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Biomedicine & Pharmacotherapy =... Nov 2023Hepatocyte damage during liver injury instigates activation of macrophages and hepatic stellate cells (HSCs) resulting in liver inflammation and fibrosis respectively....
Hepatocyte damage during liver injury instigates activation of macrophages and hepatic stellate cells (HSCs) resulting in liver inflammation and fibrosis respectively. Improving hepatocyte survival and proliferation thereby ameliorating inflammation and fibrosis represents a promising approach for the treatment of liver injury. In the liver, fibroblast growth factors (FGFs) play a crucial role in promoting hepatocyte proliferation and tissue regeneration. Among 22 FGFs, FGF7 induces hepatocyte survival and liver regeneration as shown previously in mouse models of cholestatic liver injury and partial hepatectomy. We hypothesized that FGF7 promotes hepatocyte survival and proliferation by interacting with FGFR2b, expressed on hepatocytes, and ameliorates liver injury (inflammation and early fibrogenesis) via paracrine mechanisms. To prove this hypothesis and to study the effect of FGF7 on hepatocytes and liver injury, we administered FGF7 exogenously to mice with acute carbon tetrachloride (CCl)-induced liver injury. We thereafter studied the underlying mechanisms and the effect of exogenous FGF7 on hepatocyte survival and proliferation, and the consequent paracrine effects on macrophage-induced inflammation, and HSCs activation in vitro and in vivo. We observed that the expression of FGF7 as well as FGFR2 is upregulated during acute liver injury. Co-immunostaining of FGF7 and collagen-I confirmed that FGF7 is expressed by HSCs and is possibly captured by the secreted ECM. Immunohistochemical analysis of liver sections showed increased hepatocyte proliferation upon exogenous FGF7 treatment as determined by Ki67 expression. Mechanistically, exogenous FGF7 improved hepatocyte survival (and increased drug detoxification) via AKT and ERK pathways while maintaining hepatocyte quiescence restricting hepatocarcinogenesis via P27 pathways. Flow cytometry analysis revealed that improved hepatocyte survival and proliferation leads to a decrease in infiltrated monocytes-derived macrophages, as a result of reduced CCL2 (and CXCL8) expression by hepatocytes. Moreover, conditioned medium studies showed reduced collagen-I secretion by HSCs (indicative of HSCs activation) upon treatment with FGF7-treated hepatocytes conditioned medium. Altogether, we show that exogenous administration of FGF7 induces hepatocyte survival and proliferation and leads to amelioration of inflammatory response and fibrosis in acute liver injury via paracrine mechanisms. Our study further demonstrates that FGF7, FGF7 derivatives, or nano-engineered FGF7 may benefit patients with hepatic dysfunction.
Topics: Humans; Mice; Animals; Fibroblast Growth Factor 7; Culture Media, Conditioned; Liver; Hepatocytes; Hepatic Stellate Cells; Liver Diseases; Hepatitis; Inflammation; Fibrosis; Cell Proliferation; Collagen; Liver Cirrhosis; Carbon Tetrachloride
PubMed: 37797460
DOI: 10.1016/j.biopha.2023.115612 -
Research Square Sep 2023During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the...
During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is FDA approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Other reported radioprotective drugs including Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin were also tested to validate the ability of the assays to detect cell damage and radioprotection. All of the drugs except NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified exhibiting mechanisms of action other than antioxidant activity. Hits were down-selected using EC50 values and pharmacokinetic and pharmacodynamic data from the PubChem database. This led us to test Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for in vivo radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited radioprotection equivalent to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful in vitro discovery and in vivo validation of novel radioprotective drugs with non-antioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.
PubMed: 37790388
DOI: 10.21203/rs.3.rs-3246405/v1 -
BMC Veterinary Research Sep 2023The current research aimed to evaluate the potential effect of adding platelet-rich fibrin (PRF) to the decellularized bovine pericardium (DBP) on the distal limb of...
AIM
The current research aimed to evaluate the potential effect of adding platelet-rich fibrin (PRF) to the decellularized bovine pericardium (DBP) on the distal limb of donkeys' full-thickness cutaneous wounds healing (Equus asinus).
MATERIALS AND METHODS
Healthy male donkeys (n = 12) were used in this study. Under general anesthesia, 6 cm2 full-thickness incisions were made on the middle dorsolateral surface of both forelimbs' metacarpi. The left forelimbs were control wounds, while the right wounds were treated with PRF/DBP. Control wounds were bandaged with a standard dressing after saline irrigation and were evaluated at days 4, 7, 10, 13, 16, 19, 22, 25, and 28 post-wounding. PRF/DBP-treated wounds were dressed with a combination of PRF/DBP at the first, second, and third weeks post-wounding. Clinical and histopathological examinations of the wounds were performed to assess the healing process. Additionally, the immunohistochemical evaluation and gene expression profiles of myofibroblastic and angiogenic genes (transforming growth factor-β1, vascular endothelial growth factor-A, fibroblast growth factor 7 (FGF-7), and collagen type 3α1) were analyzed.
RESULTS
PRF/DBP wounds had a significantly faster healing process (61.3 ± 2.6 days) than control wounds (90.3 ± 1.4 days) (p < 0.05). The immunohistochemical examination and gene expression profile revealed significant enrichment in PRF/DBP wounds compared to control wounds.
CONCLUSION
PRF/DBP dressing can be considered a natural and cost-effective biomaterial for enhancing the recovery of donkeys' distal limb injuries.
Topics: Male; Cattle; Animals; Platelet-Rich Fibrin; Vascular Endothelial Growth Factor A; Anesthesia, General; Bandages; Deafness; Cattle Diseases
PubMed: 37730587
DOI: 10.1186/s12917-023-03733-x -
BMC Microbiology Sep 2023Autologous hematopoietic cell transplantation (AHCT) is a well-established treatment for lymphoma. Unintended effects of this therapy include oral mucositis (OM) and...
INTRODUCTION
Autologous hematopoietic cell transplantation (AHCT) is a well-established treatment for lymphoma. Unintended effects of this therapy include oral mucositis (OM) and gastrointestinal toxicities, resulting in poor clinical outcomes. The gut microbiome has been previously linked to transplant toxicities among allogeneic recipients, but little is known about the effects of AHCT on the oral microbiome.
METHODS
Seven patients with non-Hodgkin or Hodgkin lymphoma undergoing AHCT with palifermin (keratinocyte growth factor) were included. Buccal swab samples were collected at baseline and 14- and 28-days post-treatment. Oral microbial communities were characterized with 16 S rRNA amplicon sequencing. Temporal trends in community composition, alpha diversity, and beta diversity were investigated.
RESULTS
A significant reduction in the relative abundance of the genera Gemella and Actinomyces were observed from baseline. No significant temporal differences in alpha diversity were observed. Significant changes in beta diversity were recorded.
CONCLUSION
Results of this pilot study suggest treatment with AHCT and palifermin affects the oral microbiome, resulting in temporal shifts in oral microbial community composition. Future studies are warranted to confirm these trends and further investigate the effects of AHCT on the oral microbiome and how these shifts may affect health outcomes.
Topics: Humans; Fibroblast Growth Factor 7; Pilot Projects; Hematopoietic Stem Cell Transplantation; Microbiota; Gastrointestinal Microbiome
PubMed: 37704974
DOI: 10.1186/s12866-023-03000-x -
International Journal of Molecular... Jul 2023The objective of this study was to investigate the potential effects of a formulation derived from the bioactive fraction of nanostructured (BFNB) on the promotion of...
The objective of this study was to investigate the potential effects of a formulation derived from the bioactive fraction of nanostructured (BFNB) on the promotion of hair growth in C57BL/6 mice. The characterization of the follicular phases and histomorphological analysis showed that the topical application of the formulation for 15 days significantly increased pigmentation and hair growth on the dorsum and head of the mice. Additionally, an acceleration of the follicular cycle phases was observed, along with an increase in the number of follicles, hair length, and diameter, compared to mice treated with minoxidil. In silico analysis and molecular characterization demonstrated that BFNB enhances the expression of epidermal growth factor (EGF) and fibroblast growth factor 7 (FGF7), activating the PI3K-AKT-β-catenin signaling pathway, as well as the expression of PCNA, KI-67, Cyclin D1, and Cyclin E, regulating the cell cycle and cell proliferation, crucial events for hair regeneration. Our results strongly suggest the utility of BFNB as a therapeutic alternative to stimulate hair growth and promote hair health.
Topics: Animals; Mice; beta Catenin; Catenins; Cell Proliferation; Epidermal Growth Factor; Fibroblast Growth Factor 7; Hair; Hair Follicle; Mice, Inbred C57BL; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt
PubMed: 37569486
DOI: 10.3390/ijms241512110 -
Pediatric Blood & Cancer Oct 2023
Review
Severe refractory hemorrhagic cystitis after hematopoietic cell transplantation responds to recombinant human keratinocyte growth factor-Case report and review of the literature.
Topics: Humans; Fibroblast Growth Factor 7; Hemorrhage; Cystitis; Hematopoietic Stem Cell Transplantation; BK Virus; Polyomavirus Infections
PubMed: 37533091
DOI: 10.1002/pbc.30606 -
BioRxiv : the Preprint Server For... Jul 2023During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the...
During head and neck cancer treatment, off-target ionizing radiation damage to the salivary glands commonly causes a permanent loss of secretory function. Due to the resulting decrease in saliva production, patients have trouble eating, speaking and are predisposed to oral infections and tooth decay. While the radioprotective antioxidant drug Amifostine is approved to prevent radiation-induced hyposalivation, it has intolerable side effects that limit its use, motivating the discovery of alternative therapeutics. To address this issue, we previously developed a salivary gland mimetic (SGm) tissue chip platform. Here, we leverage this SGm tissue chip for high-content drug discovery. First, we developed in-chip assays to quantify glutathione and cellular senescence (β-galactosidase), which are biomarkers of radiation damage, and we validated radioprotection using WR-1065, the active form of Amifostine. Following validation, we tested other reported radioprotective drugs, including, Edaravone, Tempol, N-acetylcysteine (NAC), Rapamycin, Ex-Rad, and Palifermin, confirming that all drugs but NAC and Ex-Rad exhibited robust radioprotection. Next, a Selleck Chemicals library of 438 FDA-approved drugs was screened for radioprotection. We discovered 25 hits, with most of the drugs identified with mechanisms of action other than antioxidant activity. Hits were down-selected using EC values and pharmacokinetics and pharmacodynamics data from the PubChem database leading to testing of Phenylbutazone (anti-inflammatory), Enoxacin (antibiotic), and Doripenem (antibiotic) for radioprotection in mice using retroductal injections. Results confirm that Phenylbutazone and Enoxacin exhibited equivalent radioprotection to Amifostine. This body of work demonstrates the development and validation of assays using a SGm tissue chip platform for high-content drug screening and the successful discovery and validation of novel radioprotective drugs with nonantioxidant primary indications pointing to possible, yet unknown novel mechanisms of radioprotection.
PubMed: 37503292
DOI: 10.1101/2023.07.12.548707 -
Frontiers in Physiology 2023Certain growth factors (GFs) are associated with constipation, but few studies has analyzed the causal associations between the two. Therefore, this study used...
Certain growth factors (GFs) are associated with constipation, but few studies has analyzed the causal associations between the two. Therefore, this study used two-sample Mendelian randomization (MR) to systematically analyze the causal associations between GF levels and constipation based on data from genome-wide association studies (GWAS). Both GF and constipation data were obtained from European populations. GFs, as an exposure variable, were obtained from a genetic map of the human plasma proteome containing 3,301 samples, another GWAS dataset on 90 circulating proteins containing 30,931 samples, and a GWAS dataset containing 3,788 samples. Constipation, as an outcome variable, was obtained from the FinnGen project containing 26,919 cases and 282,235 controls and another UK Biobank dataset containing 3,328 cases and 459,682 controls. Single-nucleotide polymorphisms strongly associated with GFs were regarded as instrumental variables. Inverse-variance weighting, MR-Egger regression, weight median, simple mode, and weight mode methods were used to determine genetic associations. Cochran's Q test, Egger intercept, and Mendelian Randomization Pleiotropy RESidual Sum and Outlier tests were used to analyze sensitivity. The IVW analysis based on FinnGen showed that NGFI-A-binding protein 2 and vascular endothelial growth factor receptor 2 were inversely associated with constipation, and that fibroblast growth factor 7 and transforming growth factor beta receptor II levels were positively associated with constipation. The IVW analysis based on UK Biobank showed that proheparin-binding epidermal growth factor, platelet-derived growth factor AA, and vascular endothelial growth factor were inversely associated with constipation. This study showed that some GFs are genetically associated with the risk of constipation.
PubMed: 37501926
DOI: 10.3389/fphys.2023.1204146 -
Thoracic Cancer Aug 2023Circular RNAs (circRNAs) are closely associated with the development of breast cancer (BC). In this study, we aimed to clarify how differentially expressed circRNAs...
BACKGROUND
Circular RNAs (circRNAs) are closely associated with the development of breast cancer (BC). In this study, we aimed to clarify how differentially expressed circRNAs affect the development of BC.
METHODS
Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect the expression of circADAM9, miR-1236-3p and fibroblast growth factor 7 (FGF7). Colony formation, 5-ethynyl-2'-deoxyuridine (EdU), wound healing, transwell, and flow cytometry were used to assess cell proliferation, migration, invasion, and apoptosis. Glucose consumption, lactic acid production and ATP levels were assessed using glycolysis metabolism analysis. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were carried out to verify the relationship between miR-1236-3p and circADAM9 or FGF7. The roles of cirADAM9 on tumor growth were analyzed using a xenograft tumor model. Ki-67 and FGF7 expression was measured via immunohistochemistry (IHC) assay. Apoptosis-related proteins and exosome markers were detected by western blot.
RESULTS
CircADAM9 was highly expressed in BC cells, and circADAM9 silencing inhibited BC cell proliferation, migration, invasion, and glycolysis, and promoted cell apoptosis. Furthermore, miR-1236-3p inhibition could overturn circADAM9 knockdown-mediated BC inhibition. Moreover, the negative influences of miR-1236-3p overexpression on BC progression were restrained via FGF7 overexpression. CircADAM9 silence also inhibited BC tumor growth in vivo.
CONCLUSION
CircADAM9 promoted BC development partly by the miR-1236-3p/FGF7 axis, highlighting a potential prognostic biomarker and therapeutic target for BC patients.
Topics: Humans; Animals; Female; Breast Neoplasms; Fibroblast Growth Factor 7; RNA, Circular; Cell Proliferation; Disease Models, Animal; Glycolysis; MicroRNAs; Cell Line, Tumor
PubMed: 37385973
DOI: 10.1111/1759-7714.15025 -
Life Sciences Aug 2023Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), shows a crucial biological significance in tissue development, wound repair,... (Review)
Review
Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), shows a crucial biological significance in tissue development, wound repair, tumorigenesis, and immune reconstruction. In the skeletal system, FGF7 directs the cellular synaptic extension of individual cells and facilities functional gap junction intercellular communication of a collective of cells. Moreover, it promotes the osteogenic differentiation of stem cells via a cytoplasmic signaling network. For cartilage, reports have indicated the potential role of FGF7 on the regulation of key molecules Cx43 in cartilage and Runx2 in hypertrophic cartilage. However, the molecular mechanism of FGF7 in chondrocyte behaviors and cartilage pathological process remains largely unknown. In this review, we systematically summarize the recent biological function of FGF7 and its regulatory role on chondrocytes and cartilage diseases, especially through the hot focus of two key molecules, Runx2 and Cx43. The current knowledge of FGF7 on the physiological and pathological processes of chondrocytes and cartilage provides us new cues for wound repair of cartilage defect and therapy of cartilage diseases.
Topics: Humans; Fibroblast Growth Factor 7; Connexin 43; Core Binding Factor Alpha 1 Subunit; Osteogenesis; Cartilage; Cell Differentiation; Chondrocytes; Cartilage Diseases
PubMed: 37245839
DOI: 10.1016/j.lfs.2023.121804