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Alfuaadi IH, Altamemi IA. IMPACT OF FGFR4 (GLY388ARG) GENE POLYMORPHISM ALONG WITH VISFATIN CYTOKINE AND HIGH MOBILITY GROUP BOX-1 (HMGB1) ON ACUTE CHOLECYSTITIS. WIADOMOSCI LEKARSKIE (WARSAW, POLAND : 1960) 2022; 75:1242-1247. [PMID: 35758438 DOI: 10.36740/wlek202205203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
OBJECTIVE The aim: Evaluating the role SNP rs351855 of (FGFR4) gene and estimating the serum concentration of Visfatin cytokine and (HMGB-1) protein in AC patients and in healthy control blood samples. PATIENTS AND METHODS Materials and methods: Blood samples were collected from 35 patients and 35 healthy controls, and then the serum was used for ELISA test, another each 2 ml blood were used for DNA extraction and rs351855 of (FGFR4) PCR assay. RESULTS Results: there was no significant difference in mean HMG and mean visfatin among (FGFR4) rs351855 genotypes in patients and control group. There was no significant difference in mean (HMG) among (FGFR) rs351855 genotypes in patients` group (p = 0.923); there was also no significant difference in mean visfatin among FGFR rs351855 genotypes in patients` group (p=0.161) rs351855 genotypes showed that the homozygous GG, heterozygous A/G and homozygous AA. Despite these minor differences there was no significant variation (p = 0.323), also no significant difference in frequency distribution of individuals according to FGFR rs351855 G>A SNP polymorphism between patients` and control groups (p = 0.454). The same was applied to recessive and allelic analysis p>0.05. CONCLUSION Conclusions: There was no role for (FGFR4) rs351855G/A SNP in disease susceptibility to acute cholecystitis in Iraqi patients. Visfatin cytokine and HMGB-1 protein might act as a good biomarker for diseases.
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Chauhan T, Mittal R, Mittal B. Evaluation of genetic association of 40 SNPs in candidate genes with cholesterol gallstone disease in north Indian population. Meta Gene 2019; 21:100579. [DOI: 10.1016/j.mgene.2019.100579] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
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Di Ciaula A, Wang DQH, Portincasa P. Cholesterol cholelithiasis: part of a systemic metabolic disease, prone to primary prevention. Expert Rev Gastroenterol Hepatol 2019; 13:157-171. [PMID: 30791781 DOI: 10.1080/17474124.2019.1549988] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2018] [Accepted: 11/15/2018] [Indexed: 02/07/2023]
Abstract
Cholesterol gallstone disease have relationships with various conditions linked with insulin resistance, but also with heart disease, atherosclerosis, and cancer. These associations derive from mechanisms active at a local (i.e. gallbladder, bile) and a systemic level and are involved in inflammation, hormones, nuclear receptors, signaling molecules, epigenetic modulation of gene expression, and gut microbiota. Despite advanced knowledge of these pathways, the available therapeutic options for symptomatic gallstone patients remain limited. Therapy includes oral litholysis by the bile acid ursodeoxycholic acid (UDCA) in a small subgroup of patients at high risk of postdissolution recurrence, or laparoscopic cholecystectomy, which is the therapeutic radical gold standard treatment. Cholecystectomy, however, may not be a neutral event, and potentially generates health problems, including the metabolic syndrome. Areas covered: Several studies on risk factors and pathogenesis of cholesterol gallstone disease, acting at a systemic level have been reviewed through a PubMed search. Authors have focused on primary prevention and novel potential therapeutic strategies. Expert commentary: The ultimate goal appears to target the manageable systemic mechanisms responsible for gallstone occurrence, pointing to primary prevention measures. Changes must target lifestyles, as well as experimenting innovative pharmacological tools in subgroups of patients at high risk of developing gallstones.
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Affiliation(s)
- Agostino Di Ciaula
- a Division of Internal Medicine , Hospital of Bisceglie , Bisceglie , Italy
| | - David Q-H Wang
- b Department of Medicine, Division of Gastroenterology and Liver Diseases , Marion Bessin Liver Research Center, Albert Einstein College of Medicine , Bronx , NY , USA
| | - Piero Portincasa
- c Department of Biomedical Sciences and Human Oncology, Clinica Medica "A. Murri" , University of Bari Medical School , Bari , Italy
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Abstract
The high prevalence of cholesterol gallstones, the availability of new information about pathogenesis, and the relevant health costs due to the management of cholelithiasis in both children and adults contribute to a growing interest in this disease. From an epidemiologic point of view, the risk of gallstones has been associated with higher risk of incident ischemic heart disease, total mortality, and disease-specific mortality (including cancer) independently from the presence of traditional risk factors such as body weight, lifestyle, diabetes, and dyslipidemia. This evidence points to the existence of complex pathogenic pathways linking the occurrence of gallstones to altered systemic homeostasis involving multiple organs and dynamics. In fact, the formation of gallstones is secondary to local factors strictly dependent on the gallbladder (that is, impaired smooth muscle function, wall inflammation, and intraluminal mucin accumulation) and bile (that is, supersaturation in cholesterol and precipitation of solid crystals) but also to "extra-gallbladder" features such as gene polymorphism, epigenetic factors, expression and activity of nuclear receptors, hormonal factors (in particular, insulin resistance), multi-level alterations in cholesterol metabolism, altered intestinal motility, and variations in gut microbiota. Of note, the majority of these factors are potentially manageable. Thus, cholelithiasis appears as the expression of systemic unbalances that, besides the classic therapeutic approaches to patients with clinical evidence of symptomatic disease or complications (surgery and, in a small subgroup of subjects, oral litholysis with bile acids), could be managed with tools oriented to primary prevention (changes in diet and lifestyle and pharmacologic prevention in subgroups at high risk), and there could be relevant implications in reducing both prevalence and health costs.
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Affiliation(s)
- Agostino Di Ciaula
- Division of Internal Medicine - Hospital of Bisceglie, ASL BAT, Bisceglie, Italy
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University of Bari Medical School, Bari, Italy
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Abstract
PURPOSE OF REVIEW Gallstone disease is a major epidemiologic and economic burden worldwide, and the most frequent form is cholesterol gallstone disease. RECENT FINDINGS Major pathogenetic factors for cholesterol gallstones include a genetic background, hepatic hypersecretion of cholesterol, and supersaturated bile which give life to precipitating cholesterol crystals that accumulate and grow in a sluggish gallbladder. Additional factors include mucin and inflammatory changes in the gallbladder, slow intestinal motility, increased intestinal absorption of cholesterol, and altered gut microbiota. Mechanisms of disease are linked with insulin resistance, obesity, the metabolic syndrome, and type 2 diabetes. The role of nuclear receptors, signaling pathways, gut microbiota, and epigenome are being actively investigated. SUMMARY Ongoing research on cholesterol gallstone disease is intensively investigating several pathogenic mechanisms, associated metabolic disorders, new therapeutic approaches, and novel strategies for primary prevention, including lifestyles.
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Affiliation(s)
| | - David Q.-H. Wang
- Department of Medicine, Division of Gastroenterology and Liver Diseases, Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Piero Portincasa
- Department of Biomedical Sciences and Human Oncology, Clinica Medica “A. Murri”, University of Bari Medical School, Bari, Italy
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Ornitz DM, Itoh N. The Fibroblast Growth Factor signaling pathway. WILEY INTERDISCIPLINARY REVIEWS. DEVELOPMENTAL BIOLOGY 2015; 4:215-66. [PMID: 25772309 PMCID: PMC4393358 DOI: 10.1002/wdev.176] [Citation(s) in RCA: 1461] [Impact Index Per Article: 146.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Revised: 11/23/2014] [Accepted: 01/08/2015] [Indexed: 12/13/2022]
Abstract
The signaling component of the mammalian Fibroblast Growth Factor (FGF) family is comprised of eighteen secreted proteins that interact with four signaling tyrosine kinase FGF receptors (FGFRs). Interaction of FGF ligands with their signaling receptors is regulated by protein or proteoglycan cofactors and by extracellular binding proteins. Activated FGFRs phosphorylate specific tyrosine residues that mediate interaction with cytosolic adaptor proteins and the RAS-MAPK, PI3K-AKT, PLCγ, and STAT intracellular signaling pathways. Four structurally related intracellular non-signaling FGFs interact with and regulate the family of voltage gated sodium channels. Members of the FGF family function in the earliest stages of embryonic development and during organogenesis to maintain progenitor cells and mediate their growth, differentiation, survival, and patterning. FGFs also have roles in adult tissues where they mediate metabolic functions, tissue repair, and regeneration, often by reactivating developmental signaling pathways. Consistent with the presence of FGFs in almost all tissues and organs, aberrant activity of the pathway is associated with developmental defects that disrupt organogenesis, impair the response to injury, and result in metabolic disorders, and cancer. For further resources related to this article, please visit the WIREs website.
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Affiliation(s)
- David M Ornitz
- Department of Developmental Biology, Washington University School of MedicineSt. Louis, MO, USA
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Correspondence to:
| | - Nobuyuki Itoh
- Graduate School of Pharmaceutical Sciences, Kyoto UniversitySakyo, Kyoto, Japan
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Shen YY, Lu YC, Shen DP, Liu YJ, Su XY, Zhu GS, Yin XL, Ni XZ. Fibroblast growth factor receptor 4 Gly388Arg polymorphism in Chinese gastric cancer patients. World J Gastroenterol 2013; 19:4568-4575. [PMID: 23901234 PMCID: PMC3725383 DOI: 10.3748/wjg.v19.i28.4568] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2013] [Revised: 02/27/2013] [Accepted: 03/29/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the contribution of the fibroblast growth factor receptor 4 (FGFR4) Gly388Arg polymorphism as a genetic risk factor for gastric cancer (GC) and to investigate any associations between this polymorphism and clinicopathological parameters and survival.
METHODS: Tumors and matched adjacent non-cancer tissues were collected from 304 GC patients, and 5 mL of venous blood was collected from 62 GC patients and 392 age- and sex-matched healthy controls without cancer history from the same ethnic population. DNA was extracted, and direct sequencing analyses were performed to genotype the FGFR4 Gly388Arg polymorphism in all the samples. Differences in the genotype frequencies of the FGFR4 Gly388Arg polymorphism between GC patients and healthy controls were estimated using the χ2 test. Binary logistic regression was used for all analysis variables to estimate risk as the ORs with 95%CIs. The relationships between the FGFR4 genotype and clinicopathological parameters were tested with the χ2 test. The Kaplan-Meier product-limit method, the log-rank test, and the Cox regression model were applied to evaluate the effect of the FGFR4 genotype on the overall survival of patients with GC.
RESULTS: In the present GC cohort, 118 patients (38.8%) were homozygous for the Gly388 allele, 124 patients (40.8%) were heterozygous, and 62 patients (20.4%) were homozygous for the Arg388 allele. The frequencies of the Gly/Gly, Gly/Arg, and Arg/Arg genotypes in the healthy controls were 33.6%, 48.0%, and 18.4%, respectively. The distributions of genotypes (χ2 = 3.589, P = 0.166) and alleles (χ2 = 0.342, P = 0.559) of the FGFR4 Gly388Arg polymorphism were not different between the GC patients and the healthy controls. Although we observed no correlation between the FGFR4 Gly388Arg polymorphism and clinicopathological parameters or survival in the total cohort of GC patients, the presence of the Arg388 allele was associated with shorter survival time in patients with GC if the tumor was small (log rank χ2 = 5.449, P = 0.020), well differentiated (log rank χ2 = 12.798, P = 0.000), T1 or T2 stage (log rank χ2 = 4.745, P = 0.029), without lymph node involvement (log rank χ2 = 6.647, P= 0.010), and at an early clinical stage (log rank χ2 = 4.615, P = 0.032).
CONCLUSION: Our results suggest that the FGFR4 Gly388Arg polymorphism is not a risk factor for GC cancer initiation but that it is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or at an early clinical stage.
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Abstract
Gallstone disease (GSD) is one of the most common biliary tract disorders worldwide. The prevalence, however, varies from 5.9-21.9% in Western society to 3.1-10.7% in Asia. Most gallstones (75%) are silent. Approximately half of symptomatic gallstone carriers experience a second episode of biliary pain within 1 year. These individuals are at increased risk of developing acute cholecystitis, acute cholangitis, and biliary pancreatitis. As can be expected, these complications burden health care systems because of their invasive nature and surgical cost. Factors that contribute to gallstone formation include supersaturation of cholesterol in bile, gallbladder hypomotility, destabilization of bile by kinetic protein factors, and abnormal mucins. Epidemiologic studies have implicated multiple environmental factors and some common genetic elements in gallstone formation. Genetic factors that influence gallstone formation have been elaborated from linkage studies of twins, families, and ethnicities. Accumulating evidence suggests that genetic factors play a role in GSD.
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Affiliation(s)
- Shih-Chang Chuang
- Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
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Di Ciaula A, Wang DQH, Bonfrate L, Portincasa P. Current views on genetics and epigenetics of cholesterol gallstone disease. CHOLESTEROL 2013; 2013:298421. [PMID: 23691293 PMCID: PMC3649201 DOI: 10.1155/2013/298421] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2013] [Revised: 03/06/2013] [Accepted: 03/20/2013] [Indexed: 02/07/2023]
Abstract
Cholesterol gallstone disease, one of the commonest digestive diseases in western countries, is induced by an imbalance in cholesterol metabolism, which involves intestinal absorption, hepatic biosynthesis, and biliary output of cholesterol, and its conversion to bile acids. Several components of the metabolic syndrome (e.g., obesity, type 2 diabetes, dyslipidemia, and hyperinsulinemia) are also well-known risk factors for gallstones, suggesting the existence of interplay between common pathophysiological pathways influenced by insulin resistance, genetic, epigenetic, and environmental factors. Cholesterol gallstones may be enhanced, at least in part, by the abnormal expression of a set of the genes that affect cholesterol homeostasis and lead to insulin resistance. Additionally, epigenetic mechanisms (mainly DNA methylation, histone acetylation/deacetylation, and noncoding microRNAs) may modify gene expression in the absence of an altered DNA sequence, in response to different lithogenic environmental stimuli, such as diet, lifestyle, pollutants, also occurring in utero before birth. In this review, we will comment on various steps of the pathogenesis of cholesterol gallstones and interaction between environmental and genetic factors. The epigenomic approach may offer new options for therapy of gallstones and better possibilities for primary prevention in subjects at risk.
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Affiliation(s)
- Agostino Di Ciaula
- Division of Internal Medicine Hospital of Bisceglie, 76011 Bisceglie, Italy
| | - David Q.-H. Wang
- Saint Louis University School of Medicine, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Edward Doisy Research Center, St. Louis, MO 63104, USA
| | - Leonilde Bonfrate
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University “Aldo Moro“ of Bari Medical School, 70124 Bari, Italy
| | - Piero Portincasa
- Clinica Medica “A. Murri”, Department of Biomedical Sciences & Human Oncology, University “Aldo Moro“ of Bari Medical School, 70124 Bari, Italy
- European Society for Clinical Investigation (ESCI), 3584 CJ Utrecht, The Netherlands
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