1-induced adipocytes. The protein demonstrated a dose-dependent increase in glucose uptake and effectively decreased lipid droplet accumulation surrounding the adipocytes. The in vivo activity of FGF21-164 was evaluated in leptin-deficient (ob/ob) and diet-induced obesity (DIO) mice. A single subcutaneous dose of FGF21-164 led to a rapid decrease in blood glucose levels and sustained normal fasting glucose levels for up to 28 days. Additionally, repeated dosing of FGF21-164 significantly curbed weight gain and reduced hepatic fat accumulation in DIO mice. Full article

Cardiovascular disease is the leading cause of death throughout most of the industrialized world. Metabolic syndrome (MetS) and its associated pathologies are underlying factors in the etiology of cardiovascular disease, as well as a plethora of other maladies which cause excess morbidity and mortality. Adipose tissue (AT) has come to be regarded as a bona fide endocrine organ which secretes specific molecular entities constituting part of a complex web of inter-organ crosstalk that functions as a key determinant of whole-body metabolic phenotype. Brown adipose tissue (BAT) has classically been regarded as a thermogenic tissue exerting its metabolic effects primarily through its capacity to oxidize substrates decoupled from ATP resynthesis, thereby resulting in increased energy expenditure (EE) and heat production. However, in recent years, BAT has begun to receive attention as a secretory organ in its own right. The molecules secreted specifically by BAT have been termed “batokines”, and currently available evidence supports the notion that batokines exert favorable metabolic effects on multiple organ systems. While maintenance of healthy body composition by conferring resistance to excessive adiposity is a rather obvious mechanism by which BAT operates via increased EE, effects on critical organs such as the heart remain unclear. This narrative review focuses on four types of batokines (FGF21, neuregulin 4, 12,13-diHOME, and BAT-derived microRNAs) for which evidence of modulation of cardiovascular function exists in the context of pathological states such as hypertension, atherosclerosis, and ischemia/reperfusion injury. Given the overwhelming burden of cardiometabolic disease, further study of the functions of BAT and its secretome is warranted and will intensify in the future. Full article

Background/Objectives: Carotid artery disease is a condition affecting 3% of the general population which significantly contributes to the development of cerebrovascular events. Fibroblast Growth Factor-23 (FGF-23) is a hormone that has been linked to atherosclerosis and increased cardiovascular risk, including stroke and myocardial infarction. This review explores the association of FGF-23 with carotid artery disease progression in an endarterectomy clinical context. Methods: Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), a search was performed relying on MEDLINE, Scopus and Web of Science, identifying publications focused on the correlation between serum FGF-23 and carotid artery disease. Assessment of study quality was made using National Heart, Lung and Blood Institute Study Quality Assessment Tool (NHLBI). Results: Three observational studies, comprising 1039 participants, were included. There was considerable heterogeneity among the populations from the different studies. Elevated FGF-23 levels were consistently associated with unstable plaque features, including intraplaque neovascularization, as identified through Superb Microvascular Imaging (SMI). Plasma levels of inflammatory mediators, such as Interleukin-6 (Il-6), Monocyte Chemoattractant Protein-1 (MCP-1), and Osteoprotegerin (OPG), positively correlated with carotid artery disease, but their link to unstable plaques is conflicting. None of the studies investigated clinical complications following carotid endarterectomy. Conclusions: FGF-23 is a potential biomarker for plaque vulnerability in carotid disease. Despite promising findings, limitations such as small sample sizes and lack of longitudinal data suggest the need for larger and more diverse studies to improve risk stratification and inform personalized treatment strategies for carotid atherosclerosis. Full article

Background: FGF23 is a phosphate homeostasis regulator; the literature suggests a link between FGF23, iron homeostasis and erythropoiesis. Little is known about the FGF23 level variations in β-thalassemia (βT), which is characterized by ineffective erythropoiesis and iron overload. Our cross-sectional study aims to evaluate the iFGF23 level variations in a large cohort of βT patients considering their bone mineral densities (BMDs) and iron loads. Methods: Clinical, biochemical and radiological data were collected from 213 transfusion-dependent βT (TDT) adults referring to the Regional HUB Centre for Thalassaemia and Haemoglobinopathies in Ferrara, Italy. The iFGF23 levels in the TDT patients were compared to the general population’s reference range. The BMDs and hearth and liver iron deposits were assessed with DEXA scans and MRI, respectively. Results: The iFGF23 distribution in the TDT subjects is significantly different from that of the general population. The iFGF23 levels are positively correlated with the age at transfusion initiation and calcium and phosphate levels and are negatively correlated with the osteocalcin plasma levels. Patients treated with deferasirox had lower iFGF23 levels than those treated with other chelators. The iFGF23 levels are not correlated with the BMD or iron status. Conclusions: These findings provide insights into the relationship between the iFGF23 and bone and iron metabolism in TDT patients. Further studies are needed to explore its potential clinical relevance. Full article

Background: The mechanisms of diabetes remission following bariatric surgery independent of calorie restriction and weight loss remain unclear. Objectives: To undertake a systematic review and meta-analysis to investigate mechanisms underpinning diabetes remission. Methods: We included individuals with type 2 diabetes who have undergone RYGB, SG, and a very low-calorie diet (VLCD). In total, 234 studies were identified (N = 52 for qualitative; N = 40 for quantitative synthesis). Review Manager v5.4 and IBM SPSS for Windows (v28.0.1.1) were used for analysis. Results: Crude annualised diabetes relapse rates for RYGB and SG are as follows: −6.98 ± 16.19 (p = 0.046) and −2.75 ± 4.94 (p = 0.08); crude remission rates for RYGB and SG, respectively, are as follows: 39.59 ± 45.93 (p = 0.000) and 33.36 ± 33.87 SG (p = 0.006). Differences in other metabolic outcomes (standardised mean difference and 95% confidence intervals (CIs)) are BMI: ([RYGB: −2.73, 95%CI: −3.14 to −2.32, p < 0.000001) (SG: −2.82, 95%CI: −5.04 to −0.60, p = 0.01)]; HbA1c: [(RYGB: −1.58, 95%CI: −2.16 to −1.00, p < 0.00001) (SG: −1.42, 95%CI: −1.69 to −1.15, p < 0.00001)]; insulin: [(RYGB: 0.16, 95%CI: −0.19 to −0.50, p = 0.37) (SG: −3.00, 95%CI: −3.17 to −2.82, p = 0.75)]; and fat mass [(RYGB: −2.56, 95%CI: −4.49 to −0.64, p = 0.009) (SG: −1.69, 95%CI: −4.58 to 1.21, p = 0.25)]. RYGB and SG produced a significant improvement in HOMA-B measurements. Adiponectin and the Matsuda index were significantly increased with RYGB. No difference was observed for other metabolic markers (RYGB: GLP-1, GIP, leptin, ghrelin, PYY) (SG: GLP-1 and FGF19) (VLCD: leptin, GLP-1, GIP, and ghrelin). Conclusions: Diabetes remission following RYGB and SG was primarily driven by improvement in beta-cell function, with improvement in insulin resistance markers also observed for RYGB, driven by reductions in fat mass. No other metabolic mechanism explaining diabetes remission was observed based on clinical studies. Full article

Recent advancements in tissue engineering and stem cell science have positioned bone disease treatment as a promising frontier in regenerative medicine. This review explores the hormonal and signaling pathways critical to bone regeneration, with a focus on their clinical relevance. Key endocrine factors, including thyroid hormones (T3 and T4), insulin-like growth factor 1 (IGF-1), bone morphogenetic proteins (BMPs), parathyroid hormone (PTH), calcitonin, and fibroblast growth factor 23 (FGF23), play pivotal roles in bone remodeling by regulating osteoblast activity, bone resorption, and mineralization. These factors primarily act through the Wnt/β-catenin, BMP, and FGF signaling pathways, which govern bone repair and regeneration. While animal models, such as axolotls, zebrafish, and Xenopus laevis, provide valuable findings about these mechanisms, translating these findings into human applications presents challenges. This review underscores the therapeutic potential of modulating these hormonal networks to enhance bone regeneration while cautioning against possible adverse effects, such as uncontrolled tissue proliferation or metabolic imbalances. By integrating knowledge from regenerative models, this work provides a foundation for optimizing hormone-based therapies for clinical applications in bone repair and disease treatment. Full article

Background: Quantifying and controlling the inbreeding level in livestock populations is crucial for the long-term sustainability of animal husbandry. However, the extent of inbreeding has not been fully understood in sheep populations on a global scale. Methods: Here, we analyzed high-depth genomes of 210 sheep from 20 worldwide breeds to identify the pattern and distribution of genome-wide runs of homozygosity (ROH) and detect candidate selected genes in ROH islands for agronomic and phenotypic traits. Results: Leveraging whole-genome sequencing data, we found a large number of short ROH (e.g., <1.0 Mb) in all breeds and observed the overall higher values of ROH statistics and inbreeding coefficient in European breeds than in Asian breeds and Dorper sheep. We identified some well-known candidate genes (e.g., CAMK4, HOXA gene family, ALOX12, FGF11, and MTOR) and 40 novel genes (e.g., KLHL1, FGFRL1, WDR62, GDF6, KHDRBS2, and PAX1) that are functionally associated with fecundity, body size, and wool-related traits in sheep. Based on the candidate genes, we revealed different genetic bases for the fecundity traits of European and Asian sheep. Conclusions: This study improves the resolution of ROH detection and provides new insights into genomic inbreeding and trait architecture in sheep as well as useful markers for future breeding practice. Full article

Objective: Rat sarcoma (Ras) proteins, Kirsten, Harvey, and Neuroblastoma rat sarcoma viral oncogene homolog (KRAS, HRAS, and NRAS, respectively), are a family of GTPases, which are key regulators of cellular growth, differentiation, and apoptosis through signal transduction pathways modulated by growth factors that have been recognized to be dysregulated in PCOS. This study explores Ras signaling proteins and growth factor-related proteins in polycystic ovary syndrome (PCOS). Methods: In a well-validated PCOS database of 147 PCOS and 97 control women, plasma was batch analyzed using Somascan proteomic analysis for circulating KRas, Ras GTPase-activating protein-1 (RASA1), and 45 growth factor-related proteins. The cohort was subsequently stratified for BMI (body mass index), testosterone, and insulin resistance (HOMA-IR) for subset analysis. Results: Circulating KRas, and RASA1 did not differ between PCOS and control women (p > 0.05). EGF1, EGFR, and EGFRvIII were decreased in PCOS (p = 0.04, p = 0.04 and p < 0.001, respectively). FGF8, FGF9, and FGF17 were increased in PCOS (p = 0.02, p = 0.03 and p = 0.04, respectively), and FGFR1 was decreased in PCOS (p < 0.001). VEGF-D (p < 0.001), IGF1 (p < 0.001), IGF-1sR (p = 0.02), and PDGFRA (p < 0.001) were decreased in PCOS compared to controls. After stratifying for BMI ≤ 29.9 kg/m², EGFR FGF8, FGFR1 VEGF-D, IGF1, and IGF-1sR differed (p < 0.05) though EGF1, EGFRvIII, FGF8, FGFR1, and VEGF-D no longer differed; after subsequently stratifying for HOMA-IR, only FGFR1, VEGF-D, IGF1, and IGF-1sR differed between groups (p < 0.05). Conclusions: Several growth factors that activate Ras differ between women with and without PCOS, and when stratified for BMI and HOMA-IR, only FGFR1, VEGF-D, IGF1, and IGF-1sR differed; these appear to be inherent features of the pathophysiology of PCOS. Full article

The continuous use of antibiotics is associated with many complications in the poultry industry. Probiotics have emerged as a viable alternative over the past few decades to counter the adverse effects of antibiotics. No candidate probiotic microorganisms have been fully evaluated in the poultry industry for their effectiveness as potential probiotics in guinea fowls (GFs) compared to chickens. Recently, a metagenome evaluation of GFs in our laboratory revealed a predominance of Lactobacillus reuteri (L. reuteri) and actinobacteria class of bacteria in their gastrointestinal tract. The aim of this study is to evaluate a well-known lactic acid probiotic bacterium (L. reuteri) and a unique probiotic (S. coelicolor) that has not been assessed in any guinea fowl species. In the current study, L. reuteri and Streptomyces coelicolor (S. coelicolor) were selected as probiotic bacteria, encapsulated, and added into French guinea fowl (FGF) feed individually at a concentration of 10⁸ cfu/g or both microorganisms combined each at 10⁴ cfu/g. In an 8-week study, 216-day-old guinea keets were randomly assigned to four dietary treatments as indicated: (1) L. reuteri (10⁸ cfu/g); (2) S. coelicolor (10⁸ cfu/g); (3) mixture of L. reuteri (10⁴ cfu/g) and S. coelicolor (10⁴ cfu/g); and (4) control treatment (no probiotics included). The L. reuteri, S. coelicolor, and L. reuteri + S. coelicolor were added into the feed using wheat middlings as a carrier at a final concentration of 10⁸ cfu/g. The FGFs that were fed diets containing L. reuteri showed improved feed consumption at 3–8 weeks of age (WOA). The guineas fed L. reuteri and S. coelicolor showed a lower feed conversion ratio (FCR), which was significant at 2 and 8 WOA, and a numerically lower 8-week average FCR when compared with other dietary treatments. Differences in body weight gain among all dietary treatments were not significant. This research suggests that L. reuteri and S. coelicolor may have the potential for use as probiotics in FGFs when used in combination or separately. Full article

MicroRNAs function as post-transcriptional regulators in gene expression and control a broad range of biological processes in metazoans. The formation of multinucleated muscles is essential for locomotion, growth, and muscle repair. microRNAs have also emerged as important regulators for muscle development and function. In order to identify new microRNAs required for muscle formation, we have performed a large microRNA overexpression screen. We screened for defects during embryonic and adult muscle formation. Here, we describe the identification of mir-276a as a regulator for muscle migration during testis formation. The mir-276a overexpression phenotype in testis muscles resembles the loss-of-function phenotype of heartless. A GFP sensor assay reveals that the 3′UTR of heartless is a target of mir-276a. Furthermore, we found that mir-276a is essential for the proper development of indirect flight muscles and describe a method for determining the number of nuclei for each of the six longitudinal muscle fibers (DLMs), which are part of the indirect flight muscles. Full article