BACKGROUND: Many nutritional supplements and pharmacological agents have been reported to show preventive effects on colorectal adenoma and colorectal cancer (CRC). We performed a network meta-analysis to summarize such evidence and assess the efficacy and safety of these agents. METHODS: We searched PubMed, Embase, and the Cochrane Library for studies published in English until October 31, 2021 that fit our inclusion criteria. We performed a systematic review and network meta-analysis to assess the comparative efficacy and safety of candidate agents (low-dose aspirin [Asp], high-dose Asp, cyclooxygenase-2 inhibitors [coxibs], calcium, vitamin D, folic acid, ursodeoxycholic acid [UDCA], estrogen, and progesterone, alone or in combination) for preventing colorectal adenoma and CRC. Cochrane risk-of-bias assessment tool was employed to evaluate the quality of each included study. RESULTS: Thirty-two randomized controlled trials (278,694 participants) comparing 13 different interventions were included. Coxibs significantly reduced the risk of colorectal adenoma (risk ratio [RR]: 0.59, 95% confidence interval [CI]: 0.44-0.79, six trials involving 5486 participants), advanced adenoma (RR: 0.63, 95% CI: 0.43-0.92, four trials involving 4723 participants), and metachronous adenoma (RR: 0.58, 95% CI: 0.43-0.79, five trials involving 5258 participants) compared with placebo. Coxibs also significantly increased the risk of severe adverse events (RR: 1.29, 95% CI: 1.13-1.47, six trials involving 7109 participants). Other interventions, including Asp, folic acid, UDCA, vitamin D, and calcium, did not reduce the risk of colorectal adenoma in the general and high-risk populations compared with placebo. CONCLUSIONS: Considering the balance between benefits and harms, regular use of coxibs for prevention of colorectal adenoma was not supported by the current evidence. Benefit of low-dose Asp for chemoprevention of colorectal adenoma still requires further evidence. REGISTRATION PROSPERO, No. CRD42022296376.
Humans ; Cyclooxygenase 2 Inhibitors ; Calcium ; Network Meta-Analysis ; Vitamins ; Colorectal Neoplasms/drug therapy* ; Chemoprevention ; Aspirin ; Adenoma/prevention & control* ; Vitamin D

OBJECTIVES: Percutaneous coronary intervention (PCI) is one of the important methods for the treatment of coronary artery disease (CAD). In-sent restenosis (ISR) after PCI for patients suffered from CAD is considered to be an essential factor affecting long-term outcomes and prognosis of this disease. This study aims to investigate the correlation between plasma Quaking (QKI) and cyclooxygenase-2 (COX-2) levels and ISR in patients with CAD. METHODS: A total of 218 consecutive CAD patients who underwent coronary angiography and coronary arterial stenting from September 2019 to September 2020 in the Department of Cardiology of Xiangya Hospital of Central South University were enrolled in this study, and 35 matched individuals from the physical examination center were served as a control group. After admission, clinical data of these 2 groups were collected. Plasma QKI and COX-2 levels were measured by enzyme linked immunosorbent assay (ELISA). Follow-up angiography was performed 12 months after PCI. CAD patients were divided into a NISR group (n=160) and an ISR group (n=58) according to the occurrence of ISR based on the coronary angiography. The clinical data, coronary angiography, and stent features between the NISR group and the ISR group were compared, and multivariate logistic regression was used to explore the factors influencing ISR. The occurrence of major adverse cardiovascular events (MACE) 1 year after operation was recorded. Fifty-eight patients with ISR were divided into an MACE group (n=24) and a non-MACE group (n=34), classified according to the occurrence of MACE, and the plasma levels of QKI and COX-2 were compared between the 2 groups. Receiver operating characteristic (ROC) curves were utilized to analyze the diagnostic value of plamsa levels of QKI and COX-2 for ISR and MACE occurrences in patients after PCI. RESULTS: Compared with control group, plasma levels of QKI and COX-2 in the CAD group decreased significantly (all P<0.001). Compared with the NISR group, the plasma levels of QKI and COX-2 also decreased obviously in the ISR group (all P<0.001), while the levels of high sensitivity C-reactive protein (hs-CRP) and glycosylated hemoglobin (HbAlc) significantly increased (all P<0.001). The level of COX-2 was negatively correlated with hs-CRP (r=-0.385, P=0.003). Multivariate logistic regression analysis showed that high level of plasma QKI and COX-2 were protective factors for in-stent restenosis after PCI, while hs-CRP was a risk factor. ROC curve analysis showed that the sensitivity and specificity of plasma QKI for evaluating the predictive value of ISR were 77.5% and 66.5%, respectively, and the sensitivity and specificity of plasma COX-2 for evaluating the predictive value of ISR were 80.0% and 70.7%, respectively. The sensitivity and specificity of plasma QKI combined with COX-2 for evaluating the predictive value of ISR were 81.3% and 74.1%, respectively. The sensitivity and specificity of plasma QKI for evaluating the prognosis of ISR were 75.0% and 64.7%, respectively. The sensitivity and specificity of plasma COX-2 for evaluating the prognosis of ISR were 75.0% and 70.6%, respectively. The sensitivity and specificity of plasma QKI combined with COX-2 for prognostic evaluation of ISR were 81.7% and 79.4%, respectively. The sensitivity and specificity of plasma COX-2 combined with QKI for evaluating ISR and MACE occurrences in patients after PCI were better than those of COX-2 or QKI alone (P<0.001). CONCLUSIONS High level of plasma QKI and COX-2 might be a protective factor for ISR, which can also predict ISR patient's prognosis.
C-Reactive Protein/analysis* ; Constriction, Pathologic/etiology* ; Coronary Angiography/adverse effects* ; Coronary Artery Disease ; Coronary Restenosis/therapy* ; Cyclooxygenase 2 ; Humans ; Percutaneous Coronary Intervention/adverse effects* ; Risk Factors ; Stents/adverse effects*

Osteoarthritis is a common disease characterized by degenerative lesions of articular cartilage in the elderly.Fufang Duzhong Jiangu Granulues(FDJG), a classical prescription for the treatment of osteoarthritis, has the effects of nourishing liver and kidney, nourishing blood and sinew, and dredging collaterals and relieving pain.In this study, molecular simulation technology was combined with molecular biology methods to explore and verify the potential pharmacodynamic substances and molecular mechanism of FDJG in the treatment of osteoarthritis.Arachidonic acid(AA) metabolic pathway is a typical anti-inflammatory pathway, and secretory phospholipase A2 group ⅡA(sPLA2-ⅡA), 5-lipoxygenase(5-LOX), cyclooxygenase-2(COX-2), and leukotriene A4 hydrolase(LTA4 H) are the key targets of the pathway.Therefore, in this study, based on the pharmacophores and molecular docking models of the four key targets in AA pathway, a total of 1 522 chemical components in 12 medicinals of FDJG were virtually screened, followed by weighted analysis of the screening results in combination with the proportions of the medicinals in the prescription.The results showed that mainly 73 components in the preparation could act on the above four targets, suggesting they might be the potential anti-osteoarthritis components of FDJG.Considering the predicted effectiveness, availability, and compatibility of the medicinals, coniferyl ferulate, olivil, and baicalin were selected for further verification.Specifically, lipopolysaccharide(LPS)-induced RAW264.7 inflammatory cell model was used to verify the anti-inflammatory activity of the three components.The results showed that the three can effectively inhibit the release of NO, supporting the above selection.In addition, targets 5-LOX, COX-2, and LTA4 H had high activity, which suggested that they may be the key anti-osteoarthritis targets of FDJG.The comprehensive activity values of Eucommiae Cortex, Achyranthis Bidentatae Radix, Ginseng Radix et Rhizoma, Lycii Fructus, and Astragali Radix were much higher than that of other medicinals in the prescription, indicating that they may be the main effective medicinals in FDJG acting on the AA pathway.In this study, the potential anti-osteoarthritis components of FDJG were obtained.Moreover, it was clarified that the anti-osteoarthritis mechanism of FDJG was to act on LOX and COX pathway in AA metabolic pathway, which provided a reference for the study of pharmacodynamic substances and molecular mechanism of FDJG.
Aged ; Anti-Inflammatory Agents/therapeutic use* ; Cyclooxygenase 2/metabolism* ; Drugs, Chinese Herbal/therapeutic use* ; Humans ; Leukotriene A4/analysis* ; Lipopolysaccharides ; Molecular Docking Simulation ; Osteoarthritis/drug therapy* ; Rhizome/chemistry*

The aim of the present study was to investigate the role of ferroptosis in acute lung injury (ALI) mouse model induced by oleic acid (OA). ALI was induced in the mice via the lateral tail vein injection of pure OA. The histopathological score of lung, lung wet-dry weight ratio and the protein content of bronchoalveolar lavage fluid (BALF) were used as the evaluation indexes of ALI. Iron concentration, glutathione (GSH) and malondialdehyde (MDA) contents in the lung tissues were measured using corresponding assay kits. The ultrastructure of pulmonary cells was observed by transmission electron microscope (TEM), and the expression level of prostaglandin-endoperoxide synthase 2 (PTGS2) mRNA was detected by quantitative polymerase chain reaction (q-PCR). Protein expression levels of glutathione peroxidase 4 (GPX4), ferritin and transferrin receptor 1 (TfR1) in lung tissues were determined by Western blot. The results showed that histopathological scores of lung tissues, lung wet-dry weight ratio and protein in BALF in the OA group were higher than those of the control group. In the OA group, the mitochondria of pulmonary cells were shrunken, and the mitochondrial membrane was ruptured. The expression level of PTGS2 mRNA in the OA group was seven folds over that in the control group. Iron overload, GSH depletion and accumulation of MDA were observed in the OA group. Compared with the control group, the protein expression levels of GPX4 and ferritin in lung tissue were down-regulated in the OA group. These results suggest that ferroptosis plays a potential role in the pathogenesis of ALI in our mouse model, which may provide new insights for development of new drugs for ALI.
Acute Lung Injury ; chemically induced ; pathology ; Animals ; Apoptosis ; Bronchoalveolar Lavage Fluid ; chemistry ; Cyclooxygenase 2 ; metabolism ; Ferritins ; metabolism ; Glutathione ; analysis ; Glutathione Peroxidase ; metabolism ; Iron ; analysis ; Iron Overload ; physiopathology ; Lung ; cytology ; pathology ; Malondialdehyde ; analysis ; Mice ; Microscopy, Electron, Transmission ; Mitochondrial Membranes ; ultrastructure ; Oleic Acid

BACKGROUND: Abnormal upregulation of prostaglandin E₂ (PGE₂) is considered to be a key oncogenic event in the development and progression of inflammation-associated human colon cancer. It has been reported that 15-hydroxyprostaglandin dehydrogenase (15-PGDH), an enzyme catabolizing PGE₂, is ubiquitously downregulated in human colon cancer. 15-Deoxy-Δ(12,14)-prostaglandin J₂ (15d-PGJ₂), a peroxisome proliferator-activated receptor γ ligand, has been shown to have anticarcinogenic activities. In this study, we investigate the effect of 15d-PGJ₂ on expression of 15-PGDH in human colon cancer HCT116 cells. METHODS: HCT116 cells were treated with 15d-PGJ₂ analysis. The expression of 15-PGDH in the treated cells was measured by Western blot analysis and RT-PCR. In addition, the cells were subjected to a 15-PGDH activity assay. To determine which transcription factor(s) and signaling pathway(s) are involved in 15d-PGJ₂-induced 15-PGDH expression, we performed a cDNA microarray analysis of 15d-PGJ₂-treated cells. The DNA binding activity of AP-1 was measured by an electrophoretic mobility shift assay. To determine whether the AP-1 plays an important role in the 15d-PGJ₂-induced 15-PGDH expression, the cells were transfected with siRNA of c-Jun, a major subunit of AP-1. To elucidate the upstream signaling pathways involved in AP-1 activation by 15d-PGJ₂, we examined its effect on phosphorylation of Akt by Western blot analysis in the presence or absence of kinase inhibitor. RESULTS: 15d-PGJ₂ (10 μM) significantly upregulated 15-PGDH expression at the mRNA and protein levels in HCT-116 cells. 15-PGDH activity was also elevated by 15d-PGJ₂. We observed that genes encoding C/EBP delta, FOS-like antigen 1, c-Jun, and heme oxygenase-1 (HO-1) were most highly induced in the HCT116 cells following 15d-PGJ₂ treatment. 15d-PGJ₂ increased the DNA binding activity of AP-1. Moreover, transfection with specific siRNA against c-Jun significantly reduced 15-PGDH expression induced by 15d-PGJ₂. 15d-PGJ₂ activates Akt and a pharmacological inhibitor of Akt, LY294002, abrogated 15d-PGJ₂-induced 15-PGDH expression. We also observed that an inhibitor of HO-1, zinc protoporphyrin IX, also abrogated upregulation of 15-PGDH and down-regulation of cyclooxygenase-2 expression induced by 15d-PGJ₂. CONCLUSIONS: These finding suggest that 15d-PGJ₂ upregulates the expression of 15-PGDH through AP-1 activation in colon cancer HCT116 cells.
Blotting, Western ; Colon ; Colonic Neoplasms ; Cyclooxygenase 2 ; DNA ; Down-Regulation ; Electrophoretic Mobility Shift Assay ; HCT116 Cells ; Heme Oxygenase-1 ; Heme ; Humans ; Oligonucleotide Array Sequence Analysis ; Oxidoreductases ; Peroxisomes ; Phosphorylation ; Phosphotransferases ; RNA, Messenger ; RNA, Small Interfering ; Transcription Factor AP-1 ; Transfection ; Up-Regulation ; Zinc

BACKGROUND/OBJECTIVES: One of the mechanisms considered to be prevalent in the development of Alzheimer's disease (AD) is hyper-stimulation of microglia. Black chokeberry (Aronia melanocapa L.) is widely used to treat diabetes and atherosclerosis, and is known to exert anti-oxidant and anti-inflammatory effects; however, its neuroprotective effects have not been elucidated thus far. MATERIALS/METHODS: We undertook to assess the anti-inflammatory effect of the ethanolic extract of black chokeberry friut (BCE) in BV2 cells, and evaluate its neuroprotective effect in the lipopolysaccharide (LPS)-induced mouse model of AD. RESULTS: Following stimulation of BV2 cells by LPS, exposure to BCE significantly reduced the generation of nitric oxide as well as mRNA levels of numerous inflammatory factors such as inducible nitric oxide synthase (iNOS), cyclooxygenase 2 (COX-2), interleukin 1 beta (IL-1β), and tumor necrosis factor alpha (TNF-α). In addition, AD was induced in a mouse model by intraperitoneal injection of LPS (250 µg/kg), subsequent to which we investigated the neuroprotective effects of BCE (50 mg/kg) on brain damage. We observed that BCE significantly reduced tissue damage in the hippocampus by downregulating iNOS, COX-2, and TNF-α levels. We further identified the quinic acids in BCE using liquid chromatography-mass spectrometry (LCMS). Furthermore, we confirmed the neuroprotective effect of BCE and quinic acid on amyloid beta-induced cell death in rat hippocampal primary neurons. CONCLUSIONS: Our findings suggest that black chokeberry has protective effects against the development of AD.
Alzheimer Disease ; Amyloid ; Animals ; Atherosclerosis ; Brain ; Cell Death ; Cyclooxygenase 2 ; Ethanol ; Hippocampus ; Inflammation ; Injections, Intraperitoneal ; Interleukin-1beta ; Mice ; Mice, Inbred ICR ; Microglia ; Neurons ; Neuroprotective Agents ; Nitric Oxide ; Nitric Oxide Synthase Type II ; Phytochemicals ; Quinic Acid ; Rats ; RNA, Messenger ; Spectrum Analysis ; Tumor Necrosis Factor-alpha

PURPOSE: The purpose of this study was to determine the impact of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), statin, and cyclooxygenase 2 (COX-2) inhibitor on the development of kidney, prostate, and urothelial cancers by analyzing the Korean National Health Insurance Service–National Sample Cohort (NHIS-NSC) database. MATERIALS AND METHODS: Among a representative sample cohort of 1,025,340 participants in NHIS-NSC database in 2002, we extracted data of 799,850 individuals who visited the hospital more than once, and finally included 321,122 individuals aged 40 and older. Following a 1-year washout period between 2002 and 2003, we analyzed 143,870 (male), 320,861 and 320,613 individuals for evaluating the risk of prostate cancer, kidney cancer and urothelial cancer developments, respectively, during 10-year follow-up periods between 2004 and 2013. The medication group consisted of patients prescribed these drugs more than 60% of the time in 2003. To adjustfor various parameters of the patients, a multivariate Cox regression model was adopted. RESULTS: During 10-year follow-up periods between 2004 and 2013, 9,627 (6.7%), 1,107 (0.4%), and 2,121 (0.7%) patients were diagnosed with prostate cancer, kidney cancer, and urothelial cancer, respectively. Notably, multivariate analyses revealed that NSAIDs significantly increased the risk of prostate cancer (hazard ratio [HR], 1.35). Also, it was found that aspirin (HR, 1.28) and statin (HR, 1.55) elevated the risk of kidney cancer. No drugs were associated with the risk of urothelial cancer. CONCLUSION: In sum, our study provides the valuable information for the impact of aspirin, NSAID, statin, and COX-2 inhibitor on the risk of prostate, kidney, and urothelial cancer development and its survival outcomes.
Anti-Inflammatory Agents ; Anti-Inflammatory Agents, Non-Steroidal ; Aspirin* ; Cohort Studies ; Cyclooxygenase 2 ; Follow-Up Studies* ; Humans ; Hydroxymethylglutaryl-CoA Reductase Inhibitors* ; Kidney ; Kidney Neoplasms ; Korea* ; Multivariate Analysis ; National Health Programs ; Prostate ; Prostatic Neoplasms

Dendrobii Caulis (DC), named 'Shihu' in Chinese, is a precious herb in traditional Chinese medicine. It is widely used to nourish stomach, enhance body fluid production, tonify "Yin" and reduce heat. More than thirty Dendrobium species are used as folk medicine. Some compounds from DC exhibit inhibitory effects on macrophage inflammation. In the present study, we compared the anti-inflammatory effects among eight Dendrobium species. The results provided evidences to support Dendrobium as folk medicine, which exerted its medicinal function partially by its inhibitory effects on inflammation. To investigate the anti-inflammatory effect of Dendrobium species, mouse macrophage cell line RAW264.7 was activated by lipopolysaccharide. The nitric oxide (NO) level was measured using Griess reagent while the pro-inflammatory cytokines were tested by ELISA. The protein expressions of inducible NO synthase (iNOS), cyclooxygenase-2 (COX-2) and mitogen-activated protein kinases (MAPKs) phosphorylation were evaluated by Western blotting analysis. Among the eight Dendrobium species, both water extracts of D. thyrsiflorum B.S.Williams (DTW) and D. chrysotoxum Lindl (DCHW) showed most significant inhibitory effects on NO production in a concentration-dependent manner. DTW also significantly reduced TNF-α, MCP-1, and IL-6 production. Further investigations showed that DTW suppressed iNOS and COX-2 expression as well as ERK and JNK phosphorylation, suggesting that the inhibitory effects of DTW on LPS-induced macrophage inflammation was through the suppression of MAPK pathways. In conclusion, D. thyrsiflorum B.S.Williams was demonstrated to have potential to be used as alternative or adjuvant therapy for inflammation.
Animals ; Anti-Inflammatory Agents ; pharmacology ; Cyclooxygenase 2 ; genetics ; Cytokines ; metabolism ; Dendrobium ; chemistry ; Gene Expression Regulation, Enzymologic ; drug effects ; Inflammation ; chemically induced ; drug therapy ; Lipopolysaccharides ; Macrophages ; drug effects ; enzymology ; Mice ; Mitogen-Activated Protein Kinases ; antagonists & inhibitors ; genetics ; metabolism ; Nitric Oxide ; analysis ; Nitric Oxide Synthase Type II ; genetics ; Phosphorylation ; drug effects ; Plant Extracts ; pharmacology ; RAW 264.7 Cells ; Signal Transduction ; drug effects

We have previously reported that NS-398, a cyclooxygenase-2 (COX-2)–selective inhibitor, inhibited replicative cellular senescence in human dermal fibroblasts and skin aging in hairless mice. In contrast, celecoxib, another COX-2–selective inhibitor, and aspirin, a non-selective COX inhibitor, accelerated the senescence and aging. To figure out causal factors for the senescence-modulating effect of the inhibitors, we here performed cDNA microarray experiment and subsequent Gene Set Enrichment Analysis. The data showed that several senescence-related gene sets were regulated by the inhibitor treatment. NS-398 up-regulated gene sets involved in the tumor necrosis factor β receptor pathway and the fructose and mannose metabolism, whereas it down-regulated a gene set involved in protein secretion. Celecoxib up-regulated gene sets involved in G2M checkpoint and E2F targets. Aspirin up-regulated the gene set involved in protein secretion, and down-regulated gene sets involved in RNA transcription. These results suggest that COX inhibitors modulate cellular senescence by different mechanisms and will provide useful information to understand senescence-modulating mechanisms of COX inhibitors.
Aging ; Animals ; Aspirin ; Celecoxib ; Cell Aging ; Cyclooxygenase 2 ; Fibroblasts* ; Fructose ; Gene Expression* ; Genes, vif ; Humans* ; Mannose ; Metabolism ; Mice ; Mice, Hairless ; Oligonucleotide Array Sequence Analysis ; RNA ; Skin Aging ; Tumor Necrosis Factor-alpha

OBJECTIVE: This study was performed to assess the cost-effectiveness of cyclooxygenase-2 (COX2)-selective inhibitor, non-selective non-steroidal anti-inflammatory drugs (NSAIDs), and non-selective NSAID with proton pump inhibitors (PPIs) while considering upper and lower gastrointestinal (GI) safety in patients with rheumatoid arthritis (RA). METHODS: A Markov model was used to estimate the costs and effectiveness. Estimates of therapeutic efficacy and upper/lower GI safety were based on results from large randomized controlled trials. The main outcome measure was cost effectiveness, based on the quality-adjusted life years (QALYs) gained. Safety parameters included clinical upper GI symptoms, uncomplicated ulcer, upper GI bleeding, upper GI perforation, clinical lower GI symptoms, lower GI bleeding, and lower GI perforation. Cost data were obtained from patients treated in a tertiary referral center in Korea. RESULTS: The expected three year cost was 3,052,800 Korean won (KRW) for COX2-selective inhibitor, 3,170,800 KRW for nonselective NSAID, and 3,325,900 KRW for non-selective NSAID with PPI. QALYs were 2.87446, 2.85320, and 2.85815, respectively. The total cost for COX2-selective inhibitor use was lower than non-selective NSAID, but QALY was higher, indicating that the incremental cost effectiveness ratio of COX2-selective inhibitor is superior. CONCLUSION: COX2-selective inhibitor has reasonable cost-effectiveness adjusted for upper and lower GI toxicity for patients with RA in Korea.
Arthritis, Rheumatoid* ; Cost-Benefit Analysis ; Cyclooxygenase 2 ; Hemorrhage ; Humans ; Korea ; Outcome Assessment (Health Care) ; Proton Pump Inhibitors ; Quality-Adjusted Life Years ; Tertiary Care Centers ; Ulcer