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Frontiers in Immunology 2023As yet, the genetic abnormalities involved in the exacerbation of Ulcerative colitis (UC) have not been adequately explored based on bioinformatic methods. (Review)
Review
BACKGROUND
As yet, the genetic abnormalities involved in the exacerbation of Ulcerative colitis (UC) have not been adequately explored based on bioinformatic methods.
MATERIALS AND METHODS
The gene microarray data and clinical information were downloaded from Gene Expression Omnibus (GEO) repository. The scale-free gene co-expression networks were constructed by R package "WGCNA". Gene enrichment analysis was performed Metascape database. Differential expression analysis was performed using "Limma" R package. The "randomForest" packages in R was used to construct the random forest model. Unsupervised clustering analysis performed by "ConsensusClusterPlus"R package was utilized to identify different subtypes of UC patients. Heat map was established using the R package "pheatmap". Diagnostic parameter capability was evaluated by ROC curve. The"XSum"packages in R was used to screen out small-molecule drugs for the exacerbation of UC based on cMap database. Molecular docking was performed with Schrodinger molecular docking software.
RESULTS
Via WGCNA, a total 77 high Mayo score-associated genes specific in UC were identified. Subsequently, the 9 gene signatures of the exacerbation of UC was screened out by random forest algorithm and Limma analysis, including BGN,CHST15,CYYR1,GPR137B,GPR4,ITGA5,LILRB1,SLFN11 and ST3GAL2. The ROC curve suggested good predictive performance of the signatures for exacerbation of UC in both the training set and the validation set. We generated a novel genotyping scheme based on the 9 signatures. The percentage of patients achieved remission after 4 weeks intravenous corticosteroids (CS-IV) treatment was higher in cluster C1 than that in cluster C2 (54% . 27%, Chi-square test, =0.02). Energy metabolism-associated signaling pathways were significantly up-regulated in cluster C1, including the oxidative phosphorylation, pentose and glucuronate interconversions and citrate cycle TCA cycle pathways. The cluster C2 had a significant higher level of CD4+ T cells. The"XSum"algorithm revealed that Exisulind has a therapeutic potential for UC. Exisulind showed a good binding affinity for GPR4, ST3GAL2 and LILRB1 protein with the docking glide scores of -7.400 kcal/mol, -7.191 kcal/mol and -6.721 kcal/mol, respectively.We also provided a comprehensive review of the environmental toxins and drug exposures that potentially impact the progression of UC.
CONCLUSION
Using WGCNA and random forest algorithm, we identified 9 gene signatures of the exacerbation of UC. A novel genotyping scheme was constructed to predict the severity of UC and screen UC patients suitable for CS-IV treatment. Subsequently, we identified a small molecule drug (Exisulind) with potential therapeutic effects for UC. Thus, our study provided new ideas and materials for the personalized clinical treatment plans for patients with UC.
Topics: Humans; Colitis, Ulcerative; Leukocyte Immunoglobulin-like Receptor B1; Molecular Docking Simulation; Gene Regulatory Networks; Nuclear Proteins
PubMed: 37539055
DOI: 10.3389/fimmu.2023.1162458 -
Journal of Molecular Signaling Nov 2016Inositol hexakisphosphate kinase 2 (IP6K2) potentiates pro-apoptotic signalling and increases the sensitivity of mammalian cells to cytotoxic agents. Diphosphoinositol...
Inositol hexakisphosphate kinase 2 (IP6K2) potentiates pro-apoptotic signalling and increases the sensitivity of mammalian cells to cytotoxic agents. Diphosphoinositol pentakisphosphate kinase (PPIP5K) generates inositol pyrophosphates (InsPPs) that are structurally distinct from those produced by IP6K2 and their possible roles in affecting cell viability remain unclear. In the present study, we tested the impact of PPIP5K1 on cellular sensitivity to various genotoxic agents to determine if PPIP5K1 and IP6K2 contribute similarly to apoptosis. We observed that PPIP5K1 overexpression decreased sensitivity of cells toward several cytotoxic agents, including etoposide, cisplatin, and sulindac. We further tested the impact of PPIP5K1 overexpression on an array of apoptosis markers and observed that PPIP5K1 decreased p53 phosphorylation on key residues, including Ser-15, -46, and -392. Overexpression of a kinase-impaired PPIP5K1 mutant failed to protect cells from apoptosis, indicating this protection is a consequence PPIP5K1 catalytic activity, in contrast with the sensitivity conferred by IP6K2, which is dependent on both catalytic and non-catalytic functions. These observations reveal distinct roles for PPIP5K1 and IP6K2 and the InsPPs they produce in controlling cell death.
PubMed: 31051014
DOI: 10.5334/1750-2187-11-4 -
Medicine Oct 2020Sulindac has been used for treating colorectal polyps widely. However, the efficacy and safety of sulindac for colorectal polyps are unclear. This study aims to evaluate...
BACKGROUND
Sulindac has been used for treating colorectal polyps widely. However, the efficacy and safety of sulindac for colorectal polyps are unclear. This study aims to evaluate the efficacy and safety of sulindac for colorectal polyps.
METHODS
Randomized controlled trials of sulindac in the treatment of colorectal polyps will be searched in PubMed, EMbase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science, and Technology Periodical Database, and China biomedical literature database (CBM) from inception to August, 2020. And Baidu Scholar, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain more relevant studies comprehensively. Two researchers will perform data extraction and risk of bias assessment independently. Statistical analysis will be conducted in RevMan 5.3.
RESULTS
This study will summarize the present evidence by exploring the efficacy and safety of sulindac in the treatment of colorectal polyps.
CONCLUSION
The findings of the study will provide helpful evidence for the efficacy and safety of sulindac in the treatment of colorectal polyps, facilitating clinical practice and further scientific studies.
ETHICS AND DISSEMINATION
The private information from individuals will not publish. This systematic review also will not involve endangering participant rights. Ethical approval is not required. The results may be published in a peer-reviewed journal or disseminated in relevant conferences.
OSF REGISTRATION NUMBER
DOI 10.17605/OSF.IO/N5GDH.
Topics: Antineoplastic Agents; Colonic Polyps; Humans; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Rectum; Research Design; Sulindac; Systematic Reviews as Topic
PubMed: 33031275
DOI: 10.1097/MD.0000000000022402 -
The Journal of Pharmacology and... Jun 2022Oxidative damage is believed to play a major role in the etiology of many age-related diseases and the normal aging process. We previously reported that sulindac, a...
Oxidative damage is believed to play a major role in the etiology of many age-related diseases and the normal aging process. We previously reported that sulindac, a cyclooxygenase (COX) inhibitor and FDA approved anti-inflammatory drug, has chemoprotective activity in cells and intact organs by initiating a pharmacological preconditioning response, similar to ischemic preconditioning (IPC). The mechanism is independent of its COX inhibitory activity as suggested by studies on the protection of the heart against oxidative damage from ischemia/reperfusion and retinal pigmented endothelial (RPE) cells against chemical oxidative and UV damage Unfortunately, sulindac is not recommended for long-term use due to toxicities resulting from its COX inhibitory activity. To develop a safer and more efficacious derivative of sulindac, we screened a library of indenes and identified a lead compound, MCI-100, that lacked significant COX inhibitory activity but displayed greater potency than sulindac to protect RPE cells against oxidative damage. MCI-100 also protected the intact rat heart against ischemia/reperfusion damage following oral administration. The chemoprotective activity of MCI-100 involves a preconditioning response similar to sulindac, which is supported by RNA sequencing data showing common genes that are induced or repressed by sulindac or MCI-100 treatment. Both sulindac and MCI-100 protection against oxidative damage may involve modulation of Wnt/β-catenin signaling resulting in proliferation while inhibiting TGFb signaling leading to apoptosis. In summary MCI-100, is more active than sulindac in protecting cells against oxidative damage, but without significant NSAID activity, and could have therapeutic potential in treatment of diseases that involve oxidative damage. In this study, we describe a novel sulindac derivative, MCI-100, that lacks significant COX inhibitory activity, but is appreciably more potent than sulindac in protecting retinal pigmented epithelial (RPE) cells against oxidative damage. Oral administration of MCI-100 markedly protected the rat heart against ischemia/reperfusion damage. MCI-100 has potential therapeutic value as a drug candidate for age-related diseases by protecting cells against oxidative damage and preventing organ failure.
PubMed: 35680377
DOI: 10.1124/jpet.122.001086 -
Journal of Physiology and Pharmacology... Jun 2018Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and fourth most frequent reason of cancer-related death throughout the world. About 70% of... (Review)
Review
Colorectal cancer (CRC) is the third most prevalent neoplasm worldwide and fourth most frequent reason of cancer-related death throughout the world. About 70% of malignant tumors are related to lifestyle and environmental factors, and better knowledge of their significance might reduce the prevalence of CRC. The cyclooxygenase-2 (COX-2) inhibitory and other direct and indirect pathways of aspirin are translated to inhibition proliferation and enhanced apoptosis of cancer cells. Many studies showed the benefits of aspirin in reducing the risk of CRC development, cancer-related mortality and adenoma prevalence rate in general population, but not in high risk populations. The role of sulindac in CRC prevention is uncertain and the use of this drug is rather uncommon. Celecoxib - COX-2 selective inhibitor- showed efficacy in decreasing of colon adenoma recurrence only in some studies. The protective role of microelements is controversial. The beneficial effects of supplementation of selenium, calcium, folic acid, methionine, antioxidant supplements and probiotics are still not certain. A high energy diet consisting of red meat, animal fat, highly processed foods and unsaturated fats increases the risk of CRC. Carcinogenic role of fat and cholesterol depends on increased production of primary bile acids. The importance of milk and dairy products in CRC prevention is controversial. Fruits, vegetables and grain are considered to have protective effects against adenoma and CRC. Excessive alcohol consumption, smoking, physical inactivity are considered as important CRC risk factors. This article briefly summarizes current state of knowledge about the role of pharmacological and dietary prevention of colorectal cancer. Moreover, it indicates that despite many studies some aspects of this issue are not clear and require future studies.
Topics: Animals; Anticarcinogenic Agents; Colorectal Neoplasms; Diet; Humans
PubMed: 30149368
DOI: 10.26402/jpp.2018.3.02 -
Pharmacological Reports : PR Aug 2023Non-steroidal anti-inflammatory drugs have been shown to inhibit the development of induced neoplasms. Our previous research demonstrated that the cytotoxicity of...
BACKGROUND
Non-steroidal anti-inflammatory drugs have been shown to inhibit the development of induced neoplasms. Our previous research demonstrated that the cytotoxicity of sulindac against melanoma cells is comparable to dacarbazine, the drug used in chemotherapy. The aim of this study was to investigate the mechanism of sulindac cytotoxicity on COLO 829 and C32 cell lines.
METHODS
The influence of sundilac on the activity of selected enzymes of the antioxidant system (superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)) and the content of hydrogen peroxide as well as the level of proteins initiating (p53, Bax) and inhibiting (Bcl-2) apoptosis were measured in melanoma cells.
RESULTS
In melanotic melanoma cells, sulindac increased the activity of SOD and the content of HO but decreased the activity of CAT and GPx. The level of p53 and Bax proteins rose but the content of Bcl-2 protein was lowered. Similar results were observed for dacarbazine. In amelanotic melanoma cells, sulindac did not cause an increase in the activity of measured enzymes or any significant changes in the level of apoptotic proteins.
CONCLUSION
The cytotoxic effect of sulindac in the COLO 829 cell line is connected to disturbed redox homeostasis by changing the activity of SOD, CAT, GPx, and level of HO. Sulindac also induces apoptosis by changing the ratio of the pro-apoptotic/anti-apoptotic protein. The presented studies indicate the possibility of developing target therapy against melanotic melanoma using sulindac.
Topics: Apoptosis Regulatory Proteins; Melanoma; Sulindac; Homeostasis; Oxidation-Reduction; Humans; Cell Line, Tumor; Antioxidants; Superoxide Dismutase; Glutathione Peroxidase; Catalase; Hydrogen Peroxide; Signal Transduction
PubMed: 37195561
DOI: 10.1007/s43440-023-00493-1 -
Cancer Prevention Research... Sep 2021Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the...
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in and mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. PREVENTION RELEVANCE: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using tools, , and models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
Topics: Adenomatous Polyposis Coli; Adenomatous Polyps; Adult; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antineoplastic Combined Chemotherapy Protocols; Bexarotene; Carcinogenesis; Case-Control Studies; Cells, Cultured; Female; Gene Expression Regulation, Neoplastic; HCT116 Cells; HT29 Cells; Humans; Intestinal Neoplasms; Male; Mice; Mice, Transgenic; Sulindac
PubMed: 34266857
DOI: 10.1158/1940-6207.CAPR-20-0496 -
Frontiers in Immunology 2023Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological...
INTRODUCTION
Triple-negative breast cancer (TNBC) comprises a heterogeneous group of clinically aggressive tumors with high risk of recurrence and metastasis. Current pharmacological treatment options remain largely limited to chemotherapy. Despite promising results, the efficacy of immunotherapy and chemo-immunotherapy in TNBC remains limited. There is strong evidence supporting the involvement of Notch signaling in TNBC progression. Expression of Notch1 and its ligand Jagged1 correlate with poor prognosis. Notch inhibitors, including g-secretase inhibitors (GSIs), are quite effective in preclinical models of TNBC. However, the success of GSIs in clinical trials has been limited by their intestinal toxicity and potential for adverse immunological effects, since Notch plays key roles in T-cell activation, including CD8 T-cells in tumors. Our overarching goal is to replace GSIs with agents that lack their systemic toxicity and ideally, do not affect tumor immunity. We identified sulindac sulfide (SS), the active metabolite of FDA-approved NSAID sulindac, as a potential candidate to replace GSIs.
METHODS
We investigated the pharmacological and immunotherapeutic properties of SS in TNBC models , and .
RESULTS
We confirmed that SS, a known γ-secretase modulator (GSM), inhibits Notch1 cleavage in TNBC cells. SS significantly inhibited mammosphere growth in all human and murine TNBC models tested. In a transplantable mouse TNBC tumor model (C0321), SS had remarkable single-agent anti-tumor activity and eliminated Notch1 protein expression in tumors. Importantly, SS did not inhibit Notch cleavage in T- cells, and the anti-tumor effects of SS were significantly enhanced when combined with a-PD1 immunotherapy in our TNBC organoids and .
DISCUSSION
Our data support further investigation of SS for the treatment of TNBC, in conjunction with chemo- or -chemo-immunotherapy. Repurposing an FDA-approved, safe agent for the treatment of TNBC may be a cost-effective, rapidly deployable therapeutic option for a patient population in need of more effective therapies.
Topics: Humans; Animals; Mice; Sulindac; Amyloid Precursor Protein Secretases; Triple Negative Breast Neoplasms; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal
PubMed: 37901240
DOI: 10.3389/fimmu.2023.1244159 -
Cancers Aug 2023Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs' associated side effects, there...
Non-steroidal anti-inflammatory drugs (NSAIDs) are promising colorectal cancer (CRC) chemopreventive drugs; however, to overcome NSAIDs' associated side effects, there is a need to develop safer and efficacious approaches. The present study was designed to evaluate (i) the efficacy of nitric-oxide releasing (NO)-Sulindac as compared to Sulindac; (ii) whether NO-Sulindac is superior to Sulindac in enhancing low-dose difluoromethylornithine (DFMO)-induced chemopreventive efficacy, and (iii) assessing the key biomarkers associated with colon tumor inhibition by these combinations. In F344 rats, colonic tumors were induced by azoxymethane (AOM). At the adenoma stage (13 weeks post AOM), groups of rats were fed the experimental diets containing 0 ppm, 500 ppm DFMO, 150 ppm Sulindac, and 200 ppm NO-Sulindac, individually or in combinations, for 36 weeks. Colon tumors were evaluated histopathologically and assayed for expression levels of proliferative, apoptotic, and inflammatory markers. Results suggest that (except for NO-Sulindac alone), DFMO, Sulindac individually, and DFMO combined with Sulindac or NO-Sulindac significantly suppressed AOM-induced adenocarcinoma incidence and multiplicities. DFMO and Sulindac suppressed adenocarcinoma multiplicity by 63% ( < 0.0001) and 51% ( < 0.0011), respectively, whereas NO-Sulindac had a modest effect (22.8%, = 0.09). Combinations of DFMO plus Sulindac or NO-Sulindac suppressed adenocarcinoma incidence (60%, < 0.0001; 50% < 0.0004), and multiplicity (81%, < 0.0001; 62%, < 0.0001). Rats that were fed the combination of DFMO plus Sulindac showed significant inhibition of tumor cell proliferation and induction of apoptosis. In addition, enhancement of p21, Bax, and caspases; downregulation of Ki-67, VEGF, and β-catenin; and modulation of iNOS, COX-2, and ODC activities in colonic tumors were observed. These observations show that a lower-dose of DFMO and Sulindac significantly enhanced CRC chemopreventive efficacy when compared to NO-Sulindac alone, and the combination of DFMO and NO-Sulindac was modestly efficacious as compared to DFMO alone.
PubMed: 37568816
DOI: 10.3390/cancers15154001 -
American Journal of Physiology.... Jul 2015Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective... (Review)
Review
Colorectal cancer (CRC) is one of the most common human malignancies and a leading cause of cancer-related deaths in developed countries. Identifying effective preventive strategies aimed at inhibiting the development and progression of CRC is critical for reducing the incidence and mortality of this malignancy. The prevention of carcinogenesis by anti-inflammatory agents including nonsteroidal anti-inflammatory drugs (NSAIDs), selective cyclooxygenase-2 (COX-2) inhibitors, and natural products is an area of considerable interest and research. Numerous anti-inflammatory agents have been identified as potential CRC chemopreventive agents but vary in their mechanism of action. This review will discuss the molecular mechanisms being studied for the CRC chemopreventive activity of NSAIDs (i.e., aspirin, sulindac, and ibuprofen), COX-2 inhibitors (i.e., celecoxib), natural products (i.e., curcumin, resveratrol, EGCG, genistein, and baicalein), and metformin. A deeper understanding of how these anti-inflammatory agents inhibit CRC will provide insight into the development of potentially safer and more effective chemopreventive drugs.
Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Cell Transformation, Neoplastic; Colorectal Neoplasms; Cyclooxygenase 2 Inhibitors; Diet; Humans; Inflammation Mediators; Phytochemicals; Risk Factors; Signal Transduction
PubMed: 26021807
DOI: 10.1152/ajpgi.00101.2014