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1.
Gene ; 808: 145989, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34624458

RESUMO

SERPINB5 is a mammary serine protease inhibitor, which is involved in various cellular functions. The aberrant expression of SERPINB5 is reported in many cancers along with GBC but limited information is available about its role in genetic predisposition for GBC. We carried out case-control study in 206 cases and 219 controls. Promoter SNPs were genotyped by Sanger's sequencing. In-silico promoter analysis and luciferase reporter assay were done to elucidate the role of promoter variants in regulation of SERPINB5 expression. Out of four SNPs, three SERPINB5 promoter variants showed association with GBC in different models. The 'C' allele of variant rs17071138 was found to be significantly associated with GBC (p = 0.017). The 'T' allele of rs3744940 significantly increased the risk for GBC in dominant (p = 0.035) and additive models (p = 0.005). Also, rs3744941 'T' allele increased the risk for GBC by dominant (p = 0.042) as well as additive models (p = 0.016). In-silico promoter analysis and luciferase reporter assay revealed the probable regulatory role of the SERPINB5 promoter variant rs17071138 on the expression. Overall, our study reveals the genetic association of SERPINB5 promoter variants with GBC and possible role of rs17071138 in the regulation of expression.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34805582

RESUMO

Nonalcoholic steatohepatitis (NASH) is the most common cause of chronic liver disease today, and it has now emerged as the leading etiology of end-stage liver disease requiring liver transplantation. It is a progressive form of non-alcoholic fatty liver disease which can not only progress to cirrhosis of liver and hepatocellular carcinoma (HCC), but is associated with increased cardiovascular risks too. Despite all the advances in the understanding of the risk factors and the pathogenetic pathways involved in the pathogenesis and progression of NASH, an effective therapy for NASH has not been developed yet. Although lifestyle modifications including dietary modifications and physical activity remain the mainstay of therapy, there is an unmet need to develop a drug or a combination of drugs which can not only reduce the fatty infiltration of the liver, but also arrest the development and progression of fibrosis and advancement to cirrhosis of liver and HCC. The pharmacologic therapies which are being developed target the various components believed to be involved in the pathogenesis of nonalcoholic fatty liver disease (NAFLD)/NASH which includes insulin resistance, lipid metabolism oxidative stress, lipid peroxidation, inflammatory and cell death pathways, and fibrosis. In this review, we summarize the current state of knowledge on pharmacotherapy of NASH, and also highlight the recent developments in the field, for optimizing the management and treatment of NASH.

3.
Indian J Gastroenterol ; 40(4): 420-444, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34219211

RESUMO

The Indian Society of Gastroenterology (ISG) felt the need to organize a consensus on Helicobacter pylori (H. pylori) infection and to update the current management of H. pylori infection; hence, ISG constituted the ISG's Task Force on Helicobacter pylori. The Task Force on H. pylori undertook an exercise to produce consensus statements on H. pylori infection. Twenty-five experts from different parts of India, including gastroenterologists, pathologists, surgeons, epidemiologists, pediatricians, and microbiologists participated in the meeting. The participants were allocated to one of following sections for the meeting: Epidemiology of H. pylori infection in India and H. pylori associated conditions; diagnosis; treatment and retreatment; H. pylori and gastric cancer, and H. pylori prevention/public health. Each group reviewed all published literature on H. pylori infection with special reference to the Indian scenario and prepared appropriate statements on different aspects for voting and consensus development. This consensus, which was produced through a modified Delphi process including two rounds of face-to-face meetings, reflects our current understanding and recommendations for the diagnosis and management of H. pylori infection. These consensus should serve as a reference for not only guiding treatment of H. pylori infection but also to guide future research on the subject.

4.
J Hum Genet ; 66(10): 947-956, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-33727629

RESUMO

Gallbladder cancer (GBC) is relatively rare but shows high frequency in certain geographical regions and ethnic groups, which include Northern and Eastern states of India. Previous studies in India have indicated the possible role of genetic predisposition in GBC pathogenesis. Although matrix metalloproteinase-14 (MMP14) is known modulator of tumour microenvironment and tumorigenesis and TCGA data also suggests its upregulation yet, its role in genetic predisposition for GBC is completely unknown. We explored MMP14 promoter genetic variants as risk factors and their implication in expression modulation and the pathogenesis of GBC. We genotyped all single nucleotide polymorphisms of MMP14 promoter by Sanger's sequencing in approximately 300 GBC and 300 control study subjects of Indian ethnicity and, in 26 GBC tissue samples. Protein expression of MMP14 in GBC tissue samples was checked by immunohistochemistry. In vitro luciferase reporter assay was carried out to elucidate role of promoter genetic variants on expression levels in two different cell lines. MMP14 promoter variants, rs1003349 (p value = 0.0008) and rs1004030 (p value = 0.0001) were significantly associated with GBC. Luciferase reporter assay showed high expression for risk alleles of both the SNPs. Genotype-phenotype correlation for rs1003349 and rs1004030, in patient sample, confirmed that risk allele carriers had higher expression levels of MMP14; moreover, the correlation pattern matched with genetic association models. Overall, this study unravels the association of MMP14 promoter SNPs with GBC which contribute to pathogenesis by increasing its expression.

6.
DNA Cell Biol ; 40(5): 706-712, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33691472

RESUMO

Serine protease inhibitor b5 (SERPINB5) is a tumor suppressor gene that plays a critical role in various cellular processes. In gallbladder cancer (GBC), SERPINB5's aberrant expression is reported but its role in genetic predisposition is not known. We enrolled 270 cases and 296 controls and genotyped them for single nucleotide polymorphisms (SNPs) using direct DNA sequencing, followed by genotype-phenotype analysis in GBC and other cancer cell lines. Luciferase assay was done to determine the role of rs2289521 SNP on expression regulation. We found that two SERPINB5 variants rs2289519 and rs2289521 are significantly associated with GBC and contribute to genetic predisposition. The TT genotype of variant rs2289519 was found to be significantly associated (p = 0.008) with GBC in a recessive model. C allele of rs2289521 increased the risk for GBC significantly at genotypic (CT, p = 0.026) and allelic (p = 0.04) levels. In silico analysis and luciferase assay uncovered the probable regulatory role of the rs2289521 variant on expression. Genotype-phenotype correlation in GBC and breast cancer cell lines showed reduced expression of SERPINB5 in the presence of C allele that was consistent with the result of luciferase assay. Overall, our study reveals the genetic association of two SERPINB5 variants with GBC and rs2289521's possible role in the regulation of expression.


Assuntos
Neoplasias da Vesícula Biliar/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Serpinas/genética , Alelos , Linhagem Celular Tumoral , Feminino , Genes Recessivos , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Luciferases/metabolismo , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Fatores de Risco
7.
JGH Open ; 5(2): 199-206, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33553656

RESUMO

Background and Aim: Acute kidney injury (AKI) is a common complication of chronic liver disease (CLD). We performed a prospective study to evaluate the risk factors and spectrum of AKI among decompensated cirrhosis (DC) patients and the impact of AKI on survival. Methods: This study was conducted in consecutive DC patients hospitalized in SCB Medical College between December 2016 and October 2018. AKI was defined as per ICA criteria. Demographic, clinical, and laboratory parameters and outcomes were compared between patients with and without AKI. Results: A total of 576 DC subjects were enrolled, 315 (54.69%) of whom had AKI; 34% (n = 106) had stage 1A, 28% (n = 90) stage 1B, 21% (n = 65) stage 2, and 17% (n = 54) stage 3 AKI. Alcohol was the predominant cause of CLD (66.7%). In 207 (65.7%) patients, diuretic/lactulose/nonsteroidal anti-inflammatory drugs use was noted, and infection was present in 190 (60.3%) patients. Compared to those without AKI, patients with AKI had higher leucocyte count, higher serum urea and creatinine, higher Child-Turcotte-Pugh, higher Model of End-Stage Liver Disease (MELD) scores (P < 0.001), longer hospital stay, and lower survival at 28 days and 90 days (P < 0.001). Besides, in patients with stages 1A to 3 AKI, there were differences in overall survival at 28 days (P < 0.001) and 90 days (P < 0.001). Conclusions: Over half of DC patients had AKI, and alcohol was the most common cause of cirrhosis in them. Use of AKI-precipitating medications was the most common cause of AKI, followed by bacterial infection. AKI patients had increased prevalence of acute-on-chronic liver failure and had prolonged hospitalization and lower survival both at 28 days and 90 days.

8.
J Biomol Struct Dyn ; : 1-17, 2021 Jan 13.
Artigo em Inglês | MEDLINE | ID: mdl-33438526

RESUMO

ATAD2 has recently been shown to promote stomach cancer. However, nothing is known about the functional network of ATAD2 in stomach carcinogenesis. This study illustrates the oncogenic potential of ATAD2 and the participation of its ATPase and bromodomain in stomach malignancy. Expression of ATAD2 in stomach cancer is analyzed by in silico and in vitro techniques including western blot and immunofluorescence microscopy of stomach cancer cells (SCCs) and tissues. The oncogenic potential of ATAD2 is examined thoroughly using genetic alterations, driver gene prediction, survival analysis, identification of interacting partners, and analysis of canonical pathways. To understand the protein-protein interactions (PPI) at residue level, molecular docking and molecular dynamics simulations (1200 ns) are performed. Enhanced expression of ATAD2 is observed in H. pylori-infected SCCs, patient biopsy tissues, and all stages and grades of stomach cancer. High expression of ATAD2 is found to be negatively correlated with the survival of stomach cancer patients. ATAD2 is a cancer driver gene with 37 mutational sites and a predictable factor for stomach cancer prognosis with high accuracy. The top canonical pathways of ATAD2 indicate its participation in stomach malignancy. The ATAD2-PPI in stomach cancer identify top-ranked partners; ESR1, SUMO2, SPTN2, and MYC show preference for the bromodomain whereas NCOA3 and HDA11 have preference for the ATPase domain of ATAD2. The oncogenic characterization of ATAD2 provides strong evidence to consider ATAD2 as a stomach cancer biomarker. These studies offer an insight for the first time into the ATAD2-PPI interface presenting a novel target for cancer therapeutics. Communicated by Ramaswamy H. Sarma.

9.
J Hepatol ; 74(2): 330-339, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-32781201

RESUMO

BACKGROUND & AIMS: Bacterial infections can trigger the development of organ failure(s) and acute-on-chronic liver failure (ACLF). Geographic variations in bacteriology and clinical practice could lead to worldwide differences in ACLF epidemiology, phenotypes and associated outcomes. Herein, we aimed to evaluate regional differences in bacterial infection-related ACLF in patients with cirrhosis admitted to hospital. METHODS: This post hoc analysis included 1,175 patients with decompensated cirrhosis (with bacterial infection on admission or nosocomial infection) from 6 geographic regions worldwide. Clinical, laboratory and microbiological data were collected from the diagnosis of infection. Patients were followed-up for organ failure(s) and ACLF development according to the EASL-CLIF criteria from enrolment to discharge/death. RESULTS: A total of 333 patients (28%) had ACLF at diagnosis of infection, while 230 patients developed ACLF after diagnosis of infection, resulting in an overall rate of bacterial infection related-ACLF of 48%, with rates differing amongst different geographic regions (38% in Southern Europe vs. 75% in the Indian subcontinent). Bacterial infection related-ACLF more frequently developed in younger patients (55 ± 13 vs. 58 ± 14 years), males (73% vs. 62%), patients with alcohol-related cirrhosis (59% vs. 45%) and those with a higher baseline MELD score (25 ± 11 vs. 16 ± 5) (all p <0.001). Spontaneous bacterial peritonitis, pneumonia or infections caused by extensively drug resistant (XDR) bacteria were more frequently associated with ACLF development. More patients with ACLF had a positive quick sequential organ failure assessment score and septic shock, resulting in a lower infection resolution rate (all p <0.001). CONCLUSIONS: Bacterial infections, especially with XDR organisms, are associated with the highest risk of ACLF development, accounting for almost half of cases globally. Geographic differences result in variable epidemiology and clinical outcomes. LAY SUMMARY: Bacterial infections can trigger a sudden deterioration in an otherwise stable cirrhotic patient, a condition known as acute-on-chronic liver failure or ACLF. This study has found that the development of ACLF following bacterial infection occurs most commonly in the Indian subcontinent and less so in Southern Europe. The common infections that can trigger ACLF include infection of the abdominal fluid, known as spontaneous bacterial peritonitis, pneumonia and by bacteria that are resistant to multiple antibiotics. Patients who develop ACLF following a bacterial infection have high death rates and are frequently unable to clear the infection.

11.
J Clin Transl Hepatol ; 8(2): 120-126, 2020 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-32832391

RESUMO

Background and Aims: Lifestyle (exercise and dietary) modification is the mainstay of treatment for non-alcoholic fatty liver disease (NAFLD). However, there is paucity of data on effect of intensity of exercise in management of NAFLD, and we aimed to study the effect of variable intensities of exercise on NAFLD. Methods: The study was performed in the Department of Gastroenterology of the SCB Medical College, Cuttack and the Biju Patnaik State Police Academy, Bhubaneswar. The subjects were police trainees [18 in a moderate intensity exercise group (MIG) and 19 in a low intensity exercise group (LIG)] recruited for a 6-month physical training course (261.8 Kcalorie, 3.6 metabolic equivalent in MIG and 153.6 Kcalorie, 2.1 metabolic equivalent in LIG). NAFLD was diagnosed by ultrasonography, with exclusion of all secondary causes of steatosis. All participants were evaluated by anthropometry (weight, height, body mass index (BMI), waist circumference), assessed for blood pressure and biochemical parameters (blood glucose, liver function test, lipid profile, serum insulin), and subjected to transabdominal ultrasonography before and after 6 months of physical training, and the results were compared. Results: Both the groups had similar BMI, fasting plasma glucose, AST, gamma-glutamyl transpeptidase, insulin, and homeostatic model assessment-insulin resistance (known as HOMA-IR) (p>0.05). However, subjects in the LIG were older and had lower alanine transaminase, higher triglycerides and lower high-density lipoproteins than MIG subjects. There was a significant reduction in BMI (27.0±2.1 to 26.8±2.0; p=0.001), fasting blood glucose (106.7±21.6 to 85.8±19.0; p<0.001), serum triglycerides (167.5±56.7 to 124.6±63.5; p=0.017), total cholesterol (216.8±29.2 to 196.7±26.6; p=0.037), low-density lipoprotein cholesterol (134.6±21.4 to 130.5±21.9; p=0.010), serum aspartate transaminase (39.3±32.2 to 30.9±11.4; p<0.001), serum alanine transaminase (56.6±28.7 to 33.0±11.3; p<0.001) and HOMA-IR (2.63±2.66 to 1.70±2.59; p<0.001) in the MIG. However, changes in these parameters in the LIG were non-significant. Hepatic steatosis regressed in 66.7% of the NAFLD subjects in the MIG but in only 26.3% of the LIG NAFLD subjects (p=0.030). Conclusions: Moderate rather than low intensity physical activity causes significant improvement in BMI, serum triglycerides, cholesterol, serum transaminases and HOMA-IR, and regression of ultrasonographic fatty change in liver among NAFLD subjects.

12.
Intest Res ; 18(4): 355-378, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32646198

RESUMO

Despite several recent advances in therapy in inflammatory bowel disease (IBD), 5-aminosalicylic acid (5-ASA) therapy has retained its place especially in ulcerative colitis. This consensus on 5-ASA is obtained through a modified Delphi process, and includes guiding statements and recommendations based on literature evidence (randomized trials, and observational studies), clinical practice, and expert opinion on use of 5-ASA in IBD by Indian gastroenterologists. The aim is to aid practitioners in selecting appropriate treatment strategies and facilitate optimal use of 5-ASA in patients with IBD.

13.
Int J Hepatol ; 2020: 1825142, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32724678

RESUMO

Background: The study was designed to assess cardiovascular risk factors flow-mediated dilatation % (FMD%) and carotid intima-media thickness (CIMT) in NAFLD. Methods: 126 NAFLD subjects and 31 chronic hepatitis B (CHB) controls were studied. Measuring carotid intima-media thickness (CIMT) and the flow-mediated dilatation % (FMD%) by brachial artery Doppler ultrasound were used to assess atherosclerosis. The risk of cardiac events at 10 years (ROCE 10) was estimated by the Prospective Cardiovascular Munster Study (PROCAM) score. Results: 58 of 126 NAFLD have coexistent metabolic syndrome. Mean CIMT was 0.73 ± 0.041 mm among NAFLD with MS, 0.66 ± 0.016 mm among NAFLD without MS, and 0.66 ± 0.037 in controls CHB patients. FMD% in NAFLD with MS was 10.43 ± 3.134%, but was 8.56 ± 3.581% in NAFLD without MS and 17.78 ± 6.051% in controls. PROCAM score of NAFLD with MS was 46.95 ± 6.509 while in NAFLD without MS was 38.2 ± 3.738. Controls had a PROCAM score of 38.13 ± 5.755. ROCE 10 in NAFLD with MS was 13.64 ± 8.568 while NAFLD without MS was 5.55 ± 1.949. Controls have a ROCE 10 of 5.95 ± 3.973. Post hoc analysis showed CIMT was dependent upon MS while FMD% was different between all subgroups hence independent of metabolic syndrome. Conclusion: The markers of endothelial dysfunction are significantly higher in patients with NAFLD than controls.

14.
Biochem Biophys Res Commun ; 523(4): 916-923, 2020 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-31959473

RESUMO

Stomach cancer is a difficult-to-treat disease. Lack of detection markers and limited understanding of the disease mechanisms contribute to the aggressive nature of stomach cancer cells (SCCs). Recently, an ATPase, ATAD2 has been found to be highly expressed in stomach cancer contributing to increased malignancy. However, nothing is known about the mechanism of ATAD2 upregulation and its involvement in stomach carcinogenesis. Since hypoxic microenvironment plays a crucial role in the progression of solid tumors like stomach cancer; we have examined the regulation and function of ATAD2 expression in hypoxic SCCs. ATAD2 is induced in hypoxia-treated SCCs. Stomach adenocarcinoma and metastatic tissues with high HIF1α level also show enhanced ATAD2 expression. In the absence of hypoxia-inducible factor HIF1α, ATAD2 protein level is found to be less indicating towards a potential correlation between them. We identify the presence of HIF1α-binding site (HBS) and HIF1α ancillary site (HAS) in the ATAD2 promoter. Using both in vitro and in vivo binding studies, we confirm that HIF1α binds with the ATAD2 promoter in hypoxic condition. ATAD2 upregulation promotes proliferation and migration of SCCs exposed to hypoxia. Thus, we identify ATAD2 as a hypoxia-responsive and HIF1α-regulated gene and elucidate that upregulated expression of ATAD2 enhances tumor-promoting functions in hypoxic SCCs. Therefore, we propose ATAD2 as a promising therapeutic target for stomach cancer.


Assuntos
ATPases Associadas a Diversas Atividades Celulares/genética , Movimento Celular/genética , Proteínas de Ligação a DNA/genética , Regulação Neoplásica da Expressão Gênica , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima/genética , ATPases Associadas a Diversas Atividades Celulares/metabolismo , Hipóxia Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Proteínas de Ligação a DNA/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Regiões Promotoras Genéticas/genética , Ligação Proteica , Ativação Transcricional/genética
16.
Indian J Gastroenterol ; 38(2): 134-142, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30949908

RESUMO

BACKGROUND AND AIM: Post-infection irritable bowel syndrome (PI-IBS) can occur following acute gastroenteritis (AGE). This study was designed to evaluate the incidence and risk factors of PI-IBS following AGE and to validate a PI-IBS risk score. METHODS: This prospective study was performed between September 2014 and October 2016 on AGE patients by documenting their AGE severity and following up after 3 and 6 months to study the development of IBS (ROME III criteria). The risk score was calculated for all the subjects, and its discrimination ability was tested. RESULTS: Out of 136 hospitalized AGE patients, 35 developed PI-IBS after 6 months. The factors associated with PI-IBS were younger age, longer duration of AGE, anxiety, depression, abdominal pain, bloody stool, vomiting, fever, family history of IBS, and positive stool culture (univariate analysis); however, on multivariate analysis, younger age (adjusted odds ratio [AOR] 0.5; p 0.03), prolonged duration of AGE (AOR 8.6; p 0.01), and abdominal cramps (AOR 2.1; p 0.02) were the independent factors influencing its occurrence. PI-IBS occurred even after infection with Vibrio cholerae. The PI-IBS risk score was significantly higher in patients who developed PI-IBS (72.4 ± 14.48 vs. 31.56 ± 20.4, p-value < 0.001); score > 50 had a sensitivity and specificity of 91.4% and 84.2%, respectively. CONCLUSION: One fourth of AGE patients developed PI-IBS after 6 months. Factors influencing its development were younger age, long duration of AGE, and abdominal pain. The PI-IBS risk score had good predictive accuracy in our population.


Assuntos
Gastroenterite/complicações , Síndrome do Intestino Irritável/epidemiologia , Síndrome do Intestino Irritável/etiologia , Doença Aguda , Fatores Etários , Infecções por Escherichia coli , Feminino , Gastroenterite/microbiologia , Humanos , Incidência , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Risco , Fatores de Risco , Fatores de Tempo , Vibrio
18.
Gastroenterology ; 156(5): 1368-1380.e10, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30552895

RESUMO

BACKGROUND & AIMS: Bacterial infections are common and life-threatening in patients with cirrhosis. Little is known about the epidemiology of bacterial infections in different regions. We performed a multicenter prospective intercontinental study to assess the prevalence and outcomes of bacterial and fungal infections in patients with cirrhosis. METHODS: We collected data from 1302 hospitalized patients with cirrhosis and bacterial or fungal infections at 46 centers (15 in Asia, 15 in Europe, 11 in South America, and 5 in North America) from October 2015 through September 2016. We obtained demographic, clinical, microbiology, and treatment data at time of diagnosis of infection and during hospitalization. Patients were followed until death, liver transplantation, or discharge. RESULTS: The global prevalence of multidrug-resistant (MDR) bacteria was 34% (95% confidence interval 31%-37%). The prevalence of MDR bacteria differed significantly among geographic areas, with the greatest prevalence in Asia. Independent risk factors for infection with MDR bacteria were infection in Asia (particularly in India), use of antibiotics in the 3 months before hospitalization, prior health care exposure, and site of infection. Infections caused by MDR bacteria were associated with a lower rate of resolution of infection, a higher incidence of shock and new organ failures, and higher in-hospital mortality than those caused by non-MDR bacteria. Administration of adequate empirical antibiotic treatment was independently associated with improved in-hospital and 28-day survival. CONCLUSIONS: In a worldwide study of hospitalized patients, we found a high prevalence of infection with MDR bacteria in patients with cirrhosis. Differences in the prevalence of MDR bacterial infections in different global regions indicate the need for different empirical antibiotic strategies in different continents and countries. While we await new antibiotics, effort should be made to decrease the spread of MDR bacteria in patients with cirrhosis.


Assuntos
Infecções Bacterianas/epidemiologia , Saúde Global , Cirrose Hepática/epidemiologia , Adulto , Idoso , Antibacterianos/uso terapêutico , Infecções Bacterianas/microbiologia , Infecções Bacterianas/mortalidade , Infecções Bacterianas/terapia , Estudos Transversais , Farmacorresistência Bacteriana Múltipla , Feminino , Mortalidade Hospitalar , Humanos , Cirrose Hepática/microbiologia , Cirrose Hepática/mortalidade , Cirrose Hepática/terapia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Micoses/epidemiologia , Micoses/microbiologia , Micoses/mortalidade , Micoses/terapia , Prevalência , Prognóstico , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
19.
Int J Biochem Cell Biol ; 103: 14-24, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30063986

RESUMO

Helicobacter pylori is the strongest known risk-factor for gastric cancer. However, its role in gastric cancer metastasis remains unclear. Previously we have reported that H. pylori promotes gastric cancer invasiveness by stabilizing the E3 ubiquitin ligase Siah2 which is mediated by Siah2 acetylation at Lys 139 (K139) residue. Here we identify that cell adhesion-related proteins testin (TES) and filamin-C (FLN-C) interact with Siah2 and get proteasomally degraded. The efficiency of TES and FLN-C degradation is significantly potentiated by K139-acetylated Siah2 (ac-K139 Siah2) in infected gastric cancer cells (GCCs). ac-Siah2-mediated downregulation of TES and FLN-C disrupts filopodia structures but promotes lamellipodia formation and enhances invasiveness and migration of infected GCCs. Since H. felis-infected mice as well as human gastric cancer biopsy samples also show high level of ac-K139 Siah2 and downregulated TES and FLN-C, we believe that acetylation of Siah2 is an important checkpoint that can be useful for therapeutic intervention.


Assuntos
Proteínas do Citoesqueleto/biossíntese , Regulação para Baixo , Filaminas/biossíntese , Regulação Neoplásica da Expressão Gênica , Infecções por Helicobacter/metabolismo , Helicobacter pylori/metabolismo , Proteínas com Domínio LIM/biossíntese , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Neoplasias Gástricas , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Invasividade Neoplásica , Proteínas de Ligação a RNA , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
20.
FASEB J ; 32(10): 5378-5389, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29688807

RESUMO

Gastric epithelial cells infected with Helicobacter pylori acquire highly invasive and metastatic characteristics. The seven in absentia homolog (Siah)2, an E3 ubiquitin ligase, is one of the major proteins that induces invasiveness of infected gastric epithelial cells. We find that p300-driven acetylation of Siah2 at lysine 139 residue stabilizes the molecule in infected cells, thereby substantially increasing its efficiency to degrade prolyl hydroxylase (PHD)3 in the gastric epithelium. This enhances the accumulation of an oncogenic transcription factor hypoxia-inducible factor 1α (Hif1α) in H. pylori-infected gastric cancer cells in normoxic condition and promotes invasiveness of infected cells. Increased acetylation of Siah2, Hif1α accumulation, and the absence of PHD3 in the infected human gastric metastatic cancer biopsy samples and in invasive murine gastric cancer tissues further confirm that the acetylated Siah2 (ac-Siah2)-Hif1α axis is crucial in promoting gastric cancer invasiveness. This study establishes the importance of a previously unrecognized function of ac-Siah2 in regulating invasiveness of H. pylori-infected gastric epithelial cells.-Kokate, S. B., Dixit, P., Das, L., Rath, S., Roy, A. D., Poirah, I., Chakraborty, D., Rout, N., Singh, S. P., Bhattacharyya, A. Acetylation-mediated Siah2 stabilization enhances PHD3 degradation in Helicobacter pylori-infected gastric epithelial cancer cells.


Assuntos
Células Epiteliais , Mucosa Gástrica , Infecções por Helicobacter , Helicobacter pylori , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares/metabolismo , Proteólise , Neoplasias Gástricas , Ubiquitina-Proteína Ligases/metabolismo , Acetilação , Linhagem Celular Tumoral , Estabilidade Enzimática , Células Epiteliais/enzimologia , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Mucosa Gástrica/enzimologia , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Infecções por Helicobacter/enzimologia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Humanos , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/patologia
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