Fibroblast Growth Factor Receptor 4 Research Articles

Discovery of 2,6-Naphthyridine Analogues as Selective FGFR4 Inhibitors for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer and is responsible for 90% of cases. Approximately 30% of patients diagnosed with HCC are identified as displaying an aberrant expression of fibroblast growth factor 19 (FGF19)-fibroblast growth factor receptor 4 (FGFR4) as an oncogenic-driver pathway. Therefore, the control of the FGF19-FGFR4 signaling pathway with selective FGFR4 inhibitors can be a promising therapy for the treatment of HCC. We herein disclose the design and synthesis of novel FGFR4 inhibitors containing a 2,6-naphthyridine scaffold. Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

Influence of temperature on embryonic development of Pontastacus leptodactylus freshwater crayfish, and characterization of growth and osmoregulation related genes

Narrow clawed crayfish, Pontastacus (Astacus) leptodactylus, represents an ecologically and economically valuable freshwater species. Despite the high importance of artificial breeding for conservation purpose and aquaculture potential, hatching protocols have not been developed so far in this species. Further, limited knowledge exists regarding the artificial egg incubation, the temperature effect on embryonic development, hatching synchronization and hatching rate. In the present study we investigated the temperature increase (from 17 oC to 22oC) effects in two different embryonic developmental stages of P. leptodactylus. Furthermore, two primer pairs for the Fibroblast Growth Factor Receptor 4 (FGFR4) gene cDNA amplification were successfully designed, characterising for the first time the FGFR4 gene in P. leptodactylus in relation to different developmental stages and temperatures. Apart from the FGFR4 gene, the Na+/K+-ATPase α-subunit expression was also explored. Both the FGFR4 and Na+/K+-ATPase α-subunit expression levels were higher in embryos closer to hatching. Egg incubation at 22oC for seven days led to significant increase of FGFR4 expression in embryos from earlier developmental stages. Nevertheless, temperature increase did not affect FGFR4 expression in eggs from latter developmental stages and Na+/K+-ATPase α-subunit expression in all developmental stages. Temperature increase represents therefore probably a promising strategy for accelerating hatching in freshwater crayfish particularly in early developmental stages. Specifically, our results indicate that FGFR4 expression increased in embryonic stages closer to hatching and that temperature influences significantly its expression in embryos from earlier developmental stages. Overall, these findings can provide a better understanding of artificial egg incubation of P. leptodactylus, and therefore can be employed for the effective management of this species, both for economic and biodiversity retention reasons.

Development of Highly Potent and Selective Covalent FGFR4 Inhibitors Based on SNAr Electrophiles.

Fibroblast growth factor receptor 4 (FGFR4) is thought to be a driver in several cancer types, most notably in hepatocellular carcinoma. One way to achieve high potency and isoform selectivity for FGFR4 is covalently targeting a rare cysteine (C552) in the hinge region of its kinase domain that is not present in other FGFR family members (FGFR1-3). Typically, this cysteine is addressed via classical acrylamide electrophiles. We demonstrate that noncanonical covalent "warheads" based on nucleophilic aromatic substitution (SNAr) chemistry can be employed in a rational manner to generate highly potent and (isoform-)selective FGFR4 inhibitors with a low intrinsic reactivity. Key compounds showed low to subnanomolar potency, efficient covalent inactivation kinetics, and excellent selectivity against the other FGFRs, the kinases with an equivalent cysteine, and a representative subset of the kinome. Moreover, these compounds achieved nanomolar potencies in cellular assays and demonstrated good microsomal stability, highlighting the potential of SNAr-based approaches in covalent inhibitor design.

Hypericin alleviates Chronic Kidney Disease induced Left Ventricular Hypertrophy via regulation of FGF23-FGFR4 signaling pathway.

Chronic kidney disease (CKD) is a significant global health threat that imposes a substantial burden on both individuals and societies. CKD frequently correlates with cardiovascular events, particularly left ventricular hypertrophy (LVH), which contributes to the high mortality rate associated with CKD. Fibroblast growth factor (FGF) 23, a hormone primarily involved in regulating calcium and phosphorus metabolism, has been identified as a major risk factor for LVH in CKD patients. Elevated serum FGF23 levels are known to induce LVH and myocardial fibrosis by activating the FGF receptor 4 (FGFR4) signal pathway. Therefore, targeting FGFR4 and its downstream signaling pathways holds potential as a treatment strategy for cardiac dysfunction in CKD. In our current study, we have discovered that Hypericin, a key component derived from Hypericum perforatum, has the ability to alleviate CKD-related LVH by targeting the FGFR4/phospholipase C gamma 1 (PLCγ1) signaling pathway. Through in vitro experiments using rat cardiac myocyte H9c2 cells, we observed that Hypericin effectively inhibits FGF23-induced hypertrophy and fibrosis by suppressing the FGFR4/PLCγ1/calcineurin/nuclear factor of activated T-cell (NFAT3) signaling pathway. Additionally, our in vivo studies using mice on a high phosphate diet and rat models of 5/6 nephrectomy demonstrated that Hypericin has therapeutic effects against CKD-induced LVH by modulating the FGFR4/PLCγ1/calcineurin/NFAT3 signaling pathway. In conclusion, our research highlights the potential of Hypericin as a candidate for the treatment of CKD-induced cardiomyopathy. By suppressing the FGFR4/PLCγ1 signaling pathway, Hypericin shoaws promise in attenuating LVH and myocardial fibrosis associated with CKD.

Abstract 638: FGFR4 mediates nuclear accumulation of NRF2 by binding to P62 in gastric cancer

Abstract Background: Helicobacter pylori (H. pylori) is the major cause of gastric cancer. Fibroblast growth factor receptor 4 (FGFR4) is a member of the highly conserved tyrosine kinase family known to be activated in cancer. Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), a transcription factor, is essential for the antioxidant response and exhibits cytoprotective properties against cellular stress and oxidative damage. This study investigates the novel functions of FGFR4 and its role in regulating the antioxidant response in gastric tumorigenesis. Methods: We used public datasets, gastric tissues from mice and human, and gastric cancer cell lines. In vitro and in vivo H. pylori infections were performed. Western blot, RT-qPCR, Immunofluorescence, flow cytometry, Immunohistochemistry, Immunoprecipitation, Proximity ligation assay and Luciferase reporter assays were performed. Results: The analysis of a public dataset revealed that overexpression of FGFR4 is associated with an oxidative stress signature and poor survival. Gene set enrichment analysis (GSEA) showed that tissue samples with high FGFR4 levels had an enrichment of NRF2 signature genes. In vitro cell models infected with H. pylori showed an increase in reactive oxygen species (ROS). Knockdown of FGFR4 resulted in significant reductions in NRF2 protein and transcriptional activity, leading to increased ROS levels and DNA damage. Immunofluorescence analysis using various models confirmed that FGFR4 knockdown reversed the accumulation of NRF2 in the nucleus. Dysplastic and neoplastic gastric lesions in the TFF1-KO mouse model exhibited high levels of both FGFR4 and NRF2. Pharmacologic inhibition or knockdown of FGFR4 significantly decreased NRF2 levels, as well as the size and number of gastric cancer spheroids. Mechanistically, elevated levels of P62 protein were associated with FGFR4 expression. Binding between FGFR4 and P62 proteins, which competes with NRF2-KEAP1 interaction, was detected using immunoprecipitation and proximity ligation assay. Immunohistochemistry analysis on a tissue microarray showed increased FGFR4 immunostaining in HGD/Cancer samples compared to adjacent normal samples, and this increase correlated with an increase in NRF2 and P62 levels. Conclusion: These findings revealed that FGFR4 has a distinct functional role in promoting gastric carcinogenesis. FGFR4 binds to P62 to inhibit the interaction between NRF2 and KEAP1, allowing NRF2 to avoid degradation facilitating its translocation and accumulation in the nucleus. The use of FGFR4 inhibitors is a viable treatment option that warrants further research in patients with gastric cancer. Citation Format: Nadeem S. Bhat, Mohammed Soutto, Xing Zhang, Zheng Chen, Shoumin Zhu, Selma Maacha, Melanie Genoula, Dunfa Peng, Heng Lu, Oliver G McDonald, Xi Steven Chen, Longlong Cao, Zekuan Xu, Wael El-Rifai. FGFR4 mediates nuclear accumulation of NRF2 by binding to P62 in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 638.

Abstract 1963: BB102, a highly selective and potent reversible-covalent FGFR4 inhibitor effective in multiple xenograft tumor models

Abstract Introduction: Fibroblast growth factor receptor 4 (FGFR4) belongs to the FGFR family which interact with fibroblast growth factors (FGFs) to regulate cell proliferation, differentiation and apoptosis. Due to unique structural domain, FGFR4 is specifically bound by FGF19 with high affinity in the presence of co-receptor β-Klotho. Hyperactivated FGF19/FGFR4 signaling, induced by FGF19/FGFR4 overexpression and FGFR4 mutation, was reported to be associated with the growth, metastasis and invasion of various cancer. Thus, FGFR4 is considered as a novel target to treat cancer with hyperactivated FGF19/FGFR4 signaling. Here we report BB102 as a highly selective and potent reversible-covalent FGFR4 inhibitor. Methods: BB102 was developed through structure-based drug design, and optimized by SAR analysis and medicinal chemistry iteration. Biochemical and cell assays were applied in evaluation of BB102 inhibitory activity. Preclinical studies including pharmacokinetic (PK) and toxicity were performed in rats and dogs. Xenograft tumor models in mice were conducted to demonstrate the in vivo efficacy of BB102. Results: As a reversible-covalent FGFR4 inhibitor, about half compound of BB102 dissociated from FGFR4 kinase within 24 h, which was conducive to overcome the fast re-synthesis rate of FGFR4 (< 2 h) in hepatocellular carcinoma cells. BB102 only inhibited kinase activity of FGFR4WT, FGFR4N535K and FGFR4V550L at nanomolar levels in 207 kinase panel screening. BB102 completely blocked the phosphorylation of the downstream protein ERK at 16.7 nM. BB102 exhibited strong inhibitory effects on the cell proliferation in vitro and tumor growth in mouse models inoculated with the high expression of both FGF19 and FGFR4, or FGFR4 mutated tumor cells. PK profile of BB102 showed good oral bioavailability (F>70%) with a nearly linear dose-dependent exposure. The compound had no effects on the respiratory and central nervous systems in rats, cardiovascular system in Beagle dogs or hERG liability in vitro. In comprehensive safety evaluation, the Severely Toxic Dose in 10% (STD10) in rats was 300 mg/kg/day and the Highest Non-Severely Toxic Dose (HNSTD) in dogs were 100 mg/kg/day. Conclusion: BB102 is a highly selective and potent reversible-covalent FGFR4 inhibitor with promising efficacy in high expression of both FGF19 and FGFR4, and/or FGFR4 mutated tumor models and good safety in preclinical studies. The phase I study of BB102 is in progress. Citation Format: Qi Wang, Gongping Duan, Wei Hua, Xianglong Wei, Min Li, Junheng Wang, Xingmin Zhang. BB102, a highly selective and potent reversible-covalent FGFR4 inhibitor effective in multiple xenograft tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1963.

Mechanism of Tianma-Gouteng granules lowering blood pressure based on the bile acid-regulated Farnesoid X Receptor-Fibroblast Growth Factor 15- Cholesterol 7α-hydroxylase pathway

Ethnopharmacological relevanceTianma-Gouteng granules (TGG) is a traditional Chinese medicine (TCM) compound that was first recorded by modern medical practitioner Hu Guangci in "New Meaning of the Treatment of Miscellaneous Diseases in Traditional Chinese Medicine". It is widely used to treat hypertensive vertigo, headache and insomnia. Aim of studyTo investigate the antihypertensive effect of TGG and explore its mechanism. Materials and methodsSpontaneously hypertensive rats (SHR) were prepared a model of the ascendant hyperactivity of liver yang syndrome (AHLYS), blood pressure and general state of rats were recorded. A series of experiments were performed by enzyme-linked immunosorbent assay (ELISA), ultra high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS), 16S rRNA sequencing, real-time fluorescence quantitative PCR (RT-qPCR), and enzymatic colorimetry. ResultsTGG can effectively lower blood pressure and improve related symptoms. TGG significantly reduced the levels of IL-1β, IL-6, TNF-α, Renin and AngII. A total of 17 differential metabolites were found in plasma, with the two most potent metabolic pathways being glycerophospholipid metabolism and primary bile acid biosynthesis. After TGG intervention, 7 metabolite levels decreased and 10 metabolite levels increased. TGG significantly increased the relative abundance of Desulfovibio, Lachnoclostridium, Turicibacter, and decreased the relative abundance of Alluobaculum and Monoglobu. TGG also downregulated Farnesoid X Receptor (FXR) and Fibroblast Growth Factor 15 (FGF15) levels in the liver and ileum, upregulated Cholesterol 7α-hydroxylase (CYP7A1) levels, and regulated total bile acid (TBA) levels. ConclusionTGG can regulate bile acid metabolism through liver-gut axis, interfere with related intestinal flora and plasma metabolites, decrease blood pressure, and positively influence the pathologic process of SHR with AHLYS. When translating animal microbiota findings to humans, validation studies are essential to confirm reliability and applicability, particularly through empirical human research.

Unveiling the mechanism of Buddleja officinalis against esophageal squamous cell carcinoma through network pharmacology and molecular docking approaches

In this research, we aim to explore the underlying mechanism of Buddleja officinalis (BO) in inhibiting esophageal squamous cell carcinoma (ESCC) by means of network pharmacology and molecular docking approaches. First, BO component targets were determined from the Traditional Chinese Medicine Systematic Pharmacology and HERB databases (known as BenCaoZuJian in Chinese transliteration), and ESCC disease targets were identified from GeneCards and DisGeNET databases. Second, the Venny 2.1 online tool was utilized to visualize the intersection targets, and shared potential targets between BO and ESCC were identified using the STRING database. Third, the component-target-pathway networks were constructed using Cytoscape software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were utilized for further analyzing the mechanism of BO in inhibiting ESCC. Finally, molecular docking technique was employed to delineate the docking profiles of BO and determine the optimal active component, which is threonine protein kinase (AKT1). We screened six active components and 227 targets from BO, of which 24 were shared targets of ESCC and BO. The network pharmacology analysis indicated core targets with high degrees, namely, serum albumin, insulin-like growth factor 1 receptor, AKT1, estrogen receptor, and basic fibroblast growth factor receptor 1, which are the most likely binding sites for the active components in BO. The related signaling pathways underpinning the inhibition of ESCC by BO encompass MAPK signaling pathway, adhesion junction pathway, and gastric cancer pathway. Moreover, linarin was recognized as the most suitable component for AKT1. Our results revealed that BO exhibits multicomponent, multi-target, and multi-pathway characteristics, which offer a scientific foundation for elucidating its therapeutic mechanism in ESCC and present novel insights for future investigations.

Sarcopenia is associated with hypomethylation of TWEAK and increased plasma levels of TWEAK and its downstream inflammatory factor TNF-α in older adults: A case-control study

BackgroundSarcopenia is a harmful condition common among older adults for which no treatment is available. Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor inducible 14 (FN14) are known to play important roles in the pathogenesis of sarcopenia. This study investigated alterations in methylation in TWEAK and Fn14 to identify potential targets for the managing sarcopenia. Materials and methodsThrough an epidemiological investigation, we detected methylation of CpG islands (CpGs) in TWEAK and Fn14 in community-dwelling older adult of Xinjiang by bisulfite sequencing. Significant CpGs associated with sarcopenia were selected for detection in 152 older individuals by pyrosequencing. Associations between CpG methylation, plasma inflammatory marker levels, and sarcopenia were analyzed. ResultsOf 38 CpGs in TWEAK and 30 CpGs in Fn14 detected in 60 individuals, 6 CpGs showed lower methylation in sarcopenia patients compared with control individuals. In 152 older adults, covariance analysis with adjustment for age, gender, triglyceride level, obesity, diabetes, and hypertension showed that the methylation levels of 6 CpGs (CpG8, CpG12, CpG13, CpG20 and CpG21of TWEAK, and CpG24 of Fn14) were significantly lower in sarcopenia patients than in control individuals. With adjustment for additional confounding factors, covariate variance analysis showed that plasma TWEAK, TNF-α and IL-10 levels in the sarcopenia group were significant higher than those in the control group (P = 0.007, P < 0.001, P = 0.003). Multivariate logistic regression analysis showed that CpG8, CpG13, CpG21, and total methylation of TWEAK (OR = 0.767, 95 % CI = 0.622–0.947; OR = 0.740, 95 % CI = 0.583–0.941; OR = 0.734, 95 % CI = 0.561–0.958; OR = 0.883, 95 % CI = 0.795–0.980) as well as CpG22 and total methylation of Fn14 were significantly associated with sarcopenia (OR = 826, 95 % CI = 0.704–0.968; OR = 0.918, 95 % CI = 0.852–0.989). From partial correlation analysis, plasma TWEAK was correlated with plasma TNF-α (r = 0.172, P = 0.042). ConclusionSarcopenia is associated with hypomethylation of TWEAK and increased plasma levels of TWEAK and its downstream inflammatory factor TNF-α in a community-dwelling population of older adults in Xinjiang.

Discovery of 6-Formylpyridyl Urea Derivatives as Potent Reversible-Covalent Fibroblast Growth Factor Receptor 4 Inhibitors with Improved Anti-Hepatocellular Carcinoma Activity.

Fibroblast growth factor receptor 4 (FGFR4) has been considered as a potential anticancer target due to FGF19/FGFR4 mediated aberrant signaling in hepatocellular carcinoma (HCC). Several FGFR4 inhibitors have been reported, but none have gained approval. Herein, a series of 5-formyl-pyrrolo[3,2-b]pyridine-3-carboxamides and a series of 6-formylpyridyl ureas were characterized as selective reversible-covalent FGFR4 inhibitors. The representative 6-formylpyridyl urea 8z exhibited excellent potency against FGFR4WT, FGFR4V550L, and FGFR4V550M with IC50 values of 16.3, 12.6, and 57.3 nM, respectively. It also potently suppressed proliferation of Ba/F3 cells driven by FGFR4WT, FGFR4V550L, and FGFR4V550M, and FGFR4-dependent Hep3B and Huh7 HCC cells, with IC50 values of 1.2, 13.5, 64.5, 15.0, and 20.4 nM, respectively. Furthermore, 8z displayed desirable microsomal stability and significant in vivo efficacy in the Huh7 HCC cancer xenograft model in nude mice. The study provides a promising new lead for anticancer drug discovery directed toward overcoming FGFR4 gatekeeper mutation mediated resistance in HCC patients.

Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine.

Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein-coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.

Fibroblast growth factor receptor-4 mediates activation of Nuclear Factor Erythroid 2-Related Factor-2 in gastric tumorigenesis

Helicobacter pylori (H. pylori) is the leading risk factor for gastric carcinogenesis. Fibroblast growth factor receptor 4 (FGFR4) is a member of transmembrane tyrosine kinase receptors that are activated in cancer. We investigated the role of FGFR4 in regulating the cellular response to H. pylori infection in gastric cancer. High levels of oxidative stress signature and FGFR4 expression were detected in gastric cancer samples. Gene set enrichment analysis (GSEA) demonstrated enrichment of NRF2 signature in samples with high FGFR4 levels. H. pylori infection induced reactive oxygen species (ROS) with a cellular response manifested by an increase in FGFR4 with accumulation and nuclear localization NRF2. Knocking down FGFR4 significantly reduced NRF2 protein and transcription activity levels, leading to higher levels of ROS and DNA damage following H. pylori infection. We confirmed the induction of FGFR4 and NRF2 levels using mouse models following infection with a mouse-adapted H. pyloristrain. Pharmacologic inhibition of FGFR4 using H3B-6527, or its knockdown, remarkably reduced the level of NRF2 with a reduction in the size and number of gastric cancer spheroids. Mechanistically, we detected binding between FGFR4 and P62 proteins, competing with NRF2-KEAP1 interaction, allowing NRF2 to escape KEAP1-dependent degradation with subsequent accumulation and translocation to the nucleus. These findings demonstrate a novel functional role of FGFR4 in cellular homeostasis via regulating the NRF2 levels in response to H. pylori infection in gastric carcinogenesis, calling for testing the therapeutic efficacy of FGFR4 inhibitors in gastric cancer models.

FGF19/FGFR4 signaling contributes to hepatocellular carcinoma survival and immune escape by regulating IGF2BP1-mediated expression of PD-L1

Immune-checkpoint blockade (ICB) therapies have been widely used in clinical treatment of cancer patients, but only 20–30% of patients benefit from immunotherapy. Therefore, it is important to decipher the molecular mechanism of resistance to ICB and develop new combined treatment strategies. PD-L1 up-regulation in tumor cells contributes to the occurrence of immune escape. Increasing evidence shows that its transcription level is affected by multiple factors, which limits the objective response rate of ICB. Fibroblast growth factor 19 (FGF19), a member of the fibroblast growth factor family, is widely involved in the malignant progression of many tumors by binding to fibroblast growth factor receptor 4 (FGFR4). In this study, we confirmed that FGF19 acts as a driver gene in hepatocellular carcinoma (HCC) progression by binding to FGFR4. The up-regulation of FGF19 and FGFR4 in HCC is associated with poor prognosis. We found that FGF19/FGFR4 promoted the proliferation and invasion of HCC cells by driving IGF2BP1 to promote PD-L1 expression. Knockdown of FGFR4 significantly reduced the expression of IGF2BP1/PD-L1 and inhibited the proliferation and invasion of HCC cells. These biological effects are achieved by inhibiting the PI3K/AKT pathway. The combination of FGFR4 knockdown and anti-PD-1 antibody greatly suppressed tumor growth and enhanced the sensitivity of immunotherapy, highlighting the clinical significance of FGF19/FGFR4 activation in immunotherapy.

Gut microbiota-bile acid crosstalk regulates murine lipid metabolism via the intestinal FXR-FGF19 axis in diet-induced humanized dyslipidemia

BackgroundDiet-induced dyslipidemia is linked to the gut microbiota, but the causality of microbiota-host interaction affecting lipid metabolism remains controversial. Here, the humanized dyslipidemia mice model was successfully built by using fecal microbiota transplantation from dyslipidemic donors (FMT-dd) to study the causal role of gut microbiota in diet-induced dyslipidemia.ResultsWe demonstrated that FMT-dd reshaped the gut microbiota of mice by increasing Faecalibaculum and Ruminococcaceae UCG-010, which then elevated serum cholicacid (CA), chenodeoxycholic acid (CDCA), and deoxycholic acid (DCA), reduced bile acid synthesis and increased cholesterol accumulation via the hepatic farnesoid X receptor-small heterodimer partner (FXR-SHP) axis. Nevertheless, high-fat diet led to decreased Muribaculum in the humanized dyslipidemia mice induced by FMT-dd, which resulted in reduced intestinal hyodeoxycholic acid (HDCA), raised bile acid synthesis and increased lipid absorption via the intestinal farnesoid X receptor-fibroblast growth factor 19 (FXR-FGF19) axis.ConclusionsOur studies implicated that intestinal FXR is responsible for the regulation of lipid metabolism in diet-induced dyslipidemia mediated by gut microbiota-bile acid crosstalk.27dVNVWG4xVHYhT6VNwbbKVideo

Roseburia intestinalis relieves intrahepatic cholestasis of pregnancy through bile acid/FXR-FGF15 in rats

Previous research has demonstrated significant differences in intestinal flora between pregnant women with intrahepatic cholestasis of pregnancy (ICP) and healthy pregnant women. The objective of our study is to identify the key bacteria involved in ICP rats and explore the underlying mechanism. We established an ICP rat model and collected rat feces for metagenomic sequencing and found that Roseburia intestinalis (R.I) is the key bacteria in ICP. Transplantation of R.I improved phenotypes associated with ICP through the bile acid/farnesoid X receptor-fibroblast growth factor 15 (FXR-FGF15) signaling pathway. We used the FXR antagonist Z-Guggulsterone (Z-Gu) to verify the key role of FXR in ICP and found that Z-Gu reversed the benefits of R.I on ICP rats. Our research highlights the important role of intestinal flora in the pathogenesis of ICP and provides a novel approach for its treatment.

Thanatophoric dysplasia in nonadherent to antenatal care in low middle income country: a rare case reports.

Thanatophoric dysplasia is a rare, fatal, and sporadic form of skeletal dysplasia caused by a mutation in fibroblast growth factor receptor 3 (FGFR3). It is characterized by a conical thorax, platyspondyly (flat vertebral bodies), and macrocephaly. This disorder can be diagnosed antenatally as early as 13 weeks of gestation. The authors reported a case of thanatophoric dysplasia on USG in a 19 year old young consanguineous female in her second trimester of pregnancy. Ultrasound examination showed a clover leaf-shaped skull, a widened anterior fontanel, a coarse and edematous face, a flattened nasal bridge, a short neck, a low set of ears, shortening of both upper and lower limbs with short fingers, bowed thighs and legs, and a relatively narrow thorax. Lung hypoplasia, polyhydramnios, and hydrops in affected individuals lead to a poor prognosis. Hence, timely intervention should be done to avoid a poor prognosis. However, a mix of sonographic, genetic, histological, and autopsy studies are applied to make the most accurate diagnosis. The authors reported this case due to the rarity of this condition and the need for a systematic and multidisciplinary approach.

Molecular Mechanisms Involved in MAFLD in Cholecystectomized Patients: A Cohort Study.

Gallstone disease and metabolic dysfunction-associated fatty liver disease (MAFLD) share numerous common risk factors and progression determinants in that they both manifest as organ-specific consequences of metabolic dysfunction. Nevertheless, the precise molecular mechanisms underlying fibrosis development in cholecystectomized MAFLD patients remain inadequately defined. This study aimed to investigate the involvement of farnesoid X receptor 1 (FXR1) and fibroblast growth factor receptor 4 (FGFR4) in the progression of fibrosis in cholecystectomized MAFLD patients. A meticulously characterized cohort of 12 patients diagnosed with MAFLD, who had undergone liver biopsies during programmed cholecystectomies, participated in this study. All enrolled patients underwent a follow-up regimen at 1, 3, and 6 months post-cholecystectomy, during which metabolic biochemical markers were assessed, along with elastography, which served as indirect indicators of fibrosis. Additionally, the hepatic expression levels of FGFR4 and FXR1 were quantified using quantitative polymerase chain reaction (qPCR). Our findings revealed a robust correlation between hepatic FGFR4 expression and various histological features, including the steatosis degree (r = 0.779, p = 0.023), ballooning degeneration (r = 0.764, p = 0.027), interphase inflammation (r = 0.756, p = 0.030), and steatosis activity score (SAS) (r = 0.779, p = 0.023). Conversely, hepatic FXR1 expression did not exhibit any significant correlations with these histological features. In conclusion, our study highlights a substantial correlation between FGFR4 expression and histological liver damage, emphasizing its potential role in lipid and glucose metabolism. These findings suggest that FGFR4 may play a crucial role in the progression of fibrosis in cholecystectomized MAFLD patients. Further research is warranted to elucidate the exact mechanisms through which FGFR4 influences metabolic dysfunction and fibrosis in this patient population.

Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma

Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive Tcell treatment for RMS. The 3A11 CAR Tcells induced robust cytokine production and cytotoxicity against RMS cell lines invitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR Tcells, confirming the selectivity of 3A11 CAR Tcells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR Tcells are persistent invivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR Tcell therapy targeting FGFR4 to treat patients with RMS.

Lonicera Caerulea Juice Alleviates Alcoholic Liver Disease by Regulating Intestinal Flora and the FXR-FGF15 Signaling Pathway.

Alcoholic liver disease (ALD) is a growing public health issue with high financial, social, and medical costs. Lonicera caerulea, which is rich in polyphenolic compounds, has been shown to exert anti-oxidative and anti-inflammatory effects. This study aimed to explore the effects and mechanisms of concentrated Lonicera caerulea juice (LCJ) on ALD in mice. ALD was established in mice via gradient alcohol feeding for 30 days. The mice in the experimental group were given LCJ by gavage. The reduction of aspartate transaminase (AST) and alanine transaminase (ALT) in the serum of mice indicated that LCJ has a liver-protective effect. LCJ improved the expression of AMPK, PPARα, and CPT1b in ALD mice to reduce the liver lipid content. Additionally, LCJ increased the expression of farnesoid X receptor (FXR), fibroblast growth factor 15 (FGF15), and fibroblast growth factor receptor 4 (FGFR4), which lowers the expression of cytochrome P450 7A1 (CYP7A1) and lessens bile acid deposition in the liver. In mice, LCJ improved the intestinal barrier by upregulating the expression of mucins and tight junction proteins in the small intestine. Moreover, it accelerated the restoration of microbial homeostasis in both the large and small intestines and increased short-chain fatty acids in the cecum. In conclusion, LCJ alleviates ALD by reducing liver and serum lipid accumulation and modulating the FXR-FGF15 signaling pathway mediated by gut microbes.

Zhuyu Pill Alleviates Nonalcoholic Fatty Liver Disease by Regulating Bile Acid Metabolism through the Gut-Liver Axis.

The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide, but there are currently limited treatment options available. Therefore, it is necessary to research new treatment strategies. Zhuyu Pill (ZYP) is a well-known herbal recipe consisting of Huanglian (Coptidis rhizoma) and Wuzhuyu (Evodiae Fructus) that has been clinically used to treat NAFLD. This study aimed to investigate the impact of ZYP on NAFLD induced by a high-fat diet (HFD) and to identify its potential mechanism. In this investigation, we used ZYP to treat a mouse model of NAFLD induced by an HFD. We conducted various analyses including assessment of serum biochemical indices, histological evaluation, fecal metabonomics analysis, western blot, and quantitative real-time polymerase chain reaction. ZYP effectively improved blood lipid levels and reduced inflammatory response in HFD mice, while also alleviating liver cell damage and lipid accumulation. Additionally, ZYP influenced the fecal bile acid (BA) metabolism profiles of HFD mice by inhibiting the signal transduction of ileal farnesoid X receptor (FXR) fibroblast growth factor 15 (FGF15), enhancing the expression of cytochrome P450 family 7 subfamily A member 1(CYP7A1), promoting BA synthesis and increasing the metabolic elimination of cholesterol. ZYP shows promise as a potential treatment for alleviating NAFLD by modulating BA metabolism through the FXR-FGF15-CYP7A1 pathway.