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Yin H, Wang C, Shuai Y, Xie Z, Liu J. Pig-Derived Probiotic Bacillus tequilensis YB-2 Alleviates Intestinal Inflammation and Intestinal Barrier Damage in Colitis Mice by Suppressing the TLR4/NF-κB Signaling Pathway. Animals (Basel) 2024; 14:1989. [PMID: 38998101 PMCID: PMC11240761 DOI: 10.3390/ani14131989] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2024] [Revised: 06/20/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024] Open
Abstract
The search for new probiotics has been regarded as an important approach to improving intestinal health in animals. Bacillus has many advantages, such as strong resistance to harmful external factors, wide distribution, and easy colonization of the intestine. Hence, this study aims to screen for a probiotic Bacillus strain that improves animal intestinal health and to elucidate its probiotic mechanism so as to provide probiotic resources for the development of feed-using probiotic formulations. In this research, a strain of Bacillus was isolated from adult pig feces and named B. tequilensis YB-2. In vitro probiotic experiments showed that B. tequilensis YB-2 had strong acid and bile salt resistance, indicating that this strain can customize in the intestine. To further explore the effect of B. tequilensis YB-2 upon animal intestinal health, DSS-induced murine colitis models were established, and the body weight, colonic morphology, inflammatory cytokines level, and intestinal-barrier- and TLR4/NF-κB-pathway-related protein were determined. The results showed that mice receiving drinking water with 3% DSS were found to develop colitis symptoms, including body weight loss and increased disease activity index (DAI); colon length and microvilli shedding were shortened; tight junctions were disrupted; goblet cells decreased; anti-inflammatory cytokines were inhibited; and pro-inflammatory cytokines and the TLR4/NF-κB signaling pathway were activated. Notably, orally received B. tequilensis YB-2 alleviated symptoms of DSS-induced colitis in mice. The above results indicated that B. tequilensis YB-2 was capable of improving colitis in mice by weakening inflammation and intestinal barrier damage, and its mechanism may involve the TLR4/NF-κB pathway. Overall, this research suggests that B. tequilensis YB-2 has the potential to serve as an animal feed additive to prevent intestinal inflammation.
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Affiliation(s)
- Heng Yin
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
| | - Chengbi Wang
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
| | - Yi Shuai
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
| | - Zhuoya Xie
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
| | - Jingbo Liu
- School of Life Science and Engineering, Southwest University of Science and Technology, Mianyang 621010, China
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2
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Saadi S, Nacer NE, Saari N, Mohammed AS, Anwar F. The underlying mechanism of nuclear and mitochondrial DNA damages in triggering cancer incidences: Insights into proteomic and genomic sciences. J Biotechnol 2024; 383:1-12. [PMID: 38309588 DOI: 10.1016/j.jbiotec.2024.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Revised: 01/02/2024] [Accepted: 01/26/2024] [Indexed: 02/05/2024]
Abstract
The attempt of this review article is to determine the impact of nuclear and mitochondrial damages on the propagation of cancer incidences. This review has advanced our understanding to altered genes and their relevant cancerous proteins. The progressive raising effects of free reactive oxygen species ROS and toxicogenic compounds contributed to significant mutation in nuclear and mitochondrial DNA where the incidence of gastric cancer is found to be linked with down regulation of some relevant genes and mutation in some important cellular proteins such as AMP-18 and CA-11. Thereby, the resulting changes in gene mutations induced the apparition of newly polymorphisms eventually leading to unusual cellular expression to mutant proteins. Reduction of these apoptotic growth factors and nuclear damages is increasingly accepted by cell reactivation effect, enhanced cellular signaling and DNA repairs. Acetylation, glycation, pegylation and phosphorylation are among the molecular techniques used in DNA repair for rectifying mutation incidences. In addition, the molecular labeling based fluorescent materials are currently used along with the bioconjugating of signal molecules in targeting disease translocation site, particularly cancers and tumors. These strategies would help in determining relevant compounds capable in overcoming problems of down regulating genes responsible for repair mechanisms. These issues of course need interplay of both proteomic and genomic studies often in combination of molecular engineering to cible the exact expressed gene relevant to these cancerous proteins.
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Affiliation(s)
- Sami Saadi
- Institute de la Nutrition, de l'Alimentation et des Technologies Agroalimetaires INATAA, Université des Frères Mentouri Constantine 1, Route de Ain El Bey, Constantine 25000, Algeria; Laboratoire de Génie Agro-Alimentaire (GeniAAl), INATAA, Université Frères Mentouri Constantine 1 UFC1, Route de Ain El Bey, Constantine 25000, Algeria.
| | - Nor Elhouda Nacer
- Department of Biology of Organisms, Faculty of Natural and Life Sciences, University of Batna 2, Batna 05000, Algeria
| | - Nazamid Saari
- Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang Selangor 43400, Malaysia
| | | | - Farooq Anwar
- Faculty of Food Science and Technology, Universiti Putra Malaysia, Serdang Selangor 43400, Malaysia; Institute of Chemistry, University of Sargodha, Sargodha 40100, Pakistan; Honorary Research Fellow: Metharath University, 99 Moo 10, Bangtoey, Samkhok, Pathum Thani 12160, Thailand
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Oszczędłowski P, Górecki K, Greluk A, Krawczyk M, Pacyna K, Kędzierawski JA, Ziółko AK, Chromiak K, Sławiński MA, Raczkiewicz P, Chylińska-Wrzos P, Jodłowska-Jędrych B, Pedrycz-Wieczorska A. All That Glitters Is Not Gold: Assessment of Bee Pollen Supplementation Effects on Gastric Mucosa. Nutrients 2023; 16:37. [PMID: 38201868 PMCID: PMC10780818 DOI: 10.3390/nu16010037] [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] [Received: 11/13/2023] [Revised: 12/13/2023] [Accepted: 12/14/2023] [Indexed: 01/12/2024] Open
Abstract
The aim of this study was to assess the influence of bee pollen supplementation on the levels of enzymes important for gastric mucosal homeostasis, namely cyclooxygenase-1 (COX-1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and a biomarker-asymmetric dimethylarginine (ADMA)-in the gastric mucosa of Wistar rats. The experimental phase divided the rats into four groups: two control groups, sedentary and active, both not supplemented, and two experimental groups, sedentary and active, supplemented with bee pollen. The results indicated that bee pollen supplementation reduced the levels of COX-1 and elevated iNOS levels, while showing no significant impact on COX-2 levels. These findings do not conclusively support the gastroprotective and anti-inflammatory effects of bee pollen on gastric mucosa. However, the supplementation could have resulted in reduced ADMA levels in the physically active supplemented group. Our study does not unequivocally demonstrate the positive effects of bee pollen supplementation on the gastric mucosa, which may be attributed to the specific metabolism and bioavailability of substances within unprocessed, dried bee pollen. Further research should explore the topic of potential therapeutic applications of bee pollen in gastrointestinal health and its interactions with ADMA signaling pathways.
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Affiliation(s)
- Paweł Oszczędłowski
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Kamil Górecki
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Aleksandra Greluk
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Milena Krawczyk
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Katarzyna Pacyna
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Jan Andrzej Kędzierawski
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Artur Kacper Ziółko
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Karol Chromiak
- Students’ Scientific Association at the Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland (K.P.)
| | - Mirosław A. Sławiński
- Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | | | - Patrycja Chylińska-Wrzos
- Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Barbara Jodłowska-Jędrych
- Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
| | - Agnieszka Pedrycz-Wieczorska
- Department of Histology, Embryology and Cytophysiology, Medical University of Lublin, Radziwiłłowska 11, 20-080 Lublin, Poland
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Tan S, Machrumnizar M. Fish and Food-Fatale: Food-borne Trematode Opisthorchis viverrini and Cholangiocarcinoma. Helminthologia 2023; 60:287-299. [PMID: 38222491 PMCID: PMC10787637 DOI: 10.2478/helm-2023-0036] [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: 03/30/2023] [Accepted: 10/20/2023] [Indexed: 01/16/2024] Open
Abstract
Neglected Tropical Diseases (NTDs) are a group of communicable diseases with a long history with human beings. NTDs are the proxy of poverty since they affect those in low-income and extreme-poverty populations, as those populations lack access to proper health care, clean water, sanitary conditions, and hygiene. NTDs create losses for a nation that come from the health and the economic sectors as well since the costs of diagnosis, prevention, and treatment strain the national purse strings. One of the 20 different forms of NTDs on the list is food-borne trematodes, comprises of Fasciola, Paragonimus, Clonorchis, and Opisthorchis. Currently, it is estimated that food-borne trematodes can cause a devastating effect on mortality and morbidity. All of them are zoonotic, as humans become infected by ingestion of a second intermediate host, such as freshwater snails, fish, or water vegetables. Opisthorchis viverrini, one of the food-borne trematodes that can be found mostly in South East Asia regions, especially in the Mekong basin, is regarded as a group 1 carcinogen leading to cholangiocarcinoma (CCA). This study aims to present the updated review of Opisthorchis viverrini and CCA.
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Affiliation(s)
- S. Tan
- Department of Parasitology, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
- Tropical Diseases and Public Health Research Centre, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
| | - M. Machrumnizar
- Department of Parasitology, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
- Tropical Diseases and Public Health Research Centre, Faculty of Medicine, Universitas Trisakti, Jakarta11440, Indonesia
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Risk of Anorectal Cancer Associated with Benign Anal Inflammatory Diseases: A Retrospective Matched Cohort Study. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19127467. [PMID: 35742716 PMCID: PMC9223752 DOI: 10.3390/ijerph19127467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 06/16/2022] [Accepted: 06/16/2022] [Indexed: 02/04/2023]
Abstract
Purpose: The purpose of our study was to evaluate the relationship between benign anal inflammatory diseases and anorectal cancer and assess its risk factors. Methods: A retrospective matched cohort study was conducted that included data from 2002 to 2013. The National Health Insurance Service National Sample Cohort data from 2002 to 2013 was used for the study. Of a total study population of 143,884 individuals, 28,110 individuals with anal fissures were assigned to the case group, while 115,774 individuals without anal fissures were assigned to the control group based on the 1:4 propensity score matching age, sex, and year (case: diagnosed year, control: health service received year). Results: The risk of anorectal cancer was higher in the case group (hazard ratio [HR]: 1.95, 95% confidence interval [CI]: 1.51–2.53) compared to the control group. After grouping anorectal cancers into anal cancer and rectal cancer, the risk remained higher in the case group (anal cancer HR: 2.79, 95% CI: 1.48–5.27; rectal cancer HR: 1.82, 95% CI; 1.37–2.42). The case group was further categorized into patients with fissures and patients with fistulas; patients with fissures showed a higher risk of developing anorectal cancer than patients with fistulas (HR: 2.05, 95% CI: 1.53–2.73 vs. HR: 1.73, 95% CI: 1.13–2.66). Study participants in their 30s and 40s had a 4.19- and 7.39-times higher risk of anorectal cancer compared to those in the higher age groups (0.64–1.84), while patients who did not have inflammatory bowel disease (IBD) had a higher risk of developing anorectal cancer (HR: 2.09, 95% CI: 1.56–2.80). Conclusions and Relevance: Patients with anal fistulas or fissures have an increased risk of being diagnosed with anorectal cancer, especially at a young age and even without IBD.
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Xing L, Fu L, Toldrá F, Teng S, Yin Y, Zhang W. The stability of dry‐cured ham‐derived peptides and its anti‐inflammatory effect in RAW264.7 macrophage cells. Int J Food Sci Technol 2022. [DOI: 10.1111/ijfs.15800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- Lujuan Xing
- Key Lab of Meat Processing and Quality Control College of Food Science and Technology Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control College of Food Science and Technology Nanjing Agricultural University Nanjing Jiangsu 210095 China
| | - Lijuan Fu
- Key Lab of Meat Processing and Quality Control College of Food Science and Technology Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control College of Food Science and Technology Nanjing Agricultural University Nanjing Jiangsu 210095 China
| | - Fidel Toldrá
- Instituto de Agroquímicay Tecnología de Alimentos (CSIC) Avenue Agustín Escardino 7 46980 Paterna Valencia Spain
| | - Shuang Teng
- Key Lab of Meat Processing and Quality Control College of Food Science and Technology Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control College of Food Science and Technology Nanjing Agricultural University Nanjing Jiangsu 210095 China
| | - Yantao Yin
- Key Lab of Meat Processing and Quality Control College of Food Science and Technology Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control College of Food Science and Technology Nanjing Agricultural University Nanjing Jiangsu 210095 China
| | - Wangang Zhang
- Key Lab of Meat Processing and Quality Control College of Food Science and Technology Jiangsu Collaborative Innovation Center of Meat Production and Processing, Quality and Safety Control College of Food Science and Technology Nanjing Agricultural University Nanjing Jiangsu 210095 China
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7
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Vega EA, Mellado S, Salehi O, Freeman R, Conrad C. Treatment of Resectable Gallbladder Cancer. Cancers (Basel) 2022; 14:1413. [PMID: 35326566 PMCID: PMC8945892 DOI: 10.3390/cancers14061413] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Revised: 02/18/2022] [Accepted: 03/06/2022] [Indexed: 02/04/2023] Open
Abstract
Gallbladder cancer (GBC) is the most common biliary tract cancer worldwide and its incidence has significant geographic variation. A unique combination of predisposing factors includes genetic predisposition, geographic distribution, female gender, chronic inflammation, and congenital developmental abnormalities. Today, incidental GBC is the most common presentation of resectable gallbladder cancer, and surgery (minimally invasive or open) remains the only curative treatment available. Encouragingly, there is an important emerging role for systemic treatment for patients who have R1 resection or present with stage III-IV. In this article, we describe the pathogenesis, surgical and systemic treatment, and prognosis.
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Affiliation(s)
- Eduardo A. Vega
- Department of Surgery, St. Elizabeth’s Medical Center, Boston University School of Medicine, Boston, MA 02135, USA; (E.A.V.); (O.S.); (R.F.)
| | | | - Omid Salehi
- Department of Surgery, St. Elizabeth’s Medical Center, Boston University School of Medicine, Boston, MA 02135, USA; (E.A.V.); (O.S.); (R.F.)
| | - Richard Freeman
- Department of Surgery, St. Elizabeth’s Medical Center, Boston University School of Medicine, Boston, MA 02135, USA; (E.A.V.); (O.S.); (R.F.)
| | - Claudius Conrad
- Department of Surgery, St. Elizabeth’s Medical Center, Boston University School of Medicine, Boston, MA 02135, USA; (E.A.V.); (O.S.); (R.F.)
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Yun TH, Jeong YY, Lee SJ, Choi YS, Ryu JM. Neutrophil-Lymphocyte and Platelet-Lymphocyte Ratios in Preoperative Differential Diagnosis of Benign, Borderline, and Malignant Ovarian Tumors. J Clin Med 2022; 11:jcm11051355. [PMID: 35268446 PMCID: PMC8911107 DOI: 10.3390/jcm11051355] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Revised: 01/22/2022] [Accepted: 01/25/2022] [Indexed: 12/14/2022] Open
Abstract
The purpose of this study was to investigate whether the neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR) can be used as supplementary tools to differentiate between benign, borderline, and malignant ovarian tumors. The ratio of patients with benign to borderline to malignant tumors was planned as 3:1:2 considering the incidence of each disease. Consecutive patients were enrolled retrospectively. Preoperative complete blood counts with differentials were investigated, and calculated NLRs and PLRs were analyzed. A total of 630 patients with ovarian tumors were enrolled in this study. The final histopathological results revealed that 318 patients had benign, 108 patients had epithelial borderline, and 204 patients had epithelial malignant ovarian tumors. The NLR and PLR were significantly higher in malignant than in benign or borderline ovarian tumors, and they did not differ significantly between benign and borderline ovarian tumors. The diagnostic cut-off value of NLR for differentiating between benign or borderline and malignant tumors was 2.36, whereas that of PLR for differentiating between benign/borderline and malignancy was 150.02. High preoperative NLR and PLR indicate that the likelihood of epithelial ovarian cancer is higher than that of benign or borderline tumors.
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Affiliation(s)
- Tae Hui Yun
- Department of Obstetrics and Gynecology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea; (T.H.Y.); (Y.Y.J.)
| | - Yoon Young Jeong
- Department of Obstetrics and Gynecology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea; (T.H.Y.); (Y.Y.J.)
| | - Sun Jae Lee
- Department of Pathology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea;
| | - Youn Seok Choi
- Department of Obstetrics and Gynecology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea; (T.H.Y.); (Y.Y.J.)
- Correspondence: (Y.S.C.); (J.M.R.); Tel.: +82-53-650-4078 (Y.S.C. & J.M.R.); Fax: +82-53-650-4078 (Y.S.C. & J.M.R.)
| | - Jung Min Ryu
- Department of Obstetrics and Gynecology, School of Medicine, Daegu Catholic University, Daegu 42472, Korea; (T.H.Y.); (Y.Y.J.)
- Correspondence: (Y.S.C.); (J.M.R.); Tel.: +82-53-650-4078 (Y.S.C. & J.M.R.); Fax: +82-53-650-4078 (Y.S.C. & J.M.R.)
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Fujiya T, Asanuma K, Koike T, Okata T, Saito M, Asano N, Imatani A, Masamune A. Nitric oxide could promote development of Barrett's esophagus by S-nitrosylation-induced inhibition of Rho-ROCK signaling in esophageal fibroblasts. Am J Physiol Gastrointest Liver Physiol 2022; 322:G107-G116. [PMID: 34786954 DOI: 10.1152/ajpgi.00124.2021] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 09/21/2021] [Indexed: 01/31/2023]
Abstract
Barrett's esophagus arises in the process of wound healing in distal esophageal epithelium damaged by gastroesophageal reflux disease. Differentiation of fibroblast into myofibroblasts, a smooth muscle cell-like phenotype and tissue contraction are crucial processes in wound healing. No study has evaluated mechanism by which luminal esophageal nitric oxide (NO) affect Rho-associated coiled coil-forming protein kinase (Rho-ROCK) signaling pathway, a key factor of tissue contraction, in stromal fibroblasts to develop Barrett's esophagus. Using esophageal fibroblasts, we performed collagen-based cell contraction assays and evaluated influence of Rho-ROCK signaling in the exposure to acidic bile salts and NOC-9, which is an NO donor. We found that enhanced cell contraction induced by acidic bile salts was inhibited by NO, accompanied by decrease in phosphorylated myosin light chain expression and stress fiber formation. NO directly S-nitrosylated GTP-RhoA and consequently blocked Rho-ROCK signaling. Moreover, exposure to NO and Y27632, a Rho-ROCK signaling inhibitor, decreased α-SMA expression and increased bone morphogenetic protein-4 (BMP4) expression and secretion. These findings could account for the increased expression of BMP4 in the columnar epithelial cells and stromal fibroblasts in human Barrett's esophagus. NO could impair wound contraction by blocking the Rho-ROCK signaling pathway and promote the development of Barrett's esophagus.NEW & NOTEWORTHY Barrett's esophagus is the condition where esophageal epithelium damaged by gastroesophageal reflux disease (GERD) is abnormally healed via replacing of metaplastic columnar epithelium, but very few studies have conducted focusing wound healing in the development of Barrett's esophagus. Esophageal luminal nitric oxide inhibits Rho-ROCK signaling pathway in esophageal fibroblasts, which leads to delay tissue contraction, a pivotal step in proper wound healing. Moreover, this inhibition increases tissue BMP4 expression. Impaired wound healing could be related to Barrett's esophagus.
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Affiliation(s)
- Taku Fujiya
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kiyotaka Asanuma
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoyuki Koike
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomoki Okata
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masahiro Saito
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoki Asano
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Akira Imatani
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Atsushi Masamune
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Kim K, Gaddam S, Liu Q. Pathogenesis, Epidemiology, and Prognosis of Pancreatic Adenocarcinomas. HEPATO-PANCREATO-BILIARY MALIGNANCIES 2022:461-481. [DOI: 10.1007/978-3-030-41683-6_28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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11
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Sarkar A, Harty S, Moeller AH, Klein SL, Erdman SE, Friston KJ, Carmody RN. The gut microbiome as a biomarker of differential susceptibility to SARS-CoV-2. Trends Mol Med 2021; 27:1115-1134. [PMID: 34756546 PMCID: PMC8492747 DOI: 10.1016/j.molmed.2021.09.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 09/28/2021] [Accepted: 09/29/2021] [Indexed: 02/07/2023]
Abstract
Coronavirus disease 2019 (COVID-19) continues to exact a devastating global toll. Ascertaining the factors underlying differential susceptibility and prognosis following viral exposure is critical to improving public health responses. We propose that gut microbes may contribute to variation in COVID-19 outcomes. We synthesise evidence for gut microbial contributions to immunity and inflammation, and associations with demographic factors affecting disease severity. We suggest mechanisms potentially underlying microbially mediated differential susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These include gut microbiome-mediated priming of host inflammatory responses and regulation of endocrine signalling, with consequences for the cellular features exploited by SARS-CoV-2 virions. We argue that considering gut microbiome-mediated mechanisms may offer a lens for appreciating differential susceptibility to SARS-CoV-2, potentially contributing to clinical and epidemiological approaches to understanding and managing COVID-19.
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Affiliation(s)
- Amar Sarkar
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
| | - Siobhán Harty
- Tandy Court, Spitalfields, Dublin 8, D08 RP20, Ireland
| | - Andrew H Moeller
- Department of Ecology and Evolutionary Biology, Cornell University, Ithaca, NY, USA
| | - Sabra L Klein
- W. Harry Feinstone Department of Molecular Microbiology and Immunology, The Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Susan E Erdman
- Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Karl J Friston
- Wellcome Centre for Human Neuroimaging, University College London, London, UK
| | - Rachel N Carmody
- Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA.
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12
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Holmes HM, Jove AG, Tan MC, El-Serag HB, Thrift AP. Alcohol consumption and the risk of gastric intestinal metaplasia in a U.S. Veterans population. PLoS One 2021; 16:e0260019. [PMID: 34780551 PMCID: PMC8592489 DOI: 10.1371/journal.pone.0260019] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Accepted: 11/01/2021] [Indexed: 12/31/2022] Open
Abstract
Background Chronic alcohol use is a risk factor for non-cardia gastric adenocarcinoma. However, it is less well understood whether alcohol use is a risk factor for premalignant mucosal changes, namely gastric intestinal metaplasia. We examined the association between various parameters of alcohol use and risk of gastric intestinal metaplasia. Methods We used data from 2084 participants (including 403 with gastric intestinal metaplasia) recruited between February 2008-August 2013 into a cross-sectional study at the Michael E. DeBakey Veterans Affairs Medical Center in Houston, Texas. All participants underwent a study upper endoscopy with systematic gastric mapping biopsies. Cases had intestinal metaplasia on any non-cardia gastric biopsy. Participants self-reported lifetime history of alcohol consumption, along with other lifestyle risk factors, through a study survey. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for categories of average alcohol consumption using multivariable logistic regression, and restricted cubic spline regression to explore the potential shape of a dose-response relationship. Results Compared to lifelong non-drinkers, individuals who consumed on average ≥28 drinks per week had no elevated risk for gastric intestinal metaplasia (adjusted OR, 1.27; 95% CI, 0.74–2.19). Based on a spline regression curve and its 95% CI, there was also no demonstrable association between cumulative lifetime alcohol consumption and risk of gastric intestinal metaplasia. Similarly, we found no association between beverage type (beer, wine, liquor/spirits) and risk for gastric intestinal metaplasia. Conclusions Neither amount of alcohol consumed nor specific beverage type was associated with risk of gastric intestinal metaplasia.
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Affiliation(s)
- Hudson M Holmes
- Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Andre G Jove
- Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Mimi C Tan
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America
| | - Hashem B El-Serag
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.,Houston VA HSR&D Center for Innovations in Quality, Effectiveness and Safety, Michael E. DeBakey Veterans Affairs Medical Center, Houston, Texas, United States of America
| | - Aaron P Thrift
- Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States of America.,Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, United States of America
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13
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Jones JO, Moody WM, Shields JD. Microenvironmental modulation of the developing tumour: an immune-stromal dialogue. Mol Oncol 2021; 15:2600-2633. [PMID: 32741067 PMCID: PMC8486574 DOI: 10.1002/1878-0261.12773] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/03/2020] [Accepted: 07/27/2020] [Indexed: 12/17/2022] Open
Abstract
Successful establishment of a tumour relies on a cascade of interactions between cancer cells and stromal cells within an evolving microenvironment. Both immune and nonimmune cellular components are key factors in this process, and the individual players may change their role from tumour elimination to tumour promotion as the microenvironment develops. While the tumour-stroma crosstalk present in an established tumour is well-studied, aspects in the early tumour or premalignant microenvironment have received less attention. This is in part due to the challenges in studying this process in the clinic or in mouse models. Here, we review the key anti- and pro-tumour factors in the early microenvironment and discuss how understanding this process may be exploited in the clinic.
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Affiliation(s)
- James O. Jones
- MRC Cancer UnitHutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
- Department of OncologyCambridge University Hospitals NHS Foundation TrustCambridgeUK
| | - William M. Moody
- MRC Cancer UnitHutchison/MRC Research CentreUniversity of CambridgeCambridgeUK
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14
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Modern possibilities and prospects of early diagnosis of stomach cancer. ACTA BIOMEDICA SCIENTIFICA 2021. [DOI: 10.29413/abs.2021-6.3.12] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
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15
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Cizkova D, Cizek M, Maloveska M, Kmetova M, Kmet V, Bujnakova D. Cell-Free Lactobacillus casei 21L10 Modulates Nitric Oxide Release and Cell Proliferation/Cell Death in Lipopolysaccharide-Challenged HT-29 Cells. Inflammation 2021; 44:2419-2428. [PMID: 34327573 DOI: 10.1007/s10753-021-01512-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Revised: 04/08/2021] [Accepted: 07/05/2021] [Indexed: 12/01/2022]
Abstract
Lactobacillus casei (L. casei) is one of the probiotic strains that may influence intestinal injury and inflammation in nonspecific intestinal diseases. We aimed to evaluate the effect of cell-free Lactobacillus casei 21L10 supernatant (LC) on the cell line HT-29 challenged with lipopolysaccharide (LPS) in order to modulate production of NO, cell proliferation, and apoptosis. Cell line HT-29 was stimulated with LPS in the presence or absence of LC. Our results showed that LC from L. casei 21L10 did not affect the viability of unstimulated HT-29 cells line. HT-29 cell line treatment with LC caused significant decrease of LPS induced NO production after 3 h, and 24 h, but not after 48 h. Proliferation activity of LPS stimulated HT-29 cell line analysed with MTT assay significantly decreased after 24 h and 48 h, but not after 3 h. The majority of LPS stimulated HT-29 cell line treated with LC showed annexin V/PI positivity at 48 h survival, which corresponded to late apoptotic/necrotic cell features. The observed differences suggest that cell-free L. casei 21L10 supernatant could participate in attenuation of LPS-induced inflammation, and may exhibit anti-proliferative and pro-apoptotic/necrotic effects. This study provides pilot data for the further development of L. casei exoproducts as an anti-inflammatory or anti-proliferative agent for the treatment of inflammatory and cancer diseases in gut. However, more data is needed before final conclusions of L. casei cell-free supernatant's efficacy can be drawn.
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Affiliation(s)
- Dasa Cizkova
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Kosice, Slovakia.,Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Milan Cizek
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Kosice, Slovakia
| | - Marcela Maloveska
- Centre of Experimental and Clinical Regenerative Medicine, University of Veterinary Medicine and Pharmacy in Kosice, Kosice, Slovakia
| | - Marta Kmetova
- University of Pavol Jozef Safarik, Faculty of Medicine, Kosice, Slovakia
| | - Vladimir Kmet
- Institute of Animal Physiology, Centre of Biosciences of the Slovak Academy of Sciences, Kosice, Slovakia
| | - Dobroslava Bujnakova
- Institute of Animal Physiology, Centre of Biosciences of the Slovak Academy of Sciences, Kosice, Slovakia.
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16
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Feng S, Shao Z, Ju L, Zhang Y. Atopy, asthma, and risk of bladder cancer: Systematic review and meta-analysis of cohort studies. EUR J INFLAMM 2021. [DOI: 10.1177/20587392211016117] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The relationship between atopic diseases and cancer at various sites has been extensively studied. Previous epidemiological studies have investigated the association between atopic diseases and bladder cancer; however, the results remain inconclusive. In this study, we performed a systematic review and meta-analysis of cohort studies published thus far to evaluate the association between atopy and the risk of bladder cancer. We conducted a systematic search in PubMed, Embase, ISI Web of Science, and Scopus to identify potentially relevant studies. The pooled risk ratio (RRs) and 95% confidence intervals (95% CIs) were calculated using a random-effect model considering the heterogeneity among studies. On the basis of our selection criteria, a total of 10 cohort studies were included in our meta-analysis involving 2,341,005 participants, of whom 1720 were patients with bladder cancer. The pooled RR of bladder cancer in the group with atopic disease versus the group without atopic disease was 1.31 (95% CI: 1.10–1.56, p < 0.01), indicating a positive association between overall atopy and bladder cancer risk. In subgroup analysis, the pooled RR of bladder cancer was 1.46 (95% CI: 1.18–1.80, p < 0.001) for asthma and 1.03 (95% CI: 0.74–1.44, p = 0.86) for allergic rhinitis. The risk of bladder cancer is positively associated with overall atopy and asthma, but is not associated with allergic rhinitis.
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Affiliation(s)
- Suoyi Feng
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
- Science Department, The John Carroll School, Bel Air, MD, USA
| | - Ziqi Shao
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei, China
| | - Longzhu Ju
- College of Veterinary Medicine, Northeast Agricultural University, Harbin, Heilongjiang, China
| | - Yiting Zhang
- Department of Economics, University of California Los Angeles, Los Angeles, CA, USA
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17
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Rimini M, Casadei-Gardini A. Angiogenesis in biliary tract cancer: targeting and therapeutic potential. Expert Opin Investig Drugs 2021; 30:411-418. [PMID: 33491502 DOI: 10.1080/13543784.2021.1881479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Introduction: Biliary Tract Cancer (BTC) is a heterogeneous group of malignant neoplasms with a complex molecular pathogenesis. The prognosis of metastatic disease is dramatically dismal and therapeutic options are scarce. Systemic chemotherapy is the gold standard for the metastatic disease. However, because of the disappointing results with conventional chemotherapy, investigators have turned to new biological therapeutic options targeting the main molecular pathways, neo-angiogenesis, involved in the disease pathogenesis.Areas covered: This paper examines the rationale of using antiangiogenic therapies in this setting, evaluates the therapeutic implications, and highlights ongoing studies and future perspectives. A Pubmed systematic review of preclinical and clinical data was performed which enabled the composition of this paper.Expert opinion: Amore in-depth understanding of the interplay between the neo-angiogenesis pathways, and the microenvironment will could propel the design new therapeutic strategies. Nowadays, the combination of antiangiogenic drugs and immune check-point inhibitors looks promising, but further, more comprehensive data are necessary to gain afuller picture. In an era of novel technologies and techniques, which includes radiomics, the challenge is to identify the biomarkers of response to antiangiogenic drugs which will permit the selection of patients that are more likely to respond to antiangiogenic therapies.
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Affiliation(s)
- Margherita Rimini
- Department of Oncology and Hematology, Division of Oncology, University Hospital Modena, Modena, Italy
| | - Andrea Casadei-Gardini
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy.,Unit of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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18
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Amin MN, Siddiqui SA, Ibrahim M, Hakim ML, Ahammed MS, Kabir A, Sultana F. Inflammatory cytokines in the pathogenesis of cardiovascular disease and cancer. SAGE Open Med 2020; 8:2050312120965752. [PMID: 33194199 PMCID: PMC7594225 DOI: 10.1177/2050312120965752] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2020] [Accepted: 09/18/2020] [Indexed: 12/14/2022] Open
Abstract
Inflammatory cytokines are highly inducible small glycoproteins or regulatory proteins of low molecular weight secreted by different cell types. They regulate intercellular communication and mediate a number of physiological functions in the human immune system. Numerous prospective studies report that inflammatory cytokines strongly predict coronary artery disease, myocardial infarction, heart failure and other adverse cardiac events. Inflammatory cascade is believed to be a causative factor in the development of atherosclerotic process. Several aspects of atherogenesis are accelerated by cytokines. This article provides an overall overview of current understanding of cytokines in various cardiovascular events. Besides, inflammatory cytokines trigger cellular events that can induce malignancy and carcinogenesis. Elevated expression of several cytokines such as interleukin-1, interleukin-6, interleukin-10, tumor necrosis factor-α, macrophage migration inhibitory factor and transforming growth factor-β are involved in tumor initiation and progression. Thus, they exert a pivotal role in cancer pathogenesis. This review highlights the role of several cytokines in various events of tumorigenesis. Actually, this article summarizes the contributions of cytokines in the pathogenesis of cardiovascular disease and cancer.
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Affiliation(s)
- Mohammad Nurul Amin
- Department of Pharmacy, Atish Dipankar
University of Science and Technology, Dhaka, Bangladesh
- Pratyasha Health Biomedical Research
Center, Dhaka, Bangladesh
| | - Shafayet Ahmed Siddiqui
- Department of Pharmacy, Atish Dipankar
University of Science and Technology, Dhaka, Bangladesh
- Pratyasha Health Biomedical Research
Center, Dhaka, Bangladesh
| | - Md Ibrahim
- College of Medicine, University of South
Alabama, Mobile, AL, USA
| | - Md Lukman Hakim
- Department of Pharmaceutical Sciences,
North South University, Dhaka, Bangladesh
| | - Md. Salim Ahammed
- Department of Pharmacy, University of
Information Technology and Sciences, Dhaka, Bangladesh
| | - Asma Kabir
- Department of Pharmacy, Atish Dipankar
University of Science and Technology, Dhaka, Bangladesh
- Pratyasha Health Biomedical Research
Center, Dhaka, Bangladesh
| | - Farhana Sultana
- Department of Pharmacy, Atish Dipankar
University of Science and Technology, Dhaka, Bangladesh
- Pratyasha Health Biomedical Research
Center, Dhaka, Bangladesh
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19
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Sierra JC, Piazuelo MB, Luis PB, Barry DP, Allaman MM, Asim M, Sebrell TA, Finley JL, Rose KL, Hill S, Holshouser SL, Casero RA, Cleveland JL, Woster PM, Schey KL, Bimczok D, Schneider C, Gobert AP, Wilson KT. Spermine oxidase mediates Helicobacter pylori-induced gastric inflammation, DNA damage, and carcinogenic signaling. Oncogene 2020; 39:4465-4474. [PMID: 32350444 PMCID: PMC7260102 DOI: 10.1038/s41388-020-1304-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/14/2020] [Accepted: 04/16/2020] [Indexed: 01/05/2023]
Abstract
Helicobacter pylori infection is the main risk factor for the development of gastric cancer, the third leading cause of cancer death worldwide. H. pylori colonizes the human gastric mucosa and persists for decades. The inflammatory response is ineffective in clearing the infection, leading to disease progression that may result in gastric adenocarcinoma. We have shown that polyamines are regulators of the host response to H. pylori, and that spermine oxidase (SMOX), which metabolizes the polyamine spermine into spermidine plus H2O2, is associated with increased human gastric cancer risk. We now used a molecular approach to directly address the role of SMOX, and demonstrate that Smox-deficient mice exhibit significant reductions of gastric spermidine levels and H. pylori-induced inflammation. Proteomic analysis revealed that cancer was the most significantly altered functional pathway in Smox-/- gastric organoids. Moreover, there was also less DNA damage and β-catenin activation in H. pylori-infected Smox-/- mice or gastric organoids, compared to infected wild-type animals or gastroids. The link between SMOX and β-catenin activation was confirmed in human gastric organoids that were treated with a novel SMOX inhibitor. These findings indicate that SMOX promotes H. pylori-induced carcinogenesis by causing inflammation, DNA damage, and activation of β-catenin signaling.
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Affiliation(s)
- Johanna C Sierra
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - M Blanca Piazuelo
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Paula B Luis
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Daniel P Barry
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Margaret M Allaman
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Mohammad Asim
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Thomas A Sebrell
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA
| | - Jordan L Finley
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Kristie L Rose
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Salisha Hill
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Steven L Holshouser
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Robert A Casero
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - John L Cleveland
- Department of Tumor Biology, Moffitt Cancer Center and Research Institute, Tampa, FL, 33612, USA
| | - Patrick M Woster
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC, 29425, USA
| | - Kevin L Schey
- Department of Biochemistry, Mass Spectrometry Research Center, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Diane Bimczok
- Department of Microbiology and Immunology, Montana State University, Bozeman, MT, 59717, USA
| | - Claus Schneider
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
| | - Alain P Gobert
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
| | - Keith T Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center, Nashville, TN, 37232, USA.
- Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA.
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, 37232, USA.
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20
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Li D, Deconda D, Li A, Habr F, Cao W. Effect of Proton Pump Inhibitor Therapy on NOX5, mPGES1 and iNOS expression in Barrett's Esophagus. Sci Rep 2019; 9:16242. [PMID: 31700071 PMCID: PMC6838155 DOI: 10.1038/s41598-019-52800-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Accepted: 10/10/2019] [Indexed: 01/08/2023] Open
Abstract
Acid reflux may contribute to the progression from Barrett’s esophagus (BE) to esophageal adenocarcinoma (EA). However, it is not clear whether the molecular changes present in BE patients are reversible after proton pump inhibitor (PPI) treatment. In this study we examined whether PPI treatment affects NOX5, microsomal prostaglandin E synthase (mPGES)-1 and inducible nitric oxide synthase (iNOS) expression. We found that NADPH oxidase 5 (NOX5), mPGES-1 and iNOS were significantly increased in BE mucosa. One-month PPI treatment significantly decreased NOX5, mPGES1 and iNOS. In BAR-T cells, NOX5 mRNA and p16 promoter methylation increased after pulsed acid treatment in a time-dependent manner. Four or eight-week-acid induced increase in NOX5 mRNA, NOX5 protein and p16 methylation may be reversible. Twelve-week acid treatment also significantly increased NOX5, mPGES1 and iNOS mRNA expression. However, twelve-week-acid-induced changes only partially restored or did not recover at all after the cells were cultured at pH 7.2 for 8 weeks. We conclude that NOX5, mPGES1 and iNOS may be reversible after PPI treatment. Short-term acid-induced increase in NOX5 expression and p16 methylation might be reversible, whereas long-term acid-induced changes only partially recovered 8 weeks after removal of acid treatment.
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Affiliation(s)
- Dan Li
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | | | - Aihua Li
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA
| | - Fadlallah Habr
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA.
| | - Weibiao Cao
- Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA. .,Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, 02903, USA.
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21
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Silva Servato JP, Ueira Vieira C, de Faria PR, Cardoso SV, Loyola AM. The importance of inducible nitric oxide synthase and nitrotyrosine as prognostic markers for oral squamous cell carcinoma. J Oral Pathol Med 2019; 48:967-975. [PMID: 31379002 DOI: 10.1111/jop.12942] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 06/30/2019] [Accepted: 07/30/2019] [Indexed: 01/07/2023]
Abstract
BACKGROUND The prognosis of human cancer depends on the deregulations of many molecular patterns. In recent years, a great interest in the intracellular signaling mechanisms related to nitric oxide (NO)-induced carcinogenesis has appeared, as one of the most preeminent prognostic markers for many types of neoplasms. In this study, we identify the levels of iNOS and nitrotyrosine in the sample of normal oral mucosa (NOM), oral leukoplakia (OL), and oral squamous cell carcinoma (OSCC). METHODS Quantitative polymerase chain reactions (qPCRs) were utilized to detect the NOS2 levels in fresh-frozen tissue samples of NOM (n = 6), OL (n = 20), and OSCC (n = 15). Moreover, the immunohistochemical method was used to examine the levels of iNOS and nitrotyrosine in 85 cases of OSCC (39 cases without metastases and 46 with metastases), 42 cases of OL, and 16 cases of NOM. RESULTS There are rising tendencies in the iNOS mRNA and protein levels during human oral carcinogenesis. Similar findings were obtained in the nitrotyrosine staining. Furthermore, iNOS and nitrotyrosine immunostaining are associated with several clinical-pathological features of OSCC (site, presence of metastasis, staging, recidivism, and survival). CONCLUSIONS The NO-signaling pathway plays a vital role in the development and progression of human oral dysplastic and neoplastic diseases. Nitrotyrosine was a significant marker for the discrimination of OSCC prognosis and survival.
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Affiliation(s)
| | - Carlos Ueira Vieira
- Department of Genetics, Institute of Biotechnology, Federal University of Uberlandia, Uberlandia, Brazil
| | - Paulo Rogério de Faria
- Department of Morphology, Biomedical Science Institute, Federal University of Uberlândia, Uberlândia, Brazil
| | - Sérgio Vitorino Cardoso
- Laboratory of Oral and Maxillofacial Pathology, Federal University of Uberlândia, Uberlândia, Brazil
| | - Adriano Mota Loyola
- Laboratory of Oral and Maxillofacial Pathology, Federal University of Uberlândia, Uberlândia, Brazil
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22
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Hays E, Bonavida B. Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies. Antioxidants (Basel) 2019; 8:E407. [PMID: 31533363 PMCID: PMC6769868 DOI: 10.3390/antiox8090407] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 09/11/2019] [Accepted: 09/13/2019] [Indexed: 12/13/2022] Open
Abstract
In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.
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Affiliation(s)
- Emily Hays
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA.
| | - Benjamin Bonavida
- Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, CA 90095, USA.
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23
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Koulis A, Buckle A, Boussioutas A. Premalignant lesions and gastric cancer: Current understanding. World J Gastrointest Oncol 2019; 11:665-678. [PMID: 31558972 PMCID: PMC6755108 DOI: 10.4251/wjgo.v11.i9.665] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 05/29/2019] [Accepted: 08/21/2019] [Indexed: 02/05/2023] Open
Abstract
Over the last two decades there has been a broad paradigm shift in our understanding of gastric cancer (GC) and its premalignant states from gross histological models to increasingly precise molecular descriptions. In this review we reflect upon the historic approaches to describing premalignant lesions and GC, highlight the current molecular landscape and how this could inform future risk assessment prevention strategies.
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Affiliation(s)
- Athanasios Koulis
- Upper Gastrointestinal Translational Laboratory, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- the Sir Peter MacCallum Department of Surgical Oncology, the University of Melbourne, Melbourne 3010, Australia
| | - Andrew Buckle
- Upper Gastrointestinal Translational Laboratory, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- the Sir Peter MacCallum Department of Surgical Oncology, the University of Melbourne, Melbourne 3010, Australia
| | - Alex Boussioutas
- Upper Gastrointestinal Translational Laboratory, Peter MacCallum Cancer Centre, Melbourne 3000, Australia
- the Sir Peter MacCallum Department of Surgical Oncology, the University of Melbourne, Melbourne 3010, Australia
- Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Parkville, 3050, Australia
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Hatamipour M, Ramezani M, Tabassi SAS, Johnston TP, Sahebkar A. Demethoxycurcumin: A naturally occurring curcumin analogue for treating non-cancerous diseases. J Cell Physiol 2019; 234:19320-19330. [PMID: 31344992 DOI: 10.1002/jcp.28626] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2018] [Revised: 03/17/2019] [Accepted: 03/19/2019] [Indexed: 02/06/2023]
Abstract
Turmeric extracts contain three primary compounds, which are commonly referred to as curcuminoids. They are curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin. While curcumin has been the most extensively studied of the curcuminoids, it suffers from low overall oral bioavailability due to extremely low absorption as a result of low water solubility and instability at acidic pH, as well as rapid metabolism and clearance from the body. However, DMC, which lacks the methoxy group on the benzene ring of the parent structure, has much greater chemical stability at physiological pH and has been recently reported to exhibit antitumor properties. However, the treatment of noncancerous diseases with DMC has not been comprehensively reviewed. Therefore, here we evaluate published scientific literature on the therapeutic properties of DMC. The beneficial pharmacological actions of DMC include anti-inflammatory, neuroprotective, antihypertensive, antimalarial, antimicrobial, antifungal, and vasodilatory properties. In addition, DMC's ability to ameliorate the effects of free radicals and an environment characterized by oxidative stress caused by the accumulation of advanced glycation end-products associated with diabetic nephropathy, as well as DMC's capacity to inhibit the migration and proliferation of vascular smooth muscle cells following balloon angioplasty are also addressed. This review collates the available literature regarding the therapeutic possibilities of DMC in noncancerous conditions.
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Affiliation(s)
- Mahdi Hatamipour
- Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mahin Ramezani
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, University of Missouri-Kansas City, Kansas City, Missouri
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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25
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Ceran MU, Tasdemir U, Colak E, Güngör T. Can complete blood count inflammatory parameters in epithelial ovarian cancer contribute to prognosis? - a survival analysis. J Ovarian Res 2019; 12:16. [PMID: 30744662 PMCID: PMC6371536 DOI: 10.1186/s13048-019-0491-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Accepted: 01/30/2019] [Indexed: 12/25/2022] Open
Abstract
Subjective The aim of the present study was to investigate the prognostic significance of preoperative complete blood count inflammatory markers in women operated for invasive Epithelial Ovarian Cancer (EOC). Method Two hundred forty four patients that underwent operation with the diagnosis of invasive EOC between 2006 and 2014 were included in the study. The date of operation, date of recurrence and final mortality evaluations were performed for survival analysis. The sensitivity, specificity, PPV and NPV were separately calculated with ROC analysis. Survival analysis was carried out with Kaplan Meier-Log Rank Method. Results Five-years overall survival rate was 56, 9% and 5-year disease-free survival (DFS) rate was 45,5%. Advanced disease stage, moderate-poor tumor differentiation, and the presence of recurrence were determined to have significant inverse relation at mean survival and 5-year survival rates. Neutrophil/lymphocyte ratio (NLR) and Platelet lymphocyte ratio (PLR) had prognostic effect on both DFS and overall survival based upon the cut-off values determined in the study (PLR = 231, s36, NLR = 3,83). Histopathological subtypes were not found to have any prognostic value. In correlation analysis, PLR and NLR had positive correlation with each other and negative correlation with overall survival. Conclusions Inflammatory markers such as NLR and PLR have independent prognostic value for women who undergo surgery for invasive EOC.
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Affiliation(s)
- Mehmet Ufuk Ceran
- Department of Gynecology and Obstetrics, Baskent University School of Medicine, Konya Medical and Research Center, Selcuklu, Konya, Turkey.
| | - Umit Tasdemir
- Department of Gynecology and Obstetrics, Baskent University School of Medicine, Konya Medical and Research Center, Selcuklu, Konya, Turkey
| | - Eser Colak
- Department of Gynecology and Obstetrics, Baskent University School of Medicine, Konya Medical and Research Center, Selcuklu, Konya, Turkey
| | - Tayfun Güngör
- Department of Gynecologic Oncology, Zekai Tahir Burak Women's Health, Education and Research Hospital, Ankara, Turkey
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27
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Abbaszadegan MR, Moghbeli M. Genetic and molecular origins of colorectal Cancer among the Iranians: an update. Diagn Pathol 2018; 13:97. [PMID: 30579343 PMCID: PMC6303916 DOI: 10.1186/s13000-018-0774-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one the leading causes of cancer related deaths among Iranians. Despite the various progresses in new therapeutic methods, it has still a low rate of survival. This high ratio of mortality is mainly related to the late diagnosis, in which the patients refer for treatment in advanced stages of tumor. MAIN BODY: colorectal cancer progression is largely associated with molecular and genetic bases. Although Iran has a high ratio of CRC mortality, there is not an efficient genetic panel for detection and prognosis. Therefore, it is critical to introduce new diagnostic markers with ability to detect in early stages. CONCLUSION Present review summarizes all of the genetic and epigenetic factors which are reported in CRC until now among the Iranian patients to pave the way of incorporation of new ethnic specific markers into the clinical practice and development of new targeted therapeutic methods.
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Affiliation(s)
| | - Meysam Moghbeli
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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28
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Seimiya T, Otsuka M, Iwata T, Tanaka E, Suzuki T, Sekiba K, Yamagami M, Ishibashi R, Koike K. Inflammation and de-differentiation in pancreatic carcinogenesis. World J Clin Cases 2018; 6:882-891. [PMID: 30568942 PMCID: PMC6288496 DOI: 10.12998/wjcc.v6.i15.882] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/03/2018] [Revised: 10/26/2018] [Accepted: 11/14/2018] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is a malignancy with an extremely poor prognosis. Chronic pancreatitis is a well-known risk factor for pancreatic cancer. Inflammation is thought to influence carcinogenesis through DNA damage and activation of intracellular signaling pathways. Many transcription factors and signaling pathways co-operate to determine and maintain cell identity at each phase of pancreatic organogenesis and cell differentiation. Recent studies have shown that carcinogenesis is promoted through the suppression of transcription factors related to differentiation. Pancreatitis also demonstrates transcriptional changes, suggesting that multifactorial epigenetic changes lead to impaired differentiation. Taken together, these factors may constitute an important framework for pancreatic carcinogenesis. In this review, we discuss the role of inflammation and de-differentiation in the development of pancreatic cancer, as well as the future of novel therapeutic applications.
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Affiliation(s)
- Takahiro Seimiya
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Motoyuki Otsuka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Takuma Iwata
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Eri Tanaka
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Tatsunori Suzuki
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuma Sekiba
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Mari Yamagami
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Rei Ishibashi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan
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29
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Wei Q, Korejo NA, Jiang J, Xu M, Zheng K, Mao D, Shi F. Mitigation of stress from gastric mucosal injuries by mulberry extract may occur via nitric oxide synthase signaling in mice. Tissue Cell 2018; 54:59-64. [PMID: 30309511 DOI: 10.1016/j.tice.2018.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 08/14/2018] [Accepted: 08/19/2018] [Indexed: 12/13/2022]
Abstract
Acute gastric mucosal injuries are serious clinical problems worldwide and are principally found with different types of stresses in animals. A constant challenge is to find original plant products that can combat stress. In the present study, we examined the effects of big-leaf mulberry extracts on stomach injury, and the activity of nitric oxide synthases (NOS) and total antioxidant activity (TAO) in the gastric mucosae of mice during water immersion and restraint stress (WIRS). Our data showed that WIRS-exposed mice produced several injuries and showed an enhanced iNOS, reduced eNOS activity, and decreased TAO activity in the stomach, whereas pretreatment with big-leaf mulberry extracts increased TAO activitiy. The data from our immunohistochemical study indicated that both iNOS and eNOS were expressed in parietal cells and blood vessels, while nNOS was only weakly expressed in parietal cells. In conclusion, our findings suggested that big-leaf mulberry mitigated WIRS-induced stomach injuries, and NOS signaling may play important roles in the mouse stomach during the recovery process.
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Affiliation(s)
- Quanwei Wei
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Nazar Ali Korejo
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Jingle Jiang
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Mulin Xu
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Kaizhi Zheng
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Dagan Mao
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China
| | - Fangxiong Shi
- College of Animal Science and Technology, Nanjing Agricultural University, Nanjing 210095, China.
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30
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Ratajczak-Wrona W, Nowak K, Garley M, Tynecka M, Jablonska E. Sex-specific differences in the regulation of inducible nitric oxide synthase by bisphenol A in neutrophils. Hum Exp Toxicol 2018; 38:239-246. [DOI: 10.1177/0960327118793188] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
The aim of the study was to evaluate the effect of bisphenol A (BPA) on nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) expression by neutrophils with regard to sex and nuclear factor-κB (NF-κB) pathway participation in this process. This study demonstrated that BPA intensifies the production of NO and the expression of iNOS in the cytoplasmic fraction of neutrophils of women as well as men. In addition, an enhanced expression of NF-κB in the cytoplasmic and nuclear fraction of neutrophils exposed to BPA was observed in the cells of both sexes. The lipopolysaccharide (LPS) stimulation of neutrophils of both sexes led to an intensification of NO production and expression of all tested proteins. However, simultaneous stimulation of neutrophils of both men and women with LPS and BPA decreased the production of NO and expression of iNOS and NF-κB in both fractions compared to the cells exposed only to xenoestrogen. Moreover, expression of iNOS and NF-κB was higher in female neutrophils than in male cells. This study demonstrated that BPA affects the production of NO with the participation of iNOS by human polymorphonuclear neutrophils. This process is associated with the activation of the NF-κB pathway. In addition, different activity of NF-κB in neutrophils, observed with respect to sex, indicates a different role of this pathway in female and male cells.
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Affiliation(s)
- W Ratajczak-Wrona
- Department of Immunology, Medical University of Bialystok, Białystok, Poland
| | - K Nowak
- Department of Immunology, Medical University of Bialystok, Białystok, Poland
| | - M Garley
- Department of Immunology, Medical University of Bialystok, Białystok, Poland
| | - M Tynecka
- Department of Immunology, Medical University of Bialystok, Białystok, Poland
| | - E Jablonska
- Department of Immunology, Medical University of Bialystok, Białystok, Poland
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31
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Vukmirovic D, Seymour C, Rollo D, Mothersill C. Cytotoxic Profiling of Endogenous Metabolites Relevant to Chronic Fatigue Immune Dysfunction Syndrome (CFIDS) on p53 Variant Human Colon Carcinoma Cell Lines. Dose Response 2018; 16:1559325818790999. [PMID: 30116169 PMCID: PMC6088487 DOI: 10.1177/1559325818790999] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2018] [Revised: 06/17/2018] [Accepted: 06/19/2018] [Indexed: 11/28/2022] Open
Abstract
Chemoprophylatic strategies against development of multifactorial diseases utilize compounds to block the multistep events in chronic inflammation and carcinogenesis. The successful chemopreventative candidate must therefore selectively inhibit growth of transformed cells and be administered frequently to confer maximal protection with minimal side effects. In addition to synthetic and exogenous natural compounds, endogenous metabolites represent another class of compounds that exhibit anticarcinogenic and anti-inflammatory properties contributing to proper cell function. To assess the effectiveness of these compounds warrants an understanding of their cytotoxic mode of action. In this study, p53 variant human colon carcinoma cell lines were chronically exposed to varying concentrations of the endogenous metabolites—phenyl acetate, ursodeoxycholate, and tauroursodeoxycholate—to determine the role of p53-induced cytotoxicity, with p53 mutant and deficient cell lines representing precancerous lesions. Cytotoxicity was assessed using clonogenic assays, and macroscopic colony counts were used to quantify cell survival. The results demonstrate that the bile acids, ursodeoxycholate and tauroursodeoxycholate, exhibit selective cytotoxicity toward nonfunctional p53 cell lines suggesting a p53-mediated role in inhibition of cell clonogenicity and potential chemopreventative properties. Although each compound displays this described effect, the tauroursodeoxycholate demonstrates high significance suggesting it might have practical uses in vivo.
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Affiliation(s)
- Dusan Vukmirovic
- Radiation Sciences Graduate Program, McMaster University, Hamilton, Canada
| | - Colin Seymour
- Department of Biology, McMaster University, Hamilton, Canada
| | - Dave Rollo
- Department of Biology, McMaster University, Hamilton, Canada
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32
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García-Heredia JM, Carnero A. Dr. Jekyll and Mr. Hyde: MAP17's up-regulation, a crosspoint in cancer and inflammatory diseases. Mol Cancer 2018; 17:80. [PMID: 29650022 PMCID: PMC5896160 DOI: 10.1186/s12943-018-0828-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 03/28/2018] [Indexed: 12/14/2022] Open
Affiliation(s)
- José M García-Heredia
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013, Sevilla, Spain.,Department of Vegetal Biochemistry and Molecular Biology, University of Seville, Seville, Spain.,CIBER de Cáncer, Instituto de Salud Carlos III, Pabellón 11, Madrid, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla, IBIS/Hospital Universitario Virgen del Rocío/ Universidad de Sevilla/Consejo Superior de Investigaciones Científicas, Avda. Manuel Siurot s/n, 41013, Sevilla, Spain. .,CIBER de Cáncer, Instituto de Salud Carlos III, Pabellón 11, Madrid, Spain.
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33
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Najafi M, Motevaseli E, Shirazi A, Geraily G, Rezaeyan A, Norouzi F, Rezapoor S, Abdollahi H. Mechanisms of inflammatory responses to radiation and normal tissues toxicity: clinical implications. Int J Radiat Biol 2018; 94:335-356. [PMID: 29504497 DOI: 10.1080/09553002.2018.1440092] [Citation(s) in RCA: 123] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2017] [Revised: 01/23/2018] [Accepted: 01/31/2018] [Indexed: 02/06/2023]
Abstract
PURPOSE Cancer treatment is one of the most challenging diseases in the present era. Among a few modalities for cancer therapy, radiotherapy plays a pivotal role in more than half of all treatments alone or combined with other cancer treatment modalities. Management of normal tissue toxicity induced by radiation is one of the most important limiting factors for an appropriate radiation treatment course. The evaluation of mechanisms of normal tissue toxicity has shown that immune responses especially inflammatory responses play a key role in both early and late side effects of exposure to ionizing radiation (IR). DNA damage and cell death, as well as damage to some organelles such as mitochondria initiate several signaling pathways that result in the response of immune cells. Massive cell damage which is a common phenomenon following exposure to a high dose of IR cause secretion of a lot of inflammatory mediators including cytokines and chemokines. These mediators initiate different changes in normal tissues that may continue for a long time after irradiation. In this study, we reviewed the mechanisms of inflammatory responses to IR that are involved in normal tissue toxicity and considered as the most important limiting factors in radiotherapy. Also, we introduced some agents that have been proposed for management of these responses. CONCLUSIONS The early inflammation during the radiation treatment is often a limiting factor in radiotherapy. In addition to the limiting factors, chronic inflammatory responses may increase the risk of second primary cancers through continuous free radical production, attenuation of tumor suppressor genes, and activation of oncogenes. Moreover, these effects may influence non-irradiated tissues through a mechanism named bystander effect.
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Affiliation(s)
- Masoud Najafi
- a Radiology and Nuclear Medicine Department, School of Paramedical Sciences , Kermanshah University of Medical Science , Kermanshah , Iran
| | - Elahe Motevaseli
- b Department of Molecular Medicine, School of Advanced Technologies in Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Alireza Shirazi
- c Department of Medical Physics and Biomedical Engineering, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Ghazale Geraily
- c Department of Medical Physics and Biomedical Engineering, Faculty of Medicine , Tehran University of Medical Sciences , Tehran , Iran
| | - Abolhasan Rezaeyan
- d Department of Medical Physics, School of Medicine , Iran University of Medical Sciences , Tehran , Iran
| | - Farzad Norouzi
- e Science and Research Branch , Azad University , Tehran , Iran
| | - Saeed Rezapoor
- f Department of Radiology, Faculty of Paramedical Sciences , Tehran University of Medical Sciences , Tehran , Iran
| | - Hamid Abdollahi
- d Department of Medical Physics, School of Medicine , Iran University of Medical Sciences , Tehran , Iran
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Chemopreventive Effect of Aster glehni on Inflammation-Induced Colorectal Carcinogenesis in Mice. Nutrients 2018; 10:nu10020202. [PMID: 29439531 PMCID: PMC5852778 DOI: 10.3390/nu10020202] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Revised: 01/31/2018] [Accepted: 02/09/2018] [Indexed: 12/11/2022] Open
Abstract
Although Aster glehni is a common dietary herb that has various bioactivities, including anti-diabetic, anti-adipogenic, and anti-inflammatory effects, A. glehni has not been studied in colon cancer. Therefore, we hypothesized the chemopreventive effects of an ethanol extract of A. glehni (AG) on azoxymethane/dextran sulfate sodium (AOM/DSS)-induced colitis-associated cancer (CAC) in mice. In this study, we found that treatment with AG significantly attenuated the AOM/DSS-induced enlargement of the spleen and shortening of the colon. In addition, colonic tumor formation, colonic damage, and increased muscle thickness were significantly reduced in AOM/DSS-induced mice fed AG. Treatment with AG also reduced intestinal interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α production and decreased inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 protein expression in mice with AOM/DSS-induced CAC. Furthermore, AG reduced nuclear factor (NF)-κB activation via phosphorylation and degradation of inhibitor of kappa Bα (IκBα), leading to inhibition of NF-κB p65 nuclear translocation. It also downregulated the expression of NF-κB-related proteins, including the B-cell lymphoma 2 (Bcl-2) family and inhibitors of apoptosis proteins (IAPs), in mice with AOM/DSS-induced CAC. Taken together, these findings suggest that the treatment with AG inhibited colitis-associated colon carcinogenesis in mice, and this chemopreventive effect was strongly mediated by suppression of the NF-κB signaling pathway, indicating that AG could be a promising protective agent against CAC.
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35
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Mandal P. Molecular signature of nitric oxide on major cancer hallmarks of colorectal carcinoma. Inflammopharmacology 2017; 26:331-336. [PMID: 29289998 DOI: 10.1007/s10787-017-0435-z] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Accepted: 12/11/2017] [Indexed: 11/28/2022]
Abstract
Colorectal cancer (CRC) is the one of the most important diseases throughout the world. Several aetiological risk factors, viz. sedentary life style, smoking, alcohol intake, less physical activity, red meat, and microbiota, are associated with the development of CRC. Molecular pathophysiology of CRC implies inflammation, metastasis, apotosis and angiogenesis. Inflammation involves interaction between various immune cells, inflammatory cells, chemokines, cytokines, and pro-inflammatory mediators, such as cyclooxygenase (COX) and lipoxygenase (LOX) pathways, which may lead to signalling towards, tumour cell proliferation, growth, and invasion whereas nitric oxide (NO) has been associated with metastasis, apoptosis, and angiogenesis. Therefore, this review emphasises on the potential molecular mechanisms associated with NO with alteration of cancer biomarkers during development of colorectal carcinogenesis.
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Affiliation(s)
- Paramita Mandal
- Department of Zoology, The University of Burdwan, Burdwan, India.
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36
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Yoon G, Oh CS, Kim HS. Hypergravity upregulates renal inducible nitric oxide synthase expression and nitric oxide production. Oncotarget 2017; 7:30147-54. [PMID: 27174912 PMCID: PMC5058670 DOI: 10.18632/oncotarget.9253] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2016] [Accepted: 04/28/2016] [Indexed: 11/25/2022] Open
Abstract
Exposure to hypergravity severely decreases renal blood flow, potentially causing renal dysfunction. Nitric oxide (NO), which is endogenously synthesized by inducible NO synthase (iNOS), plays an important role in the regulation of renal function. The purpose of this study was to examine the effect of hypergravity exposure on the production of NO in kidneys. To determine whether hypergravity induces renal hypoxia and alters renal iNOS expression and NO production, mice were exposed to short-term hypergravity at +3Gz for 1 h. The time course of iNOS mRNA expression, hypoxia-inducible factor (HIF)-1α expression, and NO production was examined. Renal HIF-1α levels were significantly elevated immediately after centrifugation, and this increase was sustained for 3 h post-exposure. iNOS mRNA levels were also significantly increased immediately after exposure and were maintained during the reoxygenation period. Immunohistochemical staining for iNOS revealed that the cortical tubular epithelium exhibited moderate to strong cytoplasmic iNOS immunoreactivity immediately after hypergravity exposure and during the reoxygenation period. The time course of NO production was similar to that of iNOS expression. Our results suggest that both hypoxia and reoxygenation might be involved in the upregulation of HIF-1α in the kidneys of mice exposed to hypergravity. Significant increases in renocortical iNOS expression immediately after centrifugation and during the reoxygenation period suggest that iNOS expression induced by hypergravity exposure might play a protective role against hypoxia/reoxygenation injury in the renal cortex. Further investigations are necessary to clarify the role of iNOS and NO in kidneys exposed to hypergravity.
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Affiliation(s)
- Gun Yoon
- Department of Obstetrics and Gynecology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan-si, Gyeongsangnam-do, Republic of Korea
| | - Choong Sik Oh
- Aerospace Medicine Research Center, Republic of Korea Air Force Aerospace Medical Center, Cheongju-si, Chungcheongbuk-do, Republic of Korea
| | - Hyun-Soo Kim
- Department of Pathology, Severance Hospital, Yonsei University College of Medicine, Seoul, Republic of Korea
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37
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Du L, Kim JJ, Shen J, Chen B, Dai N. KRAS and TP53 mutations in inflammatory bowel disease-associated colorectal cancer: a meta-analysis. Oncotarget 2017; 8:22175-22186. [PMID: 28077799 PMCID: PMC5400656 DOI: 10.18632/oncotarget.14549] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2016] [Accepted: 12/27/2016] [Indexed: 12/13/2022] Open
Abstract
Although KRAS and TP53 mutations are common in both inflammatory bowel disease-associated colorectal cancer (IBD-CRC) and sporadic colorectal cancer (S-CRC), molecular events leading to carcinogenesis may be different. Previous studies comparing the frequency of KRAS and TP53 mutations in IBD-CRC and S-CRC were inconsistent. We performed a meta-analysis to compare the presence of KRAS and TP53 mutations among patients with IBD-CRC, S-CRC, and IBD without dysplasia. A total of 19 publications (482 patients with IBD-CRC, 4,222 with S-CRC, 281 with IBD without dysplasia) met the study inclusion criteria. KRAS mutation was less frequent (RR=0.71, 95%CI 0.56-0.90; P=0.004) while TP53 mutation was more common (RR=1.24, 95%CI 1.10-1.39; P<0.001) in patients with IBD-CRC compared to S-CRC. Both KRAS (RR=3.09, 95%CI 1.47-6.51; P=0.003) and TP53 (RR=2.15, 95%CI 1.07-4.31 P=0.03) mutations were more prevalent in patients with IBD-CRC compared to IBD without dysplasia. In conclusion, IBD-CRC and S-CRC appear to have biologically different molecular pathways. TP53 appears to be more important than KRAS in IBD-CRC compared to S-CRC. Our findings suggest possible roles of TP53 and KRAS as biomarkers for cancer and dysplasia screening among patients with IBD and may also provide targeted therapy in patients with IBD-CRC.
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Affiliation(s)
- Lijun Du
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - John J Kim
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Division of Gastroenterology, Loma Linda University Medical Center, Loma Linda, USA
| | - Jinhua Shen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China.,Department of Gastroenterology, Affiliated Hospital of Shaoxing University, Shaoxing, China
| | - Binrui Chen
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Ning Dai
- Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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38
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Souza RF. Reflux esophagitis and its role in the pathogenesis of Barrett's metaplasia. J Gastroenterol 2017; 52:767-776. [PMID: 28451845 PMCID: PMC5488728 DOI: 10.1007/s00535-017-1342-1] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 04/11/2017] [Indexed: 02/04/2023]
Abstract
Reflux esophagitis damages the squamous epithelium that normally lines the esophagus, and promotes replacement of the damaged squamous lining by the intestinal metaplasia of Barrett's esophagus, the precursor of esophageal adenocarcinoma. Therefore, to prevent the development of Barrett's metaplasia and esophageal adenocarcinoma, the pathogenesis of reflux esophagitis must be understood. We have reported that reflux esophagitis, both in a rat model and in humans, develops as a cytokine-mediated inflammatory injury (i.e., cytokine sizzle), not as a caustic chemical injury (i.e., acid burn), as traditionally has been assumed. Moreover, reflux induces activation of hypoxia inducible factor (HIF)-2α, which enhances the transcriptional activity of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) causing increases in pro-inflammatory cytokines and in migration of T lymphocytes, an underlying molecular mechanism for this cytokine-mediated injury. In some individuals, reflux esophagitis heals with Barrett's metaplasia. A number of possibilities exist for the origin of the progenitor cells that give rise to this intestinal metaplasia including those of the esophagus, the proximal stomach, or the bone marrow. However, intestinal cells are not normally found in the esophagus, the stomach, or the bone marrow. Thus, the development of Barrett's intestinal metaplasia must involve some molecular reprogramming of key developmental transcription factors within the progenitor cell, a process termed transcommitment, which may be initiated by the noxious components of the gastric refluxate. This review will highlight recent studies on the pathogenesis of reflux esophagitis and on reflux-related molecular reprogramming of esophageal squamous epithelial cells in the pathogenesis of Barrett's metaplasia.
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Affiliation(s)
- Rhonda F. Souza
- Center for Esophageal Research, Baylor Scott and White Research Institute, Dallas, TX, USA
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39
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All-Trans Retinoic Acid Modulates TLR4/NF- κB Signaling Pathway Targeting TNF- α and Nitric Oxide Synthase 2 Expression in Colonic Mucosa during Ulcerative Colitis and Colitis Associated Cancer. Mediators Inflamm 2017; 2017:7353252. [PMID: 28408791 PMCID: PMC5376956 DOI: 10.1155/2017/7353252] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2016] [Revised: 01/05/2017] [Accepted: 02/19/2017] [Indexed: 12/24/2022] Open
Abstract
Colitis associated cancer (CAC) is the colorectal cancer (CRC) subtype that is associated with bowel disease such as ulcerative colitis (UC). The data on role of NF-κB signaling in development and progression of CAC were derived from preclinical studies, whereas data from human are rare. The aim of this work was to study the contribution of NF-κB pathway during UC and CAC, as well as the immunomodulatory effect of all-trans retinoic acid (AtRA). We analyzed the expression of NOS2, TNF-α, TLR4, and NF-κB, in colonic mucosa. We also studied NO/TNF-α modulation by LPS in colonic mucosa pretreated with AtRA. A marked increase in TLR4, NF-κB, TNF-α, and NOS2 expression was reported in colonic mucosa. The relationship between LPS/TLR4 and TNF-α/NO production, as well as the role of NF-κB signaling, was confirmed by ex vivo experiments and the role of LPS/TLR4 in NOS2/TNF-α induction through NF-κB pathway was suggested. AtRA downregulates NOS2 and TNF-α expression. Collectively, our study indicates that AtRA modulates in situ LPS/TLR4/NF-κB signaling pathway targeting NOS2 and TNF-α expression. Therefore, we suggest that AtRA has a potential value in new strategies to improve the current therapy, as well as in the clinical prevention of CAC development and progression.
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40
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Bagheri V, Memar B, Momtazi AA, Sahebkar A, Gholamin M, Abbaszadegan MR. Cytokine networks and their association with Helicobacter pylori infection in gastric carcinoma. J Cell Physiol 2017; 233:2791-2803. [PMID: 28121015 DOI: 10.1002/jcp.25822] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2016] [Accepted: 12/16/2016] [Indexed: 12/20/2022]
Abstract
Cytokine networks as dynamic networks are pivotal aspects of tumor immunology, especially in gastric cancer (GC), in which infection, inflammation, and antitumor immunity are key elements of disease progression. In this review, we describe functional roles of well-known GC-modulatory cytokines, highlight the functions of cytokines with more recently described roles in GC, and emphasize the therapeutic potential of targeting the complex cytokine milieu. We also focus on the role of Helicobacter pylori (HP)-induced inflammation in GC and discuss how HP-induced chronic inflammation can lead to the induction of stem cell hyperplasia, morphological changes in gastric mucosa and GC development.
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Affiliation(s)
- Vahid Bagheri
- Department of Immunology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bahram Memar
- Surgical Oncology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pathology, Faculty of Medicine, Emam Reza Hospital, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Abbas Momtazi
- Department of Medical Biotechnology, Student Research Committee, Nanotechnology Research Center, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amirhossein Sahebkar
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Biotechnology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mehran Gholamin
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Abbaszadegan
- Human Genetic Division, Immunology Research Center, Bu-Ali Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Medical Genetics Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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41
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Simone V, Brunetti O, Lupo L, Testini M, Maiorano E, Simone M, Longo V, Rolfo C, Peeters M, Scarpa A, Azzariti A, Russo A, Ribatti D, Silvestris N. Targeting Angiogenesis in Biliary Tract Cancers: An Open Option. Int J Mol Sci 2017; 18:418. [PMID: 28212293 PMCID: PMC5343952 DOI: 10.3390/ijms18020418] [Citation(s) in RCA: 52] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2016] [Revised: 02/08/2017] [Accepted: 02/10/2017] [Indexed: 12/17/2022] Open
Abstract
Biliary tract cancers (BTCs) are characterized by a bad prognosis and the armamentarium of drugs for their treatment is very poor. Although the inflammatory status of biliary tract represents the first step in the cancerogenesis, the microenvironment also plays a key role in the pathogenesis of BTCs, promoting tumor angiogenesis, invasion and metastasis. Several molecules, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF), are involved in the angiogenesis process and their expression on tumor samples has been explored as prognostic marker in both cholangiocarcinoma and gallbladder cancer. Recent studies evaluated the genomic landscape of BTCs and evidenced that aberrations in several genes enrolled in the pro-angiogenic signaling, such as FGF receptor-2 (FGFR-2), are characteristic of BTCs. New drugs targeting the signaling pathways involved in angiogenesis have been tested in preclinical studies both in vitro and in vivo with promising results. Moreover, several clinical studies tested monoclonal antibodies against VEGF and tyrosine kinase inhibitors targeting the VEGF and the MEK/ERK pathways. Herein, we evaluate both the pathogenic mechanisms of BTCs focused on angiogenesis and the preclinical and clinical data available regarding the use of new anti-angiogenic drugs in these malignancies.
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Affiliation(s)
- Valeria Simone
- Operative Unit of Internal Medicine, Hospital "F.Ferrari", 73042 Casarano (Le), Italy.
| | - Oronzo Brunetti
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Luigi Lupo
- Department of Emergency and Organ Transplantation, Institute of General Surgery and Liver Transplantation, University of Bari, 70124 Bari, Italy.
| | - Mario Testini
- Department of Biomedical Sciences and Human Oncology, Unit of Endocrine, Digestive and Emergency Surgery, 70124 Bari, Italy.
| | - Eugenio Maiorano
- Department of Emergency and Organ Transplantation, Operating Unit of Pathological Anatomy, "Aldo Moro" University, 70124 Bari, Italy.
| | - Michele Simone
- Surgical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Vito Longo
- Medical Oncology Unit, Hospital of Taranto, 74010 Taranto, Italy.
| | - Christian Rolfo
- Phase I-Early Clinical Trials Unit, Oncology Department, Antwerp University Hospital & Center for Oncological Research, 2650 Edegem, Belgium.
| | - Marc Peeters
- Oncology Department, Antwerp University Hospital, 2650 Edegem, Belgium.
| | - Aldo Scarpa
- ARC-NET (Applied Research on Cancer-Network) Research Centre, University of Verona, 37134 Verona, Italy.
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy.
| | - Amalia Azzariti
- Preclinical and Clinical Pharmacology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Antonio Russo
- Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, 90144 Palermo, Italy.
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy.
- Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
| | - Nicola Silvestris
- Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy.
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Lee SH, Park SW. [Inflammation and Cancer Development in Pancreatic and Biliary Tract Cancer]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2016; 66:325-39. [PMID: 26691190 DOI: 10.4166/kjg.2015.66.6.325] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Chronic inflammation has been known to be a risk for many kinds of cancers, including pancreatic and biliary tract cancer. Recently, inflammatory process has emerged as a key mediator of cancer development and progression. Many efforts with experimental results have been given to identify the underlying mechanisms that contribute to inflammation-induced tumorigenesis. Diverse inflammatory pathways have been investigated and inhibitors for inflammation-related signaling pathways have been developed for cancer treatment. This review will summarize recent outcomes about this distinctive process in pancreatic and biliary tract cancer. Taking this evidence into consideration, modulation of inflammatory process will provide useful options for pancreatic and biliary tract cancer treatment.
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Affiliation(s)
- Sang Hoon Lee
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Pancreatobiliary Cancer Center, Yonsei Cancer Hospital, Seoul, Korea
| | - Seung Woo Park
- Department of Internal Medicine, Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Korea.,Pancreatobiliary Cancer Center, Yonsei Cancer Hospital, Seoul, Korea
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43
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Huang WC, Tsai CC, Chan CC. Mutation analysis and copy number changes of KRAS and BRAF genes in Taiwanese cases of biliary tract cholangiocarcinoma. J Formos Med Assoc 2016; 116:464-468. [PMID: 27745798 DOI: 10.1016/j.jfma.2016.07.015] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Revised: 07/18/2016] [Accepted: 07/20/2016] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND/PURPOSE Cholangiocarcinoma (CC) is a fatal malignancy originating from biliary tracts and constitutes approximately 10-20% of hepatobiliary cancers. CC is characterized by a very poor prognosis. The definite molecular mechanisms leading to oncogenesis remain unclear. This study aimed to perform mutation analysis and copy number changes of KRAS and BRAF genes of CC in Taiwan. METHODS A total of 182 cases of biliary tact CC were studied for point mutation and quantitative real-time polymerase chain reaction analysis of KRAS and BRAF genes. The obtained data were analyzed with clinical and histopathological variables and survival. RESULTS KRAS point mutations were detected in intrahepatic CC (7.6%), common bile duct cancer (13.3%), and gallbladder carcinoma (3.3%). BRAF gene amplifications were demonstrated in intrahepatic CC (4.3%), common bile duct cancer (3.3%), and gallbladder cancer (5%). No association was observed between mutation patterns and histopathological features. The analyses of risk factors for overall survival in patients with CC revealed no significant association in age, tumor site, genetic mutation, or amplifications. The tumor stage was the significant prognostic factor. CONCLUSION Unlike other studies from American, European, or Japanese groups which showed certain levels of gene mutations in CC, our data revealed a rather low frequency of KRAS mutations and BRAF gene amplifications in CC in Taiwan. Tumor TNM stage was the only significant prognostic parameter in this analysis. It is crucial to gain more information of carcinogenesis, molecular mechanisms and therapeutic strategy in biliary tract cholangiocarcinoma.
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Affiliation(s)
- Wen-Chih Huang
- Department of Anatomic Pathology, Far Eastern Memorial Hospital, New Taipei, Taiwan; College of Nursing, National Taipei University of Nursing and Health Sciences, Taipei, Taiwan.
| | - Chien-Chen Tsai
- Department of Anatomic Pathology, Far Eastern Memorial Hospital, New Taipei, Taiwan
| | - Chih-Chieh Chan
- Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
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Asanuma K, Huo X, Agoston A, Zhang X, Yu C, Cheng E, Zhang Q, Dunbar KB, Pham TH, Wang DH, Iijima K, Shimosegawa T, Odze RD, Spechler SJ, Souza RF. In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression. Gut 2016; 65:1416-26. [PMID: 25986942 PMCID: PMC4651671 DOI: 10.1136/gutjnl-2015-309272] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 04/22/2015] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Barrett's metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype. DESIGN Oesophageal squamous cells from patients with Barrett's oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation. RESULTS In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets. CONCLUSIONS In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett's pathogenesis.
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Affiliation(s)
- Kiyotaka Asanuma
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Xiaofang Huo
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Agoston Agoston
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Xi Zhang
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Chunhua Yu
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Edaire Cheng
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Pediatrics, Children’s Medical Center and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Qiuyang Zhang
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Kerry B. Dunbar
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - Thai H. Pham
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Surgery, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX
| | - David H. Wang
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Katsunori Iijima
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Tooru Shimosegawa
- Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Robert D. Odze
- Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA
| | - Stuart J. Spechler
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
| | - Rhonda F. Souza
- Esophageal Diseases Center, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Department of Medicine, VA North Texas Health Care System and the University of Texas Southwestern Medical Center, Dallas, TX,Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX
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Barani R, Motalleb G, Maghsoudi H. Evaluation of iNOS Expression in Esophageal Cancer Patients. Gastrointest Tumors 2016; 3:44-58. [PMID: 27722156 PMCID: PMC5040924 DOI: 10.1159/000443976] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 01/13/2016] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Esophageal cancer is a public health concern around the world; this cancer is the sixth leading cause of death of cancer in the world with about 386,000 deaths per year. Its risk factors include environmental factors such as tobacco smoke, gastroesophageal reflux and genetic changes. iNOS is stated by the effect of various inflammatory factors and is thus called inducible NOS. Investigating iNOS expression is a powerful tool for understanding effective molecular parameters at tissue and cellular responses to external factors. In this research work, iNOS expression in patients with esophageal cancer was studied in Iran. MATERIALS AND METHODS 15 formalin-fixed and paraffin-embedded (FFPE) esophageal cancer tissue samples and 15 normal FFPE samples were collected from various medical centers (Zabol, Zahedan, Kashan) to measure iNOS expression by real-time reverse transcriptase polymerase chain reaction (real-time RT-PCR). All PCR reactions were conducted by three replicates for iNOS and internal control (β-actin) by 2-ΔΔCT (Livak) method. Differences were measured in target gene expression in patients and control group using the t test. All statistical analyses were done using the SPSS software. RESULTS The results showed that there was no significant difference between iNOS expression in the case and control groups (p > 0.05); however, there was an increase in iNOS expression in the case group. On the other hand, there was a significant difference between iNOS expression in males and females in the two groups of healthy subjects and patients, and it was higher in women than in men. CONCLUSION Further studies need to be conducted with larger sample sizes and in other populations to validate these findings.
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Affiliation(s)
- Romina Barani
- Department of Biotechnology, Faculty of Science, Payame Noor University, Tehran
| | | | - Hossein Maghsoudi
- Department of Biotechnology, Faculty of Science, Payame Noor University, Tehran
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Haddouche M, Meziane W, Hadjidj Z, Mesli N, Aribi M. Clinical association of baseline levels of conjugated dienes in low-density lipoprotein and nitric oxide with aggressive B-cell non-Hodgkin lymphoma and their relationship with immunoglobulins and Th1-to-Th2 ratio. J Blood Med 2016; 7:111-9. [PMID: 27330333 PMCID: PMC4898418 DOI: 10.2147/jbm.s103967] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Objective The aim of this study was to highlight the clinical association of baseline levels of conjugated dienes in low-density lipoprotein (LDL-BCD) and nitric oxide (NO) with immunoglobulins (Igs) and T helper (Th)1/Th2 ratio in patients with newly diagnosed B-cell non-Hodgkin lymphoma (NHL). Patients and methods Thirty-two newly diagnosed patients with aggressive B-cell NHL and 25 age-, sex-, and body-mass-index-matched healthy controls were randomly selected for a cross-sectional case–control study conducted at the Hematology Department of Tlemcen Medical Centre University (northwest of Algeria). Results Circulating levels of LDL-BCD and NO and those of IgA and IgM were significantly higher in patients than in controls. The levels of Th1/Th2 ratio and plasma total antioxidant capacity were significantly lower in patients compared with controls, while malondialdehyde and protein carbonyl levels were significantly higher in patients. B-cell NHL was significantly associated with high levels of LDL-BCD from 25th to 75th percentile (25th percentile: relative risk [RR] =2.26, 95% confidence interval [CI] 1.42–3.59, P=0.014; 50th percentile: RR =2.84, 95% CI 1.72–4.68, P<0.001; 75th percentile: RR =5.43, 95% CI 2.58–11.42, P<0.001). Similarly, the disease was significantly associated with high levels of NO production from 25th to 75th percentile (25th percentile: RR =2.07, 95% CI 1.25–3.44, P=0.024; 50th percentile: RR =2.78, 95% CI 1.63–4.72, P<0.001; 75th percentile: RR =4.68, 95% CI 2.21–9.91, P<0.001). Moreover, LDL-BCD levels were positively and significantly correlated with interferon (IFN)-γ, whereas NO levels were inversely and significantly correlated with IFN-γ and Th1/Th2 ratio. Conclusion LDL-BCD and NO production seem to be associated with aggressive B-cell NHL and alteration of Th1/Th2 ratio. Our results have to be examined using ex vivo mechanistic studies leading to further investigations of these parameters, with an interest in the link between Epstein–Barr virus infection and NO and immunoglobulins.
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Affiliation(s)
- Mustapha Haddouche
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Algeria; Department of Biology, University of Tlemcen, Algeria
| | - Warda Meziane
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Algeria; Department of Biology, University of Tlemcen, Algeria
| | - Zeyneb Hadjidj
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Algeria; Department of Biology, University of Tlemcen, Algeria
| | - Naima Mesli
- Hematology Department, Tlemcen Medical Centre University, Tlemcen, Algeria
| | - Mourad Aribi
- Laboratory of Applied Molecular Biology and Immunology, University of Tlemcen, Algeria; Department of Biology, University of Tlemcen, Algeria
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Kao NJ, Hu JY, Wu CS, Kong ZL. Curcumin represses the activity of inhibitor-κB kinase in dextran sulfate sodium-induced colitis by S-nitrosylation. Int Immunopharmacol 2016; 38:1-7. [PMID: 27233000 DOI: 10.1016/j.intimp.2016.05.015] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 04/18/2016] [Accepted: 05/17/2016] [Indexed: 11/16/2022]
Abstract
In this study, we investigated the preventive effects of curcumin using dextran sulfate sodium (DSS)-induced colitis and the potential role of curcumin in regulation of anti-inflammation through S-nitrosylation. After curcumin treatment for 6days, the body weight and disease activity index of DSS-induced mice was alleviated and the colonic length was also rescued. Western blot presented that the protein expression of iNOS can be reduced by curcumin. Consistently, mRNA level of iNOS and pro-inflammatory cytokines, such as TNFα, IL-1β, and IL-6, was also repressed. Moreover, Curcumin reduced the amount of nitrite in DSS-induced colitis but not affected total S-nitrosylation level on proteins on day 6, indicating that curcumin inhibited NO oxidation. Furthermore, the protection of S-nitrosylation on IKKβ in DSS-induced colitis for 6days by curcumin caused the repression of IκB phosphorylation and NF-κB activation. In conclusion, this study verified that curcumin-mediated S-nitrosylation may be as an important regulator for anti-inflammation in DSS-induced colitis of mice.
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Affiliation(s)
- Ning-Jo Kao
- Department of Food Science, University of National Taiwan Ocean University, Keelung, Taiwan
| | - Jia-Yuan Hu
- Department of Food Science, University of National Taiwan Ocean University, Keelung, Taiwan
| | - Chien-Sheng Wu
- Department of Food Science, University of National Taiwan Ocean University, Keelung, Taiwan
| | - Zwe-Ling Kong
- Department of Food Science, University of National Taiwan Ocean University, Keelung, Taiwan.
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Adiabouah Achy-Brou CA, Billack B. A comparative assessment of the cytotoxicity and nitric oxide reducing ability of resveratrol, pterostilbene and piceatannol in transformed and normal mouse macrophages. Drug Chem Toxicol 2016; 40:36-46. [PMID: 27079867 DOI: 10.3109/01480545.2016.1169542] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
The present study investigated the pharmacological effects of three stilbenoids, resveratrol (RES), pterostilbene (PTR) and piceatannol (PIC), in transformed and normal macrophages. Our first aim was to comparatively assess the cytotoxicity of RES, PTR and PIC in unstimulated transformed mouse macrophages (RAW 264.7 cells) and primary peritoneal macrophages (PMs) harvested from both wild type and Nrf2 (nuclear factor erythroid 2-related factor 2)-deficient female mice. Our second aim was to investigate whether the inhibitory effect of RES, PTR and PIC on nitric oxide (NO) release from stimulated PMs depends on the status of the transcription factor Nrf2. The rationale for investigating Nrf2 status was based upon recent reports showing that certain compounds (sulforaphane and linalool) suppress LPS-induced inflammation in an Nrf2-dependent manner. Cell viability studies confirmed our prior work in unstimulated RAW 264.7 cells, with cytotoxic potency decreasing in the order of PTR > PIC > RES. Unstimulated PMs, regardless of Nrf2 status, were less sensitive to stilbenes, requiring at least a threefold higher stilbene concentration to inhibit cell viability, with cytotoxic potency again decreasing in the order of PTR > PIC > RES. In studies focused on our second aim, IC50 values for NO inhibition (measured as [Formula: see text]) in wild type PMs were similar for all three stilbenes (∼10 μM). In Nrf2-deficient PMs, the IC50 for NO inhibition by PIC did not change; however, a rightward shift in the concentration effect curve was observed for both RES and PTR, indicating a role for Nrf2 in the suppression of LPS-induced [Formula: see text] accumulation by these particular stilbenes.
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Affiliation(s)
| | - Blase Billack
- a Department of Pharmaceutical Sciences , College of Pharmacy and Health Sciences, St. John's University , Jamaica , NY , USA
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Genetic Abnormalities in Biliary Brush Samples for Distinguishing Cholangiocarcinoma from Benign Strictures in Primary Sclerosing Cholangitis. Gastroenterol Res Pract 2016; 2016:4381513. [PMID: 27127503 PMCID: PMC4834158 DOI: 10.1155/2016/4381513] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2015] [Accepted: 02/22/2016] [Indexed: 12/14/2022] Open
Abstract
Background. Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease and is strongly associated with cholangiocarcinoma (CCA). The lack of efficient diagnostic methods for CCA is a major problem. Testing for genetic abnormalities may increase the diagnostic value of cytology. Methods. We assessed genetic abnormalities for CDKN2A, TP53, ERBB2, 20q, MYC, and chromosomes 7 and 17 and measures of genetic clonal diversity in brush samples from 29 PSC patients with benign biliary strictures and 12 patients with sporadic CCA or PSC-associated CCA. Diagnostic performance of cytology alone and in combination with genetic markers was evaluated by sensitivity, specificity, and area under the curve analysis. Results. The presence of MYC gain and CDKN2A loss as well as a higher clonal diversity was significantly associated with malignancy. MYC gain increased the sensitivity of cytology from 50% to 83%. However, the specificity decreased from 97% to 76%. The diagnostic accuracy of the best performing measures of clonal diversity was similar to the combination of cytology and MYC. Adding CDKN2A loss to the panel had no additional benefit. Conclusion. Evaluation of MYC abnormalities and measures of clonal diversity in brush cytology specimens may be of clinical value in distinguishing CCA from benign biliary strictures in PSC.
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Huang FY, Chan AOO, Rashid A, Wong DKH, Seto WK, Cho CH, Lai CL, Yuen MF. Interleukin-1β increases the risk of gastric cancer through induction of aberrant DNA methylation in a mouse model. Oncol Lett 2016; 11:2919-2924. [PMID: 27073577 DOI: 10.3892/ol.2016.4296] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2015] [Accepted: 02/16/2016] [Indexed: 01/25/2023] Open
Abstract
Interleukin-1β (IL-1β) has a significant role in chronic gastric inflammation and manifestations of gastric diseases. The present study aimed to elucidate the specific role of IL-1β in induction of DNA methylation using IL-1 receptor type 1 knockout (IL-1R1-/-) mice. In the present study, wild-type (WT) and IL-1R1-/- mice were injected with IL-1β (5 µg/kg/day). Serum levels of IL-1β, interleukin-6 (IL-6) and nitric oxide (NO) were measured by enzyme-linked immunosorbent or NO assays. E-cadherin (E-cad) methylation status and messenger (m)RNA expression of IL-1β, IL-6, E-cad and inducible nitric oxide synthase (iNOS) were analyzed. Results from the present study indicated significantly higher IL-1β mRNA expression (P<0.001) in WT mice compared with IL-1R1-/- mice. IL-1β and IL-6 release was significantly increased in treated WT mice compared with IL-1R1-/- mice at 1 h, 4 h and 8 h (all P<0.005). IL-1β release was only detected in WT mice following a second dose measured at day 3, week 1 and week 2 when compared with IL-1R1-/- mice. Promoter methylation of E-cad and a decrease in gene expression was observed in treated WT mice. mRNA expression of iNOS in WT mice was significantly increased at week 1 compared with IL-1R1-/- mice (P=0.0411). Furthermore, a significantly increased level of NO production was observed in treated WT mice (P<0.005 at 8 h and week 1; P<0.001 at 4 h and day 3) when compared with IL-1R1-/- mice. The present results indicated that IL-1β was able to directly induce DNA methylation, which may link inflammation-induced epigenetic changes and the development of gastric diseases.
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Affiliation(s)
- Fung-Yu Huang
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Annie On-On Chan
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China; Gastroenterology and Hepatology Center, The Hong Kong Sanatorium and Hospital, Hong Kong, SAR, P.R. China
| | - Asif Rashid
- Department of Pathology, The University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Danny Ka-Ho Wong
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Wai-Kay Seto
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Chi-Hin Cho
- School of Biomedical Sciences and Institute of Digestive Diseases, Faculty of Medicine, The Chinese University of Hong Kong, SAR, P.R. China
| | - Ching-Lung Lai
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
| | - Man-Fung Yuen
- Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, SAR, P.R. China
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