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Wu S, Chen Y, Chen Z, Wei F, Zhou Q, Li P, Gu Q. Reactive oxygen species and gastric carcinogenesis: The complex interaction between Helicobacter pylori and host. Helicobacter 2023; 28:e13024. [PMID: 37798959 DOI: 10.1111/hel.13024] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 09/10/2023] [Accepted: 09/21/2023] [Indexed: 10/07/2023]
Abstract
Helicobacter pylori (H. pylori) is a highly successful human pathogen that colonizes stomach in around 50% of the global population. The colonization of bacterium induces an inflammatory response and a substantial rise in the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), mostly derived from host neutrophils and gastric epithelial cells, which play a crucial role in combating bacterial infections. However, H. pylori has developed various strategies to quench the deleterious effects of ROS, including the production of antioxidant enzymes, antioxidant proteins as well as blocking the generation of oxidants. The host's inability to eliminate H. pylori infection results in persistent ROS production. Notably, excessive ROS can disrupt the intracellular signal transduction and biological processes of the host, incurring chronic inflammation and cellular damage, such as DNA damage, lipid peroxidation, and protein oxidation. Markedly, the sustained inflammatory response and oxidative stress during H. pylori infection are major risk factor for gastric carcinogenesis. In this context, we summarize the literature on H. pylori infection-induced ROS production, the strategies used by H. pylori to counteract the host response, and subsequent host damage and gastric carcinogenesis.
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Affiliation(s)
- Shiying Wu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Yongqiang Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Ziqi Chen
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Fangtong Wei
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Qingqing Zhou
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Ping Li
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
| | - Qing Gu
- Key Laboratory for Food Microbial Technology of Zhejiang Province, College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou, China
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Saxena K, Deshwal A, Pudake RN, Jain U, Tripathi RM. Recent progress in biomarker-based diagnostics of Helicobacter pylori, gastric cancer-causing bacteria. Biomark Med 2023; 17:679-691. [PMID: 37934044 DOI: 10.2217/bmm-2023-0316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2023] Open
Abstract
The progression of any disease and its outcomes depend on the complicated interaction between pathogens, host and environmental factors. Thus, complete knowledge of bacterial toxins involved in pathogenesis is necessary to develop diagnostic methods and alternative therapies, including vaccines. This review summarizes recently employed biomarkers to diagnose the presence of Helicobacter pylori bacteria. The authors review distinct types of disease-associated biomarkers such as urease, DNA, miRNA, aptamers and bacteriophages that can be utilized as targets to detect Helicobacter pylori and, moreover, gastric cancer in its early stage. A detailed explanation is also given in the context of the recent utilization of these biomarkers in the development of a highly specific and sensitive biosensing platform.
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Affiliation(s)
- Kirti Saxena
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
| | - Akanksha Deshwal
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
| | - Ramesh Namdeo Pudake
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
| | - Utkarsh Jain
- School of Health Sciences & Technology (SoHST), University of Petroleum & Energy Studies (UPES), Bidholi, Dehradun, 248007, India
| | - Ravi Mani Tripathi
- Amity Institute of Nanotechnology (AINT), Amity University Uttar Pradesh (AUUP), Sector 125, Noida, 201313, India
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Helicobacter pylori Thioredoxin1 May Play a Highly Pathogenic Role via the IL6/STAT3 Pathway. Gastroenterol Res Pract 2022; 2022:3175935. [PMID: 35958524 PMCID: PMC9359846 DOI: 10.1155/2022/3175935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/27/2022] [Accepted: 07/06/2022] [Indexed: 01/10/2023] Open
Abstract
Background Recent studies have shown that CagA is considered highly pathogenic to helicobacter pylori (HP) in Western populations. However, in East Asia, CagA positive HP can be up to 90%, but not all patients will lead to gastric cancer. Our research group has found that HP thioredoxin1 (Trx1) may be a marker of high pathogenicity. Here, we investigate whether HP Trx1 exerts high pathogenicity and its internal molecular mechanism. Materials and Methods We constructed the coculture system of high-Trx1 HP and low-Trx1 HP strains with gastric epithelial cell lines separately and detected the influence of HP strains. The cells were stained by AM/PI, and the cell's mortality was assessed by fluorescence microscope. The cell's supernatants or precipitates were collected to detect the expression of IL6. In addition, the cell's precipitates were collected, and the expression of p-STAT3 was detected by western blot. Furthermore, the cell's supernatants were collected for detecting the expression of 8-OHDG to investigate the extent of DNA damage. Results The high-Trx1 HP can cause higher mortality of GES-1 cells compared with the low-Trx1 HP group (high-Trx1 HP (4.53 ± 0.56) %, low-Trx1 HP (0.39 ± 0.10) %, P < 0.001). The mRNA and protein level of IL-6 in AGS and GES-1 cells were increased during HP infection, and the expression of IL-6 in the High-Trx1 HP group was much higher than the low-Trx1 HP group. Besides, the expression of p-STAT3 was higher in the HP-positive gastric mucosa. And the expression of p-STAT3 in the high-Trx1 HP group was significantly upregulated compared with the low-Trx1 HP group. Furthermore, the expression of 8-OHDG in the high-Trx1 group was much higher than the low-Trx1 group (high-Trx1 HP (5.47 ± 1.73) ng/ml, low-Trx1 HP (2.89 ± 1.72) ng/ml, P < 0.05). Conclusion HP Trx1 may play as a marker of high pathogenicity, and the high-Trx1 HP could mediate the pathogenic process of HP infection via the IL6/STAT3 pathway.
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da Mata AMOF, Paz MFCJ, de Menezes AAPM, dos Reis AC, da Silva Souza B, de Carvalho Sousa CD, Machado SA, Medeiros TSG, Sarkar C, Islam MT, Sharifi-Rad J, Daştan SD, Alshehri MM, de Castro e Sousa JM, de Carvalho Melo Cavalcante AA. Evaluation of mutagenesis, necrosis and apoptosis induced by omeprazole in stomach cells of patients with gastritis. Cancer Cell Int 2022; 22:154. [PMID: 35436881 PMCID: PMC9016981 DOI: 10.1186/s12935-022-02563-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 03/30/2022] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Gastritis is a superficial and prevalent inflammatory lesion that is considered a public health concern once can cause gastric ulcers and gastric cancer, especially when associated with Helicobacter pylori infection. Proton pump inhibitors, such as omeprazole, are the most widely used drugs to treat this illness. The aim of the study was evaluate cytogenetic effects of omeprazole in stomach epithelial cells of patients with gastritis in presence and absence of H. pylori, through cytogenetic biomarkers and catalse and superoxide dismutase analysis. METHODS The study included 152 patients from the Gastroenterology Outpatient Clinic of Hospital Getúlio Vargas, Teresina-Brazil, that reported continuous and prolonged omeprazole use in doses of 20, 30 and 40 mg/kg. The participants were divided into groups: (1) patients without gastritis (n = 32); (2) patients without gastritis but with OME use (n = 24); (3) patients with gastritis (n = 26); (4) patients with gastritis undergoing OME therapy (n = 26); (5) patients with gastritis and H. pylori (n = 22) and (6) patients with gastritis and H. pylori on OME therapy (n = 22). RESULTS OME induced cytogenetic imbalance in the stomach epithelium through the formation of micronuclei (group 6 > 1, 2, 3, 4, 5; group 5 > 1, 2, 3; group 4 > 1, 2, 3); bridges (groups 4 and 6 > 1, 2, 3, 5 and group 2 > 3, 5); buds (groups 2,4,6 > , 1, 3, 5); binucleated cells (group 6 > 1, 2, 3, 4, 5; group 4 > 1, 2, 3); (groups 2 and 3 > 1); picnoses (group 6 > 1, 2, 3, 4, 5), groups 2 and 5 > 1, 3; group 4 > 1, 2, 3, 5); cariorrexis (groups 6 and 4 > 1, 2, 3, 5; groups 2, 3, 5 > 1) and karyolysis (groups 2, 4, and 6 > 1, 3, 5; groups 3 and 5 > 1). The OME cytogenetic instability was associated with H. pylori infection, indicating clastogenic/aneugenic effects, chromosomes alterations, gene expression changes, cytotoxicity and apoptosis. CONCLUSIONS The cytogenetic changescan be attributed to several mechanisms that are still unclear, including oxidative damage, as observed by increased catalase and superoxide dismutase expresion. Positive correlations between antioxidant enzymes were found with micronuclei formation, and were negative for picnoses. Thus, the continuous and prolonged omeprazole use induces genetic instability, which can be monitored through cytogenetic analyzes, as precursor for gastric cancer.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Chandan Sarkar
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University Bangladesh, Gopalganj, 8100 Bangladesh
| | - Muhammad Torequl Islam
- Department of Pharmacy, Bangabandhu Sheikh Mujibur Rahman Science and Technology University Bangladesh, Gopalganj, 8100 Bangladesh
| | - Javad Sharifi-Rad
- Phytochemistry Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Facultad de Medicina, Universidad del Azuay, Cuenca, Ecuador
| | - Sevgi Durna Daştan
- Department of Biology, Faculty of Science, Sivas Cumhuriyet University, 58140 Sivas, Turkey
- Beekeeping Development Application and Research Center, Sivas Cumhuriyet University, 58140 Sivas, Turkey
| | - Mohammed M. Alshehri
- Pharmaceutical Care Department, Ministry of National Guard-Health Affairs, Riyadh, Saudi Arabia
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Prasad SK, Bhat S, Shashank D, C R A, R S, Rachtanapun P, Devegowda D, Santhekadur PK, Sommano SR. Bacteria-Mediated Oncogenesis and the Underlying Molecular Intricacies: What We Know So Far. Front Oncol 2022; 12:836004. [PMID: 35480118 PMCID: PMC9036991 DOI: 10.3389/fonc.2022.836004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/22/2022] [Indexed: 01/10/2023] Open
Abstract
Cancers are known to have multifactorial etiology. Certain bacteria and viruses are proven carcinogens. Lately, there has been in-depth research investigating carcinogenic capabilities of some bacteria. Reports indicate that chronic inflammation and harmful bacterial metabolites to be strong promoters of neoplasticity. Helicobacter pylori-induced gastric adenocarcinoma is the best illustration of the chronic inflammation paradigm of oncogenesis. Chronic inflammation, which produces excessive reactive oxygen species (ROS) is hypothesized to cause cancerous cell proliferation. Other possible bacteria-dependent mechanisms and virulence factors have also been suspected of playing a vital role in the bacteria-induced-cancer(s). Numerous attempts have been made to explore and establish the possible relationship between the two. With the growing concerns on anti-microbial resistance and over-dependence of mankind on antibiotics to treat bacterial infections, it must be deemed critical to understand and identify carcinogenic bacteria, to establish their role in causing cancer.
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Affiliation(s)
- Shashanka K Prasad
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, Jagadguru Sri Shivarathreeshwara (JSS) Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Smitha Bhat
- Department of Biotechnology and Bioinformatics, Faculty of Life Sciences, Jagadguru Sri Shivarathreeshwara (JSS) Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Dharini Shashank
- Department of General Surgery, Adichunchanagiri Institute of Medical Sciences, Mandya, India
| | - Akshatha C R
- Department of Medical Oncology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India
| | - Sindhu R
- Department of Microbiology, Faculty of Life Sciences, Jagadguru Sri Shivarathreeshwara (JSS) Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Pornchai Rachtanapun
- School of Agro-Industry, Faculty of Agro-Industry, Chiang Mai University, Chiang Mai, Thailand
- Cluster of Agro Bio-Circular-Green Industry (Agro BCG), Chiang Mai University, Chiang Mai, Thailand
| | - Devananda Devegowda
- Centre of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Prasanna K Santhekadur
- Centre of Excellence in Molecular Biology and Regenerative Medicine (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education and Research (JSSAHER), Mysuru, India
| | - Sarana Rose Sommano
- Cluster of Agro Bio-Circular-Green Industry (Agro BCG), Chiang Mai University, Chiang Mai, Thailand
- Department of Plant and Soil Sciences, Faculty of Agriculture, Chiang Mai University, Chiang Mai, Thailand
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Murata-Kamiya N, Hatakeyama M. Helicobacter pylori-induced DNA double-strand break in the development of gastric cancer. Cancer Sci 2022; 113:1909-1918. [PMID: 35359025 PMCID: PMC9207368 DOI: 10.1111/cas.15357] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 03/22/2022] [Accepted: 03/30/2022] [Indexed: 01/10/2023] Open
Abstract
Infection with cagA-positive Helicobacter pylori strains plays an etiological role in the development of gastric cancer. The CagA protein is injected into gastric epithelial cells through a bacterial Type IV secretion system. Inside the host cells, CagA promiscuously associates with multiple host cell proteins including the prooncogenic phosphatase SHP2 that is required for full activation of the RAS-ERK pathway. CagA-SHP2 interaction aberrantly activates SHP2 and thereby deregulates RAS-ERK signaling. Cancer is regarded as a disease of the genome, indicating that H. pylori-mediated gastric carcinogenesis is also associated with genomic alterations in the host cell. Indeed, accumulating evidence has indicated that H. pylori infection provokes DNA double-strand breaks (DSBs) by both CagA-dependent and -independent mechanisms. DSBs are repaired by either error-free homologous recombination (HR) or error-prone non-homologous end joining (NHEJ) or microhomology-mediated end joining (MMEJ). Infection with cagA-positive H. pylori inhibits RAD51 expression while dampening cytoplasmic-to-nuclear translocalization of BRCA1, causing replication fork instability and HR defects (known as "BRCAness"), which collectively provoke genomic hypermutation via non-HR-mediated DSB repair. H. pylori also subverts multiple DNA damage responses including DNA repair systems. Infection with H. pylori additionally inhibits the function of the p53 tumor suppressor, thereby dampening DNA damage-induced apoptosis while promoting proliferation of CagA-delivered cells. Thus, H. pylori cagA-positive strains promote abnormal expansion of cells with BRCAness, which dramatically increases the chance of generating driver gene mutations in the host cells. Once such driver mutations are acquired, H. pylori CagA is no longer required for subsequent gastric carcinogenesis (Hit-and-Run carcinogenesis).
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Affiliation(s)
- Naoko Murata-Kamiya
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Masanori Hatakeyama
- Department of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan
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Bayraktar N, Güler İ, Bayraktar M, Koyuncu I. Investigation the levels of endotoxin and 8-hydroxy-2'-deoxyguanosine in sera of patients with Helicobacter pylori-positive peptic ulcer. Int J Clin Pract 2021; 75:e14501. [PMID: 34117680 DOI: 10.1111/ijcp.14501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 06/10/2021] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Peptic ulcer is considered an important public health problem and generally associated with complicated conditions such as bleeding and perforation. The aim of this study is to reflect the rate of oxidative damage in the body among dyspeptic patients with Helicobacter pylori-positive peptic ulcer by measuring 8-hydroxy-2'-deoxyguanosine (8-OHdG) level in serum samples and its association with the level of bacterial endotoxin. METHODS Patients referred to Harran University Gastroenterology Outpatient Clinic with dyspeptic complaints were enrolled in this study. According to gastrointestinal endoscopy findings, 43 dyspeptic patients with H pylori-positive peptic ulcer patients and 43 healthy volunteers were included in this study. Infection with H pylori was diagnosed by H pylori urea breath and stool antigen tests. Serum 8-OHdG and endotoxins were measured by ELISA. RESULTS A total of 43 dyspeptic patients with peptic ulcer (13 women and 30 men) and 43 healthy individuals (16 women and 27 men) were enrolled in the study. In biopsies taken endoscopically, H pylori severity was mild in 19 patients (43.9%), moderate in 21 patients (48.5%) and severe in 3 patients (7.6%). 8-OHdG was compared with the healthy and patient group. It was observed that there was a statistically significant difference (P < .01). In addition, a weak correlation was found between OHdG and bacterial endotoxin. CONCLUSION Serum 8-OHdG and endotoxin levels are only weakly associated implying that they reflect specific aspects of oxidative damage. Helicobacter pylori and its endotoxin have a significant role in peptic ulcer pathogenesis. The detection of serum 8-OHdG in dyspeptic patients may be used as a biomarker for the presence of peptic ulcers.
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Affiliation(s)
- Nihayet Bayraktar
- Department of Medical Biochemistry, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
| | - İslim Güler
- Department of Medical Biochemistry, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
| | - Mehmet Bayraktar
- Department of Medical Microbiology, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
| | - Ismail Koyuncu
- Department of Medical Biochemistry, Faculty of Medicine, Harran University, Şanlıurfa, Turkey
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Salamatullah AM, Subash-Babu P, Nassrallah A, Alshatwi AA, Alkaltham MS. Cyclotrisiloxan and β-Sitosterol rich Cassia alata (L.) flower inhibit HT-115 human colon cancer cell growth via mitochondrial dependent apoptotic stimulation. Saudi J Biol Sci 2021; 28:6009-6016. [PMID: 34588918 PMCID: PMC8459119 DOI: 10.1016/j.sjbs.2021.06.065] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 02/07/2023] Open
Abstract
Cancer traits dependent chemo and radiotherapy display acute toxicity and long-term side effects. Since last two decades, researchers investigated a new anticancer agents derived from plants. Cassia alata (L.) is a medicinal herb distributed in the tropical and humid regions. In this study, C. alata flower methanol extract (CME) have been prepared using cold percolation method and the phytochemical components were identified using GC–MS analysis. CME have been used to study the antiproliferative and apoptosis properties against human colon cancer HT-115 colon cancer cells, its molecular mechanism have been explored. 0.2 mg/mL dose of CME, inhibited 50% of HT-115 colon cancer cell growth after 48hr was confirmed the significant antiproliferation effect. In normal cells such as Vero cells and hMSCs, 0.2 mg/mL dose of CME shown only 4% and 5% growth inhibition confirmed the HT-115 cell specific cytotoxic effect. This effect might be due to the availability of phytoactive biomolecules in CME such as, cyclotrisiloxan, beta-sitosterol and alpha-tocopherol have been confirmed by GC–MS. Most interestingly, PI and AO/ErBr staining of CME treated HT-115 cells shown early (25%), pro (17%) and late (8%) apoptotic and 3% necrotic cells after 48 hr. Treatment with CME extract showed potential effect on the inhibition of protumorigenic inflammatory and oxidative stress genes. Protumorigenic COX-2/PGE-2 and TNF-α/NF-κB immune axis were normalized after CME treatment. Amounts of both apoptosis related mRNA p53, Bax, caspase 3 and p21 genes were upregulated, whereas it resulted in significant reduction in the anti-apoptotic marker mdm2 and Bcl-2 genes. In conclusion, bioactive compounds present in CME potentially inhibit HT-115 colon cancer cell proliferation via an inhibition of protumorigenic immune axis and stimulation of mitochondria dependent apoptotic pathway without necrotic effect.
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Affiliation(s)
- Ahmad Mohammad Salamatullah
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - P Subash-Babu
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - Amr Nassrallah
- Biochemistry Department Cairo University Research Park (CURP), Facility of Agriculture, Cairo University, Giza 12613, Egypt
| | - Ali A Alshatwi
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
| | - Mohammed Saeed Alkaltham
- Department of Food Science and Nutrition, College of Food and Agricultural Sciences, King Saud University, P.O. Box 2460, Riyadh 11451, Saudi Arabia
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Protective Effects of Anwulignan against HCl/Ethanol-Induced Acute Gastric Ulcer in Mice. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2021; 2021:9998982. [PMID: 34335857 PMCID: PMC8298145 DOI: 10.1155/2021/9998982] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Accepted: 06/30/2021] [Indexed: 02/06/2023]
Abstract
Gastric ulcer is one of the most common gastrointestinal diseases. Anwulignan (AN) is a major active component of Schisandra sphenanthera Rehd. This study was designed to evaluate the protective effect of AN against the acute gastric ulcer induced by HCl/ethanol in mice. The mice were given HCl/ethanol by gavage to establish an acute gastric ulcer model. Then, the serum and gastric tissue samples were taken for biochemical analyses. The results showed that the pretreatment with AN could significantly reduce the gastric ulcer index (GUI) and increase the ulcer inhibition rate, indicating that AN can protect against gastric ulcers. AN showed its antioxidant roles by decreasing the content of reactive oxygen species (ROS), malondialdehyde (MDA), and 8-hydroxydeoxyguanosine (8-OHdG) and increasing the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) and anti-inflammatory roles by decreasing the content of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), and myeloperoxidase (MPO) and increasing the content of interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10), prostaglandin E2 (PGE2), and nitric oxide (NO) in both serum and gastric tissue. Furthermore, AN also activated the NRF2/ARE signaling pathway and inhibited the MAPK/NF-κB signaling pathway. AN improves the acute gastric ulcer induced by HCl/ethanol in mice, which may be mainly through its antioxidant capacity and anti-inflammatory effect.
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Palrasu M, Zaika E, El-Rifai W, Que J, Zaika AI. Role of Bacterial and Viral Pathogens in Gastric Carcinogenesis. Cancers (Basel) 2021; 13:1878. [PMID: 33919876 PMCID: PMC8070847 DOI: 10.3390/cancers13081878] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/02/2021] [Accepted: 04/11/2021] [Indexed: 01/10/2023] Open
Abstract
Gastric cancer (GC) is one of the deadliest malignancies worldwide. In contrast to many other tumor types, gastric carcinogenesis is tightly linked to infectious events. Infections with Helicobacter pylori (H. pylori) bacterium and Epstein-Barr virus (EBV) are the two most investigated risk factors for GC. These pathogens infect more than half of the world's population. Fortunately, only a small fraction of infected individuals develops GC, suggesting high complexity of tumorigenic processes in the human stomach. Recent studies suggest that the multifaceted interplay between microbial, environmental, and host genetic factors underlies gastric tumorigenesis. Many aspects of these interactions still remain unclear. In this review, we update on recent discoveries, focusing on the roles of various gastric pathogens and gastric microbiome in tumorigenesis.
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Affiliation(s)
- Manikandan Palrasu
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Elena Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
| | - Wael El-Rifai
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
| | - Jianwen Que
- Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA;
| | - Alexander I. Zaika
- Department of Surgery, University of Miami, Miami, FL 33136, USA; (M.P.); (E.Z.); (W.E.-R.)
- Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33136, USA
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Abstract
Background: Various microorganisms such as bacteria, virus, and fungi can infect humans and cause not just a simple infection but septic conditions, organ dysfunction, and precancerous conditions or cancer involving various organ systems. After the discovery of the microscope, it was easier to discover and study such microorganisms, as in the case of Helicobacter pylori, a pathogen that was seen in the distant era of the nineteenth century but without being recognized as such. It took 100 years to later discover the pathogenesis and the cancer that this bacterium can cause. Since it was discovered, until today, there has been a continuous search for the understanding of its pathogenetic mechanisms, and the therapeutic approach is continuously updated. Methods: We investigated how diagnosis and therapy were dealt with in the past and how researchers sought to understand, exactly, the pathogenetic biomolecular mechanisms of H. pylori, from the genesis of the infection to the current knowledge, with an analysis of carcinogenic mechanisms in the stomach. We have examined the scientific evolution of the knowledge of the disease over these 40 years in the gastroenterological and pharmacological fields. This was possible through a search in the databases of Medline, the WHO website, the Centers for Disease Control and Prevention (CDC) website, PubMed, and Web of Science to analyze the earlier and the latest data regarding H. pylori. Results: With the scientific discoveries over time, thanks to an increasing number of progressions in scientific research in the analysis of the gastric mucosa, the role of Helicobacter pylori in peptic ulcer, carcinogenesis, and in some forms of gastric lymphoma was revealed. Furthermore, over the years, the biomolecular mechanism involvement in some diseases has also been noted (such as cardiovascular ones), which could affect patients positive for H. pylori. Conclusions: Thanks to scientific and technological advances, the role of the bacterium H. pylori in carcinogenesis has been discovered and demonstrated, and new prospective research is currently attempting to investigate the role of other factors in the stomach and other organs. Cancer from H. pylori infection had a high incidence rate compared to various types of cancer, but in recent years, it is improving thanks to the techniques developed in the detection of the bacterium and the evolution of therapies. Thus, although it has become an increasingly treatable disease, there is still continuous ongoing research in the field of treatment for resistance and pharma compliance. Furthermore, in this field, probiotic therapy is considered a valid adjuvant.
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Kontizas E, Tastsoglou S, Karamitros T, Karayiannis Y, Kollia P, Hatzigeorgiou AG, Sgouras DN. Impact of Helicobacter pylori Infection and Its Major Virulence Factor CagA on DNA Damage Repair. Microorganisms 2020; 8:microorganisms8122007. [PMID: 33339161 PMCID: PMC7765595 DOI: 10.3390/microorganisms8122007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2020] [Revised: 12/11/2020] [Accepted: 12/14/2020] [Indexed: 01/10/2023] Open
Abstract
Helicobacter pylori infection induces a plethora of DNA damages. Gastric epithelial cells, in order to maintain genomic integrity, require an integrous DNA damage repair (DDR) machinery, which, however, is reported to be modulated by the infection. CagA is a major H. pylori virulence factor, associated with increased risk for gastric carcinogenesis. Its pathogenic activity is partly regulated by phosphorylation on EPIYA motifs. Our aim was to identify effects of H. pylori infection and CagA on DDR, investigating the transcriptome of AGS cells, infected with wild-type, ΔCagA and EPIYA-phosphorylation-defective strains. Upon RNA-Seq-based transcriptomic analysis, we observed that a notable number of DDR genes were found deregulated during the infection, potentially resulting to base excision repair and mismatch repair compromise and an intricate deregulation of nucleotide excision repair, homologous recombination and non-homologous end-joining. Transcriptome observations were further investigated on the protein expression level, utilizing infections of AGS and GES-1 cells. We observed that CagA contributed to the downregulation of Nth Like DNA Glycosylase 1 (NTHL1), MutY DNA Glycosylase (MUTYH), Flap Structure-Specific Endonuclease 1 (FEN1), RAD51 Recombinase, DNA Polymerase Delta Catalytic Subunit (POLD1), and DNA Ligase 1 (LIG1) and, contrary to transcriptome results, Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) upregulation. Our study accentuates the role of CagA as a significant contributor of H. pylori infection-mediated DDR modulation, potentially disrupting the balance between DNA damage and repair, thus favoring genomic instability and carcinogenesis.
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Affiliation(s)
- Eleftherios Kontizas
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Department of Genetics and Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, 15772 Athens, Greece;
- Correspondence: (E.K.); (D.N.S.); Tel.: +30-210-647-8812 (E.K.); +30-210-647-8824 (D.N.S.)
| | - Spyros Tastsoglou
- Department of Electrical and Computer Engineering, University of Thessaly, 38221 Volos, Greece;
- DIANA-Lab, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Timokratis Karamitros
- Bioinformatics and Applied Genomics Unit, Hellenic Pasteur Institute, 11521 Athens, Greece;
| | - Yiannis Karayiannis
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Department of Genetics and Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Panagoula Kollia
- Department of Genetics and Biotechnology, Faculty of Biology, National and Kapodistrian University of Athens, 15772 Athens, Greece;
| | - Artemis G. Hatzigeorgiou
- DIANA-Lab, Hellenic Pasteur Institute, 11521 Athens, Greece;
- DIANA-Lab, Department of Computer Science and Biomedical Informatics, University of Thessaly, 35131 Lamia, Greece
| | - Dionyssios N. Sgouras
- Laboratory of Medical Microbiology, Hellenic Pasteur Institute, 11521 Athens, Greece;
- Correspondence: (E.K.); (D.N.S.); Tel.: +30-210-647-8812 (E.K.); +30-210-647-8824 (D.N.S.)
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13
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Zhang X, Li L. The Significance of 8-oxoGsn in Aging-Related Diseases. Aging Dis 2020; 11:1329-1338. [PMID: 33014540 PMCID: PMC7505272 DOI: 10.14336/ad.2019.1021] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 10/21/2019] [Indexed: 01/10/2023] Open
Abstract
Aging is a common risk factor for the occurrence and development of many diseases, such as Parkinson’s disease, Alzheimer’s disease, diabetes, hypertension, atherosclerosis and coronary heart disease, and cancer, among others, and is a key problem threatening the health and life expectancy of the elderly. Oxidative damage is an important mechanism involved in aging. The latest discovery pertaining to oxidative damage is that 8-oxoGsn (8-oxo-7,8-dihydroguanosine), an oxidative damage product of RNA, can represent the level of oxidative stress. The significance of RNA oxidative damage to aging has not been fully explained, but the relationship between the accumulation of 8-oxoGsn, a marker of RNA oxidative damage, and the occurrence of diseases has been confirmed in many aging-related diseases. Studying the aging mechanism, monitoring the aging level of the body and exploring the corresponding countermeasures are of great significance for achieving healthy aging and promoting public health and social development. This article reviews the progress of research on 8-oxoGsn in aging-related diseases.
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Affiliation(s)
- Xinmu Zhang
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
| | - Lin Li
- Department of Medical Oncology, Beijing Hospital, National Center of Gerontology, Beijing, China
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14
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Wang S, Liang T, Luo Q, Li P, Zhang R, Xu M, Su J, Xu T, Wu Q. H9N2 swine influenza virus infection-induced damage is mediated by TRPM2 channels in mouse pulmonary microvascular endothelial cells. Microb Pathog 2020; 148:104408. [PMID: 32707310 DOI: 10.1016/j.micpath.2020.104408] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 01/10/2023]
Abstract
Oxidative stress is implicated in the pathogenesis of influenza virus infection. Increasing evidences show that transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable non-selective cation channel, plays an important role in the pathomechanism of reactive oxygen species (ROS)-coupled diseases. The present study investigated the role of TRPM2 in pulmonary microvascular endothelial cells (PMVECs) during H9N2 influenza virus infection. We knocked down TRPM2 in PMVECs using TRPM2 shRNA lentiviral particles. Subsequently, we utilized enzyme-linked immunosorbent assay and flow cytometry to compare ROS levels, DNA damage, mitochondrial integrity, apoptosis, and inflammatory factors between control and TRPM2-knockdown PMVECs following H9N2 influenza virus infection. Inhibition of TRPM2 channels reduced H9N2 virus-induced intracellular ROS production, decreased DNA damage, and inhibited H9N2-induced cellular apoptosis. This study shows that the inhibition of TRPM2 channels may protect PMVECs from the damage caused by H9N2 virus infection. Our results highlight the importance of TRPM2 in modulating ROS production, apoptosis, mitochondrial dysfunction, cytokine expression, and DNA damage in H9N2 virus-infected PMVECs, and suggest that TRPM2 may be a potential antiviral target.
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Affiliation(s)
- Shaohua Wang
- Key Laboratory of Animal Epidemiology and Zoonosis of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, PR China
| | - Ting Liang
- Key Laboratory of Preventive Veterinary Medicine, Department of Veterinary Medicine, Animal Science College, Hebei North University, Zhangjiakou, 075131, Hebei, PR China
| | - Qiang Luo
- Key Laboratory of Preventive Veterinary Medicine, Department of Veterinary Medicine, Animal Science College, Hebei North University, Zhangjiakou, 075131, Hebei, PR China
| | - Peiyao Li
- Key Laboratory of Preventive Veterinary Medicine, Department of Veterinary Medicine, Animal Science College, Hebei North University, Zhangjiakou, 075131, Hebei, PR China
| | - Ruihua Zhang
- Key Laboratory of Preventive Veterinary Medicine, Department of Veterinary Medicine, Animal Science College, Hebei North University, Zhangjiakou, 075131, Hebei, PR China
| | - Mingju Xu
- Key Laboratory of Preventive Veterinary Medicine, Department of Veterinary Medicine, Animal Science College, Hebei North University, Zhangjiakou, 075131, Hebei, PR China
| | - Jingliang Su
- Key Laboratory of Animal Epidemiology and Zoonosis of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, PR China
| | - Tong Xu
- Key Laboratory of Preventive Veterinary Medicine, Department of Veterinary Medicine, Animal Science College, Hebei North University, Zhangjiakou, 075131, Hebei, PR China.
| | - Qingmin Wu
- Key Laboratory of Animal Epidemiology and Zoonosis of the Ministry of Agriculture, College of Veterinary Medicine, China Agricultural University, Beijing, 100193, PR China.
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15
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Raza Y, Ahmed A, Khan A, Chishti AA, Akhter SS, Mubarak M, Bernstein C, Zaitlin B, Kazmi SU. Helicobacter pylori severely reduces expression of DNA repair proteins PMS2 and ERCC1 in gastritis and gastric cancer. DNA Repair (Amst) 2020; 89:102836. [PMID: 32143126 DOI: 10.1016/j.dnarep.2020.102836] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 02/24/2020] [Accepted: 02/24/2020] [Indexed: 01/10/2023]
Abstract
Gastric cancers are the third leading cause of cancer mortality in the world. Helicobacter pylori causes over 60 % of all stomach cancers. Colonization of the gastric mucosa by H. pylori results in increased DNA damage. Repair of DNA damage may also be reduced by H. pylori infection. Reduced DNA repair in combination with increased DNA damage can cause carcinogenic mutations. During progression to gastric cancer, gastric epithelium goes through stages of increasing pathology. Determining the levels of DNA repair enzymes during progression to gastric cancer could illuminate treatment approaches. Our aim is to determine the level of gastric expression of DNA repair proteins ERCC1 (a nucleotide excision repair enzyme) and PMS2 (a mismatch repair enzyme) in the presence of H. pylori infection at successive stages of gastric pathology and in gastric cancers. We analyzed gastric tissues of 300 individuals, including 30 without dyspepsia, 200 with dyspepsia and 70 with gastric cancers. The presence of H. pylori, gastric pathology and expression of DNA repair proteins ERCC1 and PMS2 were evaluated. Infection by H. pylori carrying the common cagA gene reduced median nuclear expression of ERCC1 and PMS2 to less than 20 % and 15 % of normal, respectively, in all pathologic stages preceding cancer. ERCC1 and PMS2 nuclear expression was 0-5 % of normal in gastric cancers. H. pylori can cause deficiency of ERCC1 and PMS2 protein expression. These deficiencies are associated with gastric pathology and cancer. This reduction in DNA repair likely causes carcinogenic mutations. Substantially reduced ERCC1 and PMS2 expression appears to be an early step in progression to H. pylori-induced gastric cancer.
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Affiliation(s)
- Yasir Raza
- Department of Microbiology, University of Karachi, Karachi, Pakistan; Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA.
| | - Ayaz Ahmed
- Dr. Panjwani Center for Molecular Medicine & Drug Research, University of Karachi, Karachi, Pakistan.
| | - Adnan Khan
- Department of Microbiology, University of Karachi, Karachi, Pakistan.
| | | | | | - Muhammad Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan.
| | - Carol Bernstein
- Department of Cellular and Molecular Medicine, College of Medicine, University of Arizona, Tucson, AZ, USA.
| | - Beryl Zaitlin
- Zaitlin Geoconsulting Ltd., Calgary, Alberta, Canada.
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16
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Sokolova O, Naumann M. Crosstalk Between DNA Damage and Inflammation in the Multiple Steps of Gastric Carcinogenesis. Curr Top Microbiol Immunol 2019; 421:107-137. [PMID: 31123887 DOI: 10.1007/978-3-030-15138-6_5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Over the last years, intensive investigations in molecular biology and cell physiology extended tremendously the knowledge about the association of inflammation and cancer. In frame of this paradigm, the human pathogen Helicobacter pylori triggers gastritis and gastric ulcer disease, and contributes to the development of gastric cancer. Mechanisms, by which the bacteria-induced inflammation in gastric mucosa leads to intestinal metaplasia and carcinoma, are represented in this review. An altered cell-signaling response and increased production of free radicals by epithelial and immune cells account for the accumulation of DNA damage in gastric mucosa, if infection stays untreated. Host genetics and environmental factors, especially diet, can accelerate the process, which offers the opportunity of intervention based on a balanced nutrition. It is supposed that inflammation might influence stem- or progenitor cells in gastric tissue predisposing for metaplasia or tumor relapse. Herein, DNA is strongly mutated and labile, which restricts therapy options. Thus, the understanding of the mechanisms that underlie gastric carcinogenesis will be of preeminent importance for the development of strategies for screening and early detection. As most gastric cancer patients face late-stage disease with a poor overall survival, the development of multi-targeted therapeutic intervention strategies is a major challenge for the future.
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Affiliation(s)
- Olga Sokolova
- Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany.
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto von Guericke University, Leipziger Str. 44, 39120, Magdeburg, Germany
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17
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Ohtake S, Kawahara T, Ishiguro Y, Takeshima T, Kuroda S, Izumi K, Miyamoto H, Uemura H. Oxidative stress marker 8-hydroxyguanosine is more highly expressed in prostate cancer than in benign prostatic hyperplasia. Mol Clin Oncol 2018; 9:302-304. [PMID: 30112175 DOI: 10.3892/mco.2018.1665] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 07/02/2018] [Indexed: 01/10/2023] Open
Abstract
Oxidative stress is a primary cause of vascular endothelial damage. In the prostate, ischemia increases the levels of reactive oxygen species, growth factors and cytokines, and induces the development of angiogenesis, which results in cancer progression. The expression levels of an oxidative stress marker, 8-hydroxyguanosine (8-OHdG), were compared between prostate cancer and non-neoplastic prostate tissues. A prostate tissue microarray composed of 10 cases of prostatic adenocarcinoma and 70 cases of benign prostatic hyperplasia was immunohistochemically stained for 8-OHdG. All cases expressed 8-OHdG. The levels of 8-OHdG expression in prostatic cancer (30.0% moderate and 70.0% strong) were significantly higher than those in benign prostatic hyperplasia (71.4% moderate and 28.6% strong; (p<0.01). Notably, 8-OHdG is expressed more highly in prostate cancer tissues in comparison to benign prostate tissues.
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Affiliation(s)
- Shinji Ohtake
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.,Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Takashi Kawahara
- Department of Urology, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa 236-0004, Japan.,Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Yukari Ishiguro
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Teppei Takeshima
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Shinnosuke Kuroda
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Koji Izumi
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
| | - Hiroshi Miyamoto
- Departments of Pathology and Laboratory Medicine, Urology, and Oncology, University of Rochester Medical Center, Rochester, NY 14627, USA
| | - Hiroji Uemura
- Department of Urology and Renal Transplantation, Yokohama City University Medical Center, Yokohama, Kanagawa 232-0024, Japan
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18
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Wada Y, Takemura K, Tummala P, Uchida K, Kitagaki K, Furukawa A, Ishige Y, Ito T, Hara Y, Suzuki T, Mimuro H, Board PG, Eishi Y. Helicobacter pylori induces somatic mutations in TP53 via overexpression of CHAC1 in infected gastric epithelial cells. FEBS Open Bio 2018; 8:671-679. [PMID: 29632819 PMCID: PMC5881537 DOI: 10.1002/2211-5463.12402] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2017] [Revised: 01/29/2018] [Accepted: 02/07/2018] [Indexed: 01/10/2023] Open
Abstract
Infection with Helicobacter pylori is known to decrease the level of glutathione in gastric epithelial cells and increase the production of reactive oxygen species (ROS), which can lead to DNA damage and the development of gastric cancer. Cation transport regulator 1 (CHAC1) has γ‐glutamylcyclotransferase activity that degrades glutathione. We found that cagA‐positive H. pylori infection triggered CHAC1 overexpression in human gastric epithelial (AGS) cells leading to glutathione degradation and the accumulation of ROS. Nucleotide alterations in the TP53 tumour suppressor gene were induced in AGS cells overexpressing CHAC1, whereas no mutations were detected in cells overexpressing a catalytically inactive mutant of CHAC1. A high frequency of TP53 mutations occurred in H. pylori‐infected AGS cells, but this was prevented in cells transfected with CHAC1 siRNA. These findings indicate that H. pylori‐mediated CHAC1 overexpression degrades intracellular glutathione, allowing the accumulation of ROS which subsequently causes mutations that could contribute to the development of gastric cancer.
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Affiliation(s)
- Yuriko Wada
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
| | - Kosuke Takemura
- Department of Urology Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital Japan
| | - Padmaja Tummala
- The ACRF Department of Cancer Biology and Therapeutics Group of Molecular Genetics The John Curtin School of Medical Research Australian National University Canberra ACT Australia
| | - Keisuke Uchida
- Division of Surgical Pathology Tokyo Medical and Dental University Hospital Japan
| | - Keisuke Kitagaki
- Division of Surgical Pathology Tokyo Medical and Dental University Hospital Japan
| | - Asuka Furukawa
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
| | - Yuuki Ishige
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
| | - Takashi Ito
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
| | - Yukichi Hara
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
| | - Takashige Suzuki
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
| | - Hitomi Mimuro
- Department of Infection Microbiology Division of Infectious Diseases Research Institute for Microbial Diseases University of Osaka Japan
| | - Philip G Board
- The ACRF Department of Cancer Biology and Therapeutics Group of Molecular Genetics The John Curtin School of Medical Research Australian National University Canberra ACT Australia
| | - Yoshinobu Eishi
- Department of Human Pathology Graduate School and Faculty of Medicine Tokyo Medical and Dental University Japan
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19
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Raza Y, Khan A, Khan AI, Khan S, Akhter S, Mubarak M, Ahmed A, Kazmi SU. Combination of Interleukin 1 Polymorphism and Helicobacter pylori Infection: an Increased Risk of Gastric Cancer in Pakistani Population. Pathol Oncol Res 2017; 23:873-880. [PMID: 28110439 DOI: 10.1007/s12253-017-0191-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 01/09/2017] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori is one of the major risk factors involved in the development ofgastritis and gastric cancer (GC). H. pylori infection leads to increased production of pro-inflammatory cytokines by the host. Carriage of specific polymorphisms in cytokine genes may be associated with host susceptibility to the development of GC. We investigated the role of host genetic factors including polymorphisms of IL-1B and IL-1RN in correlation with gastritis and GC in H. pylori infected Pakistani population. A total of 230 gastritis cases and 100 GC cases were genotyped for IL 1B-511 and IL-1RN penta-allelic variable number of tandem repeats (VNTRs). A combination of IL-1B-511*T and IL-1RN*2 alleles (OR 19.064; 95% CI 2.319-156.7; p = 0.001) in H. pylori infected individuals had markedly increased risk of GC development. In Pakistani population, an increased risk of GC development is associated with the carriage of IL-1B-511*T and IL-1RN*2 alleles. Synergistic effect of H. pylori infection and IL-1B-511*T/IL-1RN*2 genotypes was also observed in association with significantly higher risk of developing GC. Further prospective and large scale studies are needed to establish the clinical impact of these findings.
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Affiliation(s)
- Yasir Raza
- Stem Cell Research Laboratory, Sindh Institute of Urology and Transplantation, Deewan Farooq Medical Complex, Chand Bibi Road, Karachi, Pakistan.
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan.
| | - Adnan Khan
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan
| | - Asif Iqbal Khan
- Department of Molecular Pathology, Dow University of Health and Sciences, Karachi, Pakistan
| | - Saeed Khan
- Department of Molecular Pathology, Dow University of Health and Sciences, Karachi, Pakistan
| | - Shakeel Akhter
- Department of Surgery and Medicine, Civil Hospital Karachi, Karachi, Pakistan
| | - Muhammad Mubarak
- Department of Histopathology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan
| | - Ayaz Ahmed
- Dr. Panjwani Center For Molecular Medicine And Drug Research, Karachi, Pakistan
| | - Shahana Urooj Kazmi
- Immunology and Infectious Diseases Research Laboratory, Department of Microbiology, University of Karachi, Karachi, Pakistan
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20
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Carvalho-Silva M, Gomes LM, Scaini G, Rebelo J, Damiani AP, Pereira M, Andrade VM, Gava FF, Valvassori SS, Schuck PF, Ferreira GC, Streck EL. Omega-3 fatty acid supplementation decreases DNA damage in brain of rats subjected to a chemically induced chronic model of Tyrosinemia type II. Metab Brain Dis 2017; 32:1043-1050. [PMID: 28315992 DOI: 10.1007/s11011-017-9994-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 03/13/2017] [Indexed: 01/10/2023]
Abstract
Tyrosinemia type II is an inborn error of metabolism caused by a mutation in a gene encoding the enzyme tyrosine aminotransferase leading to an accumulation of tyrosine in the body, and is associated with neurologic and development difficulties in numerous patients. Because the accumulation of tyrosine promotes oxidative stress and DNA damage, the main aim of this study was to investigate the possible antioxidant and neuroprotective effects of omega-3 treatment in a chemically-induced model of Tyrosinemia type II in hippocampus, striatum and cerebral cortex of rats. Our results showed chronic administration of L-tyrosine increased the frequency and the index of DNA damage, as well as the 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels in the hippocampus, striatum and cerebral cortex. Moreover, omega-3 fatty acid treatment totally prevented increased DNA damage in the striatum and hippocampus, and partially prevented in the cerebral cortex, whereas the increase in 8-OHdG levels was totally prevented by omega-3 fatty acid treatment in hippocampus, striatum and cerebral cortex. In conclusion, the present study demonstrated that the main accumulating metabolite in Tyrosinemia type II induce DNA damage in hippocampus, striatum and cerebral cortex, possibly mediated by free radical production, and the supplementation with omega-3 fatty acids was able to prevent this damage, suggesting that could be involved in the prevention of oxidative damage to DNA in this disease. Thus, omega-3 fatty acids supplementation to Tyrosinemia type II patients may represent a new therapeutic approach and a possible adjuvant to the curren t treatment of this disease.
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Affiliation(s)
- Milena Carvalho-Silva
- Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil
| | - Lara M Gomes
- Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil
| | - Giselli Scaini
- Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil
| | - Joyce Rebelo
- Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil
| | - Adriani P Damiani
- Laboratório de Biologia Celular e Molecular, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Maiara Pereira
- Laboratório de Biologia Celular e Molecular, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Vanessa M Andrade
- Laboratório de Biologia Celular e Molecular, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Fernanda F Gava
- Laboratório de Sinalização Neural e Psicofarmacologia, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Samira S Valvassori
- Laboratório de Sinalização Neural e Psicofarmacologia, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Patricia F Schuck
- Laboratório de Erros Inatos do Metabolismo, Programa de Pós-Graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense, Criciúma, SC, Brazil
| | - Gustavo C Ferreira
- Laboratório de Neuroquímica, Instituto de Biofísica Carlos Chagas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Emilio L Streck
- Laboratório de Bioenergética, Programa de Pós-graduação em Ciências da Saúde, Universidade do Extremo Sul Catarinense (UNESC), Av. Universitária, 1105, Criciúma, SC, 88806-000, Brazil.
- Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Porto Alegre, RS, Brazil.
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21
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Packiriswamy N, Coulson KF, Holcombe SJ, Sordillo LM. Oxidative stress-induced mitochondrial dysfunction in a normal colon epithelial cell line. World J Gastroenterol 2017; 23:3427-3439. [PMID: 28596679 PMCID: PMC5442079 DOI: 10.3748/wjg.v23.i19.3427] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2016] [Revised: 01/13/2017] [Accepted: 03/15/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine how a normal human colon cell line reacts to microbial challenge as a way to study oxidative stress-induced responses associated with inflammatory bowel disease.
METHODS Normal human colon epithelial cells (ATCC® CRL.1790™) were stimulated with either heat killed E. coli or heat killed murine cecal contents (HKC) and examined for several relevant biomarkers associated with inflammation and oxidative stress including cytokine production, mitochondrial autophagy and oxidant status. TNFα, IL-1β and IL-8 protein concentrations were measured within the supernatants. Fluorescent microscopy was performed to quantify the production of reactive oxygen species (ROS) using an oxidation responsive fluorogenic probe. Mitochondrial morphology and mitochondrial membrane potential was assessed by dual staining using COXIV antibody and a dye concentrating in active mitochondria. Mitochondrial ROS scavenger was used to determine the source of ROS in stimulated cells. Autophagy was detected by staining for the presence of autophagic vesicles. Positive controls for autophagy and ROS/RNS experiments were treated with rapamycin and chloroquine. Mitochondrial morphology, ROS production and autophagy microscopy experiments were analyzed using a custom acquisition and analysis microscopy software (ImageJ).
RESULTS Exposing CRL.1790 cells to microbial challenge stimulated cells to produce several relevant biomarkers associated with inflammation and oxidative stress. Heat killed cecal contents treatment induced a 10-12 fold increase in IL-8 production by CRL.1790 cells compared to unstimulated controls at 6 and 12 h (P < 0.001). Heat killed E. coli stimulation resulted in a 4-5 fold increase in IL-8 compared to the unstimulated control cells at each time point (P < 0.001). Both heat killed E. coli and HKC stimulated robust ROS production at 6 (P < 0.001), and 12 h (P < 0.01). Mitochondrial morphologic abnormalities were detected at 6 and 12 h based on reduced mitochondrial circularity and decreased mitochondrial membrane potential, P < 0.01. Microbial stimulation also induced significant autophagy at 6 and 12 h, P < 0.01. Lastly, blocking mitochondrial ROS generation using mitochondrial specific ROS scavenger reversed microbial challenge induced mitochondrial morphologic abnormalities and autophagy.
CONCLUSION The findings from this study suggest that CRL.1790 cells may be a useful alternative to other colon cancer cell lines in studying the mechanisms of oxidative stress events associated with intestinal inflammatory disorders.
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Wang Y, Zhao Y, Zhao Y, Luo X, Guo Z, Zhang R. Cancer risk associated single nucleotide polymorphisms of mitochondrial D-loop and 8-hydroxy-2'-deoxyguanosine levels in gastric cancer. BIOTECHNOL BIOTEC EQ 2017. [DOI: 10.1080/13102818.2016.1270173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Yingnan Wang
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Yufei Zhao
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Yue Zhao
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Xiaoxu Luo
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Zhanjun Guo
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
| | - Ruixing Zhang
- Department of Gastroenterology and Hepatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, P.R. China
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Lei Z, Tian D, Zhang C, Zhao S, Su M. Clinicopathological and prognostic significance of GPX2 protein expression in esophageal squamous cell carcinoma. BMC Cancer 2016; 16:410. [PMID: 27388201 PMCID: PMC4936229 DOI: 10.1186/s12885-016-2462-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 06/27/2016] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Chaoshan region, a littoral area of Guangdong province in southern China, has a high incidence of esophageal squamous cell carcinoma (ESCC). At present, the prognosis of ESCC is still very poor, therefore, there is urgent need to seek valuable molecular biomarker for prognostic evaluation to guide clinical treatment. GPX2, a selenoprotein, was exclusively expressed in gastrointestinal tract and has an anti-oxidative damage and anti-tumour effect in the progress of tumourigenesis. METHODS We collected 161 ESCC patients samples, among which 83 patients were followed up. We employed immunochemistry analysis, western blotting and quantitative real-time PCR for measuring the expression of GPX2 within ESCC samples. We analysed the relationship between the expression of GPX2 and clinicopathological parameters of 161 patients with ESCC by Chi-square or Fisher's exact test. The survival analysis of GPX2 expression within ESCC tissues was evaluated by the Kaplan-Meier method and Cox-regression. RESULTS A significant higher expression level of GPX2 was detected in tumour tissues compared to that in non-tumour tissues (P < 0.001). Moreover, GPX2 expression has statistically significant difference in the tumour histological grade of ESCC (P < 0.001), while there was no statistically significant difference in age, sex, tumour size, tumour location, gross morphology and clinical TNM stages (P > 0.05). Meanwhile, the expression of GPX2 protein was obviously down-regulated within poorly differentiated ESCC. Last, survival analysis revealed that tumour histological grade and clinical TNM stages, both of the clinical pathological parameters of ESCC, were associated with the prognosis of patients with ESCC (respectively, P = 0.009, HR (95 % CI) = 1.885 (1.212 ~ 2.932); P = 0.007, HR (95 % CI) = 2.046 (1.318 ~ 3.177)). More importantly, loss expression of GPX2 protein predicted poor prognosis in patients with ESCC (P < 0.001, HR (95 % CI) = 5.700 (2.337 ~ 13.907)). CONCLUSIONS Collectively, these results suggested that the expression of GPX2 was significantly up-regulated within ESCC tumour tissues. GPX2 might be an important predictor for the prognosis of ESCC and a potential target for intervention and treatment of ESCC.
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Affiliation(s)
- Zhijin Lei
- />Department of Pathology and Institute of Clinical Pathology, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
| | - Dongping Tian
- />Department of Pathology and Institute of Clinical Pathology, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
- />Forensic Identification Center of Shantou University, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
| | - Chong Zhang
- />Department of Pathology and Institute of Clinical Pathology, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
| | - Shukun Zhao
- />Department of Pathology and Institute of Clinical Pathology, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
| | - Min Su
- />Department of Pathology and Institute of Clinical Pathology, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
- />Forensic Identification Center of Shantou University, Shantou University Medical College, Shantou, Guangdong People’s Republic of China
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Krüger NJ, Knüver MT, Zawilak-Pawlik A, Appel B, Stingl K. Genetic Diversity as Consequence of a Microaerobic and Neutrophilic Lifestyle. PLoS Pathog 2016; 12:e1005626. [PMID: 27166672 PMCID: PMC4864210 DOI: 10.1371/journal.ppat.1005626] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2016] [Accepted: 04/21/2016] [Indexed: 01/10/2023] Open
Abstract
As a neutrophilic bacterium, Helicobacter pylori is growth deficient under extreme acidic conditions. The gastric pathogen is equipped with an acid survival kit, regulating urease activity by a pH-gated urea channel, opening below pH 6.5. After overcoming acid stress, the bacterium’s multiplication site is situated at the gastric mucosa with near neutral pH. The pathogen exhibits exceptional genetic variability, mainly due to its capability of natural transformation, termed competence. Using single cell analysis, we show here that competence is highly regulated in H. pylori. DNA uptake complex activity was reversibly shut down below pH 6.5. pH values above 6.5 opened a competence window, in which competence development was triggered by the combination of pH increase and oxidative stress. In contrast, addition of sublethal concentrations of the DNA-damaging agents ciprofloxacin or mitomycin C did not trigger competence development under our conditions. An oxygen-sensitive mutant lacking superoxide dismutase (sodB) displayed a higher competent fraction of cells than the wild type under comparable conditions. In addition, the sodB mutant was dependent on adenine for growth in broth and turned into non-cultivable coccoid forms in its absence, indicating that adenine had radical quenching capacity. Quantification of periplasmically located DNA in competent wild type cells revealed outstanding median imported DNA amounts of around 350 kb per cell within 10 min of import, with maximally a chromosomal equivalent (1.6 Mb) in individual cells, far exceeding previous amounts detected in other Gram-negative bacteria. We conclude that the pathogen’s high genetic diversity is a consequence of its enormous DNA uptake capacity, triggered by intrinsic and extrinsic oxidative stress once a neutral pH at the site of chronic host colonization allows competence development. Natural transformation, i.e. the capacity to take up DNA from the environment, is one of the crucial means for horizontal gene transfer and genetic diversity in bacteria. The human gastric pathogen Helicobacter pylori is confronted with acid stress before entering its multiplication site, the gastric mucosa. The bacterium causes lifelong chronic gastritis and is perfectly adapted to the human host, crucially by displaying unusual genetic diversity. Using a single cell approach and well-controlled conditions, we show here that the amount of imported DNA in competent H. pylori is outstanding, far exceeding previous measurement with other Gram-negative bacteria. Furthermore, DNA uptake activity was tightly regulated and limited to pH above 6.5, conditions thought to be met in close contact with the gastric mucosa. In addition, we show that within this pH competence window, competence development was triggered by an increase in pH in combination with the level of oxidative stress. Our data provide explanations for the extraordinary high genetic diversity, often referred to as genome plasticity of this unusual microaerobic pathogen.
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Affiliation(s)
- Nora-Johanna Krüger
- Federal Institute for Risk Assessment, Department of Biological Safety, National Reference Laboratory for Campylobacter, Berlin, Germany
| | - Marie-Theres Knüver
- Federal Institute for Risk Assessment, Department of Biological Safety, National Reference Laboratory for Campylobacter, Berlin, Germany
| | - Anna Zawilak-Pawlik
- Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Department of Microbiology, Wroclaw, Poland
| | - Bernd Appel
- Federal Institute for Risk Assessment, Department of Biological Safety, National Reference Laboratory for Campylobacter, Berlin, Germany
| | - Kerstin Stingl
- Federal Institute for Risk Assessment, Department of Biological Safety, National Reference Laboratory for Campylobacter, Berlin, Germany
- * E-mail:
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Yeniova AO, Uzman M, Kefeli A, Basyigit S, Ata N, Dal K, Guresci S, Nazligul Y. Serum 8 Hydroxydeoxyguanosine and Cytotoxin Associated Gene A as Markers for Helicobacter pylori Infection. Asian Pac J Cancer Prev 2016. [PMID: 26225653 DOI: 10.7314/apjcp.2015.16.13.5199] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Helicobacter pylori (H.pylori) is associated with chronic gastritis, peptic ulcers, gastric adenocarcinomas and mucosa associated tissue lymphomas. Cytotoxin associated gene A (CagA) is one of the virulence factors of H.pylori. It is hypothesized that reactive oxygen species (ROS) play roles in H.pylori associated disease especially in development of gastric adenocarcinoma. Individuals infected with H.pylori bearing CagA produce more ROS than others. 8-hydroxydeoxyguanosine (8OHdG) is an in vitro marker of DNA damage and oxidative stress. The aim of this study was to investigate the relationship between 8OHdG level, H.pylori infection and CagA and alterations of serum 8OHdG level after H.pylori eradication. MATERIALS AND METHODS Patients admitted with dyspeptic complaints and upper gastrointestinal endoscopy were assessed. H.pylori was determined from histopathology of specimens. Serum 8OHdG levels of three groups (H.pylori negative, H. pylori positive CagA negative and H.pylori positive CagA positive) were compared. Patients with H.pylori infection received eradication therapy. Serum 8OHdG levels pretreatment and posttreatment were also compared. RESULTS In total, 129 patients (M/F, 57/72) were enrolled in the study. Serum 8OHdG level of H.pylori negative, H. pylori positive CagA negative and H.pylori positive CagA positive groups were significantly different (5.77±1.35 ng/ml, 5.43±1.14 ng/ml and 7.57±1.25 ng/ml respectively, p=0.05). Furthermore, eradication therapy reduced serum 8OHdG level (6.10±1.54 ng/ml vs 5.55±1.23 ng/ml, p=0.05). CONCLUSIONS Individuals infected with H.pylori bearing CagA strains have the highest serum 8OHdG level and eradication therapy decreases the serum 8OHdG level. To the best of our knowledge this is the first study that evaluated the effect of CagA virulence factor on serum 8OHdG level and the effect of eradication therapy on serum 8OHdG levels together. Eradication of CagA bearing H.pylori may prevent gastric adenocarcinoma by decreasing ROS. 8OHdG level may thus be a good marker for prevention from gastric adenocarcinoma.
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Abstract
The Database of Human Gastric Cancer (DBGC) is a comprehensive database that integrates various human gastric cancer-related data resources. Human gastric cancer-related transcriptomics projects, proteomics projects, mutations, biomarkers and drug-sensitive genes from different sources were collected and unified in this database. Moreover, epidemiological statistics of gastric cancer patients in China and clinicopathological information annotated with gastric cancer cases were also integrated into the DBGC. We believe that this database will greatly facilitate research regarding human gastric cancer in many fields. DBGC is freely available at http://bminfor.tongji.edu.cn/dbgc/index.do
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Electrochemical immunoassay for the biomarker 8-hydroxy-2′-deoxyguanosine using a glassy carbon electrode modified with chitosan and poly(indole-5-carboxylic acid). Mikrochim Acta 2015. [DOI: 10.1007/s00604-015-1652-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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da Rosa MS, Scaini G, Damiani AP, Longaretti LM, Pereira M, Seminotti B, Zapelini HG, Schuck PF, Streck EL, de Andrade VM, Wajner M, Leipnitz G. Evidence that 3-hydroxy-3-methylglutaric and 3-methylglutaric acids induce DNA damage in rat striatum. Metab Brain Dis 2015; 30:1055-62. [PMID: 25939283 DOI: 10.1007/s11011-015-9675-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2014] [Accepted: 04/23/2015] [Indexed: 01/10/2023]
Abstract
3-Hydroxy-3-methylglutaryl-CoA lyase (HL) deficiency is a rare autosomal recessive disorderaffecting the final step of leucine degradation and ketogenesis and biochemically characterized by the predominant accumulation of 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA) acids in biological fluids and tissues of affected patients. Considering that previous studies reported that HMG and MGA have pro oxidant properties, the present study evaluated the ex vivo and in vitro effects of HMG and MGA on frequency and index of DNA damage in cerebral cortex and striatum of young rats. The ex vivo effects of both organic acids on 8-hydroxy-2'-deoxyguanosine (OHdG) levels and their in vitro effects on 2',7'-dichlorofluorescin (DCFH) oxidation and glutathione (GSH) concentrations in rat striatum were also determined. We also investigated the ex vivo effects of both organic acids on 8-hydroxy-2'-deoxyguanosine (OHdG) levels in rat striatum. In the ex vivo experiments, DNA damage was determined in striatum homogenates prepared 30 min after a single intrastriatal administration of HMG or MGA. On the other hand, the in vitro evaluation was performed after an incubation of rat cerebral cortex or striatum homogenates or slices in the presence of HMG or MGA during 1 h at 37 °C. We observed that the intrastriatal administration of HMG and MGA increased the frequency and the index of DNA damage, as well as OHdG staining in rat striatum. We also verified that MGA, but not HMG, increased DNA damage frequency and index in vitro in striatum of rats. In contrast, no alterations were verified in vitro in cerebral cortex. Finally, we found that HMG and MGA increased DCFH oxidation and decreased GSH concentrations in rat striatum. Therefore, it may be presumed that DNA damage provoked by HMG and MGA possibly via reactive species generation is involved, at least in part, in the pathophysiology of brain injury, particularly in the striatum of HL-deficient patients.
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Affiliation(s)
- Mateus Struecker da Rosa
- Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos N° 2600 - Attached, CEP 90035-003, Porto Alegre, RS, Brazil
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