Cyclooxygenase-2/prostaglandin E2 pathway regulates infectious bronchitis virus replication in avian macrophages.

Infectious bronchitis virus (IBV) is a significant respiratory pathogen that affects chickens worldwide. As an avian coronavirus, IBV leads to productive infection in chicken macrophages. However, the effects of IBV infection in macrophages on cyclooxygenase-2 (COX-2) expression are still to be elucidated. Therefore, we investigated the role of IBV infection on the production of COX-2, an enzyme involved in the synthesis of prostaglandin E2 (PGE2) in chicken macrophages. The chicken macrophage cells were infected with two IBV strains, and the cells and culture supernatants were harvested at predetermined time points to measure intracellular and extracellular IBV infection. IBV infection was quantified as has been the COX-2 and PGE2 productions. We found that IBV infection enhances COX-2 production at both mRNA and protein levels in chicken macrophages. When a selective COX-2 antagonist was used to reduce the COX-2 expression in macrophages, we observed that IBV replication decreased. When IBV-infected macrophages were treated with PGE2 receptor (EP2 and EP4) inhibitors, IBV replication was reduced. Upon utilizing a selective COX-2 antagonist to diminish PGE2 expression in macrophages, a discernible decrease in IBV replication was observed. Treatment of IBV-infected macrophages with a PGE2 receptor (EP2) inhibitor resulted in a reduction in IBV replication, whereas the introduction of exogenous PGE2 heightened viral replication. Additionally, pretreatment with a Janus-kinase two antagonist attenuated the inhibitory effect of recombinant chicken interferon (IFN)-γ on viral replication. The evaluation of immune mediators, such as inducible nitric oxide (NO) synthase (iNOS), NO, and interleukin (IL)-6, revealed enhanced expression following IBV infection of macrophages. In response to the inhibition of COX-2 and PGE2 receptors, we observed a reduction in the expressions of iNOS and IL-6 in macrophages, correlating with reduced IBV infection. Overall, IBV infection increased COX-2 and PGE2 production in addition to iNOS, NO, and IL-6 expression in chicken macrophages in a time-dependent manner. Inhibition of the COX-2/PGE2 pathway may lead to increased macrophage defence mechanisms against IBV infection, resulting in a reduction in viral replication and iNOS and IL-6 expressions. Understanding the molecular mechanisms underlying these processes may shed light on potential antiviral targets for controlling IBV infection.

Combination Nano-Delivery Systems Remodel the Immunosuppressive Tumor Microenvironment for Metastatic Triple-Negative Breast Cancer Therapy.

Triple-negative breast cancer (TNBC) is an aggressive type of breast cancer for which effective therapies are lacking. Targeted remodeling of the immunosuppressive tumor microenvironment (TME) and activation of the body's immune system to fight tumors with well-designed nanoparticles have emerged as pivotal breakthroughs in tumor treatment. To simultaneously remodel the immunosuppressive TME and trigger immune responses, we designed two potential therapeutic nanodelivery systems to inhibit TNBC. First, the bromodomain-containing protein 4 (BRD4) inhibitor JQ1 and the cyclooxygenase-2 (COX-2) inhibitor celecoxib (CXB) were coloaded into chondroitin sulfate (CS) to obtain CS@JQ1/CXB nanoparticles (NPs). Then, the biomimetic nanosystem MM@P3 was prepared by coating branched polymer poly(ß-amino ester) self-assembled NPs with melittin embedded macrophage membranes (MM). Both in vitro and in vivo, the CS@JQ1/CXB and MM@P3 NPs showed excellent immune activation efficiencies. Combination treatment exhibited synergistic cytotoxicity, antimigration ability, and apoptosis-inducing and immune activation effects on TNBC cells and effectively suppressed tumor growth and metastasis in TNBC tumor-bearing mice by activating the tumor immune response and inhibiting angiogenesis. In summary, this study offers a novel combinatorial immunotherapeutic strategy for the clinical TNBC treatment.

Celecoxib alleviates nociceptor sensitization mediated by interleukin-1beta-primed annulus fibrosus cells.

PURPOSE: This study aims to analyze the effect of pro-inflammatory cytokine-stimulated human annulus fibrosus cells (hAFCs) on the sensitization of dorsal root ganglion (DRG) cells. We further hypothesized that celecoxib (cxb) could inhibit hAFCs-induced DRG sensitization. METHODS: hAFCs from spinal trauma patients were stimulated with TNF-α or IL-1ß. Cxb was added on day 2. On day 4, the expression of pro-inflammatory and neurotrophic genes was evaluated using RT-qPCR. Levels of prostaglandin E2 (PGE-2), IL-8, and IL-6 were measured in the conditioned medium (CM) using ELISA. hAFCs CM was then applied to stimulate the DRG cell line (ND7/23) for 6 days. Then, calcium imaging (Fluo4) was performed to evaluate DRG cell sensitization. Both spontaneous and bradykinin-stimulated (0.5 µM) calcium responses were analyzed. The effects on primary bovine DRG cell culture were performed in parallel to the DRG cell line model. RESULTS: IL-1ß stimulation significantly enhanced the release of PGE-2 in hAFCs CM, while this increase was completely suppressed by 10 µM cxb. hAFCs revealed elevated IL-6 and IL-8 release following TNF-α and IL-1ß treatment, though cxb did not alter this. The effect of hAFCs CM on DRG cell sensitization was influenced by adding cxb to hAFCs; both the DRG cell line and primary bovine DRG nociceptors showed a lower sensitivity to bradykinin stimulation. CONCLUSION: Cxb can inhibit PGE-2 production in hAFCs in an IL-1ß-induced pro-inflammatory in vitro environment. The cxb applied to the hAFCs also reduces the sensitization of DRG nociceptors that are stimulated by the hAFCs CM.

Сyclooxygenase-2 Inhibitor Parecoxib Reduces LPS-Induced Activation of BV2 Microglia Cells.

We studied the inhibitory effect of cyclooxygenase-2 inhibitor parecoxib on LPS-induced activation of BV2 microglia cells. The optimal dose of parecoxib (80 µmol/liter) was evaluated by the Cell Counting Kit-8. The cells were divided into the following groups: control (intact cells without treatment); LPS (treatment with 1 µg/ml LPS for 6 h), and experimental (pretreatment with 80 µmol/liter parecoxib for 24 h followed by incubation with 1 µg/ml LPS for 6 h). Cell morphology and proliferation and the expression of NLRP3, caspase-1, pro-caspase-1, and IL-1ß were assessed. LPS induced significant morphological changes and decreased proliferation of primary BV2 cells in comparison with the control. These changes were prevented by parecoxib pretreatment. LPS significantly increased NLRP3 inflammatory vesicle activation and expression of NLRP3, caspase-1, pro-caspase-1, and IL-1ß in comparison with the control group; pretreatment with parecoxib prevented all these changes. Our results suggest that pretreatment with parecoxib inhibited LPS-induced activation of BV2 microglial cells and probably inhibited NLRP3 inflammasome activation.

Cyclooxygenase-2 inhibitor rofecoxib prevents chondrocytes against hypertrophy via Wnt/ß-catenin pathway.

Previous reports indicated that specific cyclooxygenase-2 (COX-2) inhibitor suppresses osteoarthritis (OA). This study aimed to further explore the possible mechanism of Rofecoxib as a COX-2 inhibitor on the inhibition of chondrocyte (CH) hypertrophic development and tested the optimal treatment of Rofecoxib on CH. Basically, IL-1ß was used as a stimulus to establish a degenerated CH model. Immunofluorescence, Western blot, and RT-PCR were performed to determine the gene expression of Axin2, ß-catenin, GSK3ß, collagen X, collagen II, COX-2, PGE-2, SOX-9, Runx-2, and MMP- 13 expression. Cell Counting Kit (CCK-8) assay was used to analyze the viability of CHs. The data indicated that Rofecoxib significantly inhibited COX-2 expression and had less harmful effects on CH viability. Rofecoxib reversed the IL-1ß-induced upregulation of collagen X, COX-2, PGE-2, Runx-2, and MMP-13 expression, and promoted the viability of collagen II, SOX-9 expression of CHs. Furthermore, Rofecoxib suppressed Axin2, ß-catenin, and GSK3ß expression of the Wnt pathway, which was activated by IL-1ß or human recombinant Wnt-1 protein treatment. Therefore, Rofecoxib is an effective COX-2 inhibitor that protects CHs from hypertrophy by suppression of the Wnt/ß-catenin pathway.

Suppressive Effects of Ursolic Acid on Human Endometriotic Stromal Cells Survival.

BACKGROUND/AIMS: The identification of new compound candidates for endometriosis treatment is needed. Cyclooxygenase-2 (COX-2) is considered a crucial target to control the progress and recurrence of endometriosis. Here, we identified ursolic acid (UA) as a natural inhibitor of COX-2 and investigated its effects on endometriosis progression. METHODS: Primary human endometriotic stromal cells isolated from patients with endometriosis were exposed to UA at concentrations of 15, 30, 45, and 60 µM. 3-(4,5-Dimethylthiaziazol-2-yl)-2,5-diphenyl tetrazolium bromide assays, 5'-bromo-2'-deoxy-uridine assays, and Caspase-3 activity measurements were performed to detect cell growth and apoptosis. Enzyme-linked immunosorbent assays were used to detect COX-2 and vascular endothelial growth factor (VEGF) protein expression and prostaglandin E2 (PGE2) levels. Capillary-tubule formation assays using human umbilical vein endothelial cells were also carried out to determine angiogenesis. RESULTS: UA significantly decreased cell viability, inhibited proliferation, and increased caspase-3 activity in a dose-dependent manner. COX-2 protein expression and the subsequent PGE2 production were both reduced by UA. Meanwhile, UA exposure decreased VEGF secretion in the stromal cells and the capillary-tubule formation assay confirmed the inhibitory effect of UA on angiogenesis. Furthermore, UA increased the phosphorylation of c-Jun N-terminal kinase and p38. CONCLUSIONS: Our data suggest that UA plays a role as a natural inhibitor of COX-2 to control the survival of human endometriotic stromal cells by inhibiting proliferation and angiogenesis and promoting apoptosis.

Biochemical control of the combination of cyclooxygenase-2 inhibitor and 125 I-brachytherapy for prostate cancer: Post hoc analysis of an open-label controlled randomized trial.

OBJECTIVES: To evaluate the use of cyclooxygenase-2 inhibitors in patients receiving low-dose-rate brachytherapy for prostate cancer. METHODS: A total of 310 patients with prostate cancer (cT1c-3aN0M0) who received low-dose-rate brachytherapy between May 2010 and July 2013 were enrolled and allocated to one of the two treatment groups (tamsulosin alone 0.2 mg/day for 6 months vs tamsulosin 0.2 mg/day for 6 months plus celecoxib 200 mg/day for 3 months). The primary end-point was the chronological change in international prostate symptom score, and the number of patients was assessed for the primary end-point. Biochemical recurrence-free, cancer-specific survival and overall survival rates 5 years after the last patient received low-dose-rate brachytherapy were retrospectively examined. RESULTS: The median follow-up period after low-dose-rate brachytherapy was 72.0 months (range 3-99 months). A total of 12 (3.9%) patients experienced biochemical recurrence. The biochemical recurrence-free rate in the celecoxib group (5-year biochemical recurrence-free rate 98.5%) was significantly better (log-rank test P = 0.023, 95% confidence interval 0.07-0.63, hazard ratio 0.20) than that in the tamsulosin group (5-year biochemical recurrence-free rate 93.4%). None of the patients died from prostate cancer. However, 14 (4.5%) patients died of other causes. No significant difference was observed in terms of overall survival between the celecoxib and tamsulosin groups. CONCLUSIONS: The combination of cyclooxygenase-2 inhibitor and low-dose-rate brachytherapy can contribute to a better biochemical control of prostate cancer.

Preventative effect of celecoxib in dimethylbenz[a]anthracene-induced ovarian cancer in rats.

PURPOSE: The present study investigated the preventive effect of the cyclooxygenase (COX)-2 inhibitor, celecoxib, in 7,12-dimethylbenz[a]anthracene (DMBA)-induced ovarian cancer in a rat model. METHODS: A diet containing celecoxib (1500 ppm) was started 2 weeks before the introduction of DMBA. DMBA-soaked cotton threads were surgically applied to induce ovarian cancer in female Wistar rats. Tumor growth and survival were observed for 24 weeks. RESULTS: During the study period, an overall tumor incidence of 97.5% was observed and 65% of tumors were ovarian adenocarcinoma. The celecoxib diet significantly reduced the incidence and size of DMBA-induced ovarian cancers and significantly improved survival of tumor-bearing rats. The preventive effect of celecoxib was associated with increased apoptosis. CONCLUSION: DMBA-induced ovarian cancer in rats recapitulates many pathophysiological features of the human counterpart. Our results provide supportive evidence that celecoxib has a preventive effect on development of ovarian cancer in a rat model.

Celecoxib Down-Regulates the Hypoxia-Induced Expression of HIF-1α and VEGF Through the PI3K/AKT Pathway in Retinal Pigment Epithelial Cells.

BACKGROUND/AIMS: The goal of this study was to detect the expression of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) in human retinal pigmented epithelial (RPE) cells treated with celecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor, under hypoxic and normoxic conditions and to explore the signaling mechanism involved in regulating the hypoxia-induced expression of HIF-1α and VEGF in RPE cells. METHODS: D407 cells were cultured in normoxic or hypoxic conditions, with or without celecoxib or a PI3K inhibitor (LY294002). The anti-proliferative effect of celecoxib was assessed using the MTT assay. RT-PCR, Western blotting and ELISA were performed to detect the levels of PI3K, phosphorylated AKT (p-AKT), HIF-1α, VEGF and COX-2. RESULTS: Celecoxib inhibited the proliferation of RPE cells in a dose-dependent manner. Celecoxib suppressed the expression of VEGF at both the mRNA and protein levels and decreased HIF-1α protein expression. HIF-1α activation was regulated by the PI3K/AKT pathway. The celecoxib-induced down-regulation of HIF-1α and VEGF required the suppression of the hypoxia-induced PI3K/AKT pathway. However, the down-regulation of COX-2 did not occur in cells treated with celecoxib. CONCLUSIONS: The antiangiogenic effects of celecoxib in RPE cells under hypoxic conditions resulted from the inhibition of HIF-1α and VEGF expression, which may be partly mediated by a COX-2-independent, PI3K/AKT-dependent pathway.

Tumor-Associated Macrophages in the Development of 4-Nitroquinoline-1-Oxide-Induced Tongue Squamous Cell Carcinoma in a Mouse Model.

OBJECTIVE: We aimed to determine the distribution of tumor-associated macrophages (TAMs) in the development of tongue squamous cell carcinoma (SCC) and to elucidate the role of TAMs in the progression of tongue SCC. METHODS: The expression of the macrophage markers nitric oxide synthase, Retnla, and mannose receptor 1 in the development of tongue SCC was longitudinally observed using real-time quantitative polymerase chain reaction. Additionally, an immunohistochemical study using an anti-mannose receptor (MR) antibody was performed. RESULTS: The numbers of both of M1 and M2 macrophages in the tongues of mice treated with 4-nitroquinoline-1-oxide (4NQO) were significantly lower compared with those of normal tongues. The cyclooxygenase-2 (COX-2) inhibitor did not prevent cancer progression and did not affect the total number of macrophages in the tongues of 4NQO-treated mice. In the immunohistochemical studies, MR staining was observed in lymphangioendothelium in the subepithelial area of the tongues. The staining intensity of the MR was significantly stronger in the 4NQO-treated mice compared with that in control mice and 4NQO-treated mice treated with the COX-2 inhibitor. CONCLUSION: TAMs may not contribute to the development of 4NQO-induced tongue SCC. MR expression is associated with the progression of 4NQO-induced tongue SCC.

Proton Pump Inhibitors Increase Incidence of Nonsteroidal Anti-Inflammatory Drug-Induced Small Bowel Injury: A Randomized, Placebo-Controlled Trial.

BACKGROUND & AIMS: Some studies have reported a high incidence of small bowel injuries in 60%-80% of subjects who take nonselective nonsteroidal anti-inflammatory drugs and PPIs simultaneously. We performed a randomized, double-blind, controlled study to determine whether proton pump inhibitors (PPIs) exacerbate nonsteroidal anti-inflammatory drug-induced small bowel injury. METHODS: Fifty-seven healthy subjects were randomly assigned groups given the cyclooxygenase (COX) 2 inhibitor celecoxib (200 mg, twice daily) plus placebo for 2 weeks (COX-2 + placebo group, n = 30), or celecoxib plus the PPI rabeprazole (20 mg, once daily) for 2 weeks (COX-2 + PPI group, n = 27). The study was performed from October 2012 through September 2013 at a tertiary medical center in Japan. All subjects were evaluated by capsule endoscopy at the start of the study and then after 2 weeks administration of celecoxib with rabeprazole or placebo. The incidence rates and the numbers of small bowel injuries (ulcers and erosions) that were observed under capsule endoscopy were compared between groups. The primary endpoint was the incidence of mucosal injuries at the second capsule endoscopy examination. RESULTS: A significantly higher proportion of subjects in the COX-2 + PPI group developed small bowel injury (12 of 27 subjects; 44.4%) than in the COX-2 + placebo group (5 of 30 subjects; 16.7%; P = .04). Subjects in the COX-2 + PPI group had a significant increase in risk of small bowel injury compared with the COX-2 + placebo group (relative risk, 2.67; 95% confidence interval, 1.08-6.58). The number of erosions in each member of the COX-2 + PPI group was greater than in each member of the COX-2 + placebo group (P = .02). The number of ulcers did not differ between groups. Twenty-six percent of subjects in the COX-2 + PPI group developed mucosal injury in the jejunum, compared with none of the subjects in the COX-2 + placebo group (P = .003); no such trend was found in the ileum. CONCLUSIONS: In a randomized, controlled trial, PPIs increased the risk of short-term nonsteroidal anti-inflammatory drug-induced small bowel injury. UMIN clinical trial registry number: UMIN000008883.

Effect of perioperative parecoxib sodium on postoperative pain control for transcatheter arterial chemoembolization for inoperable hepatocellular carcinoma: a prospective randomized trial.

OBJECTIVES: Pain is one of the most common side effects of transcatheter arterial chemoembolization (TACE) treatment. This study aimed to assess the analgesic effect of parecoxib sodium for postoperative pain control in patients with inoperable hepatocellular carcinoma (HCC) undergoing TACE. MATERIALS AND METHODS: This randomized placebo-controlled prospective clinical study was conducted at a single cancer centre. Patients were randomly assigned to receive parecoxib sodium (experimental group; n = 60) or 0.9 % sodium chloride (control group; n = 60) 1 h before TACE and once every 12 h for 2 days after TACE. Pain level, morphine consumption, adverse events, and quality of life were evaluated and compared between the two groups. RESULTS: Pain scores, percentage distribution of pain categories, and morphine consumption were significantly lower in the experimental group than in the control group (P < 0.05). Fever score comparisons revealed significantly better body temperature balance in the experimental group than in the control group (P = 0.024). Quality-of-life scores in the experimental group were significantly better than those in the control group (P < 0.05). CONCLUSIONS: Our results demonstrate that the perioperative administration of parecoxib significantly improved its effectiveness in the control of postoperative pain after TACE. KEY POINTS: • Perioperative administration of parecoxib is effective for control of pain after TACE. • COX-2 inhibitors provide effective and safe pain control. • Parecoxib helps improve quality-of-life after TACE for patients with inoperable hepatocellular carcinoma.

Complete remission of pancreatic head desmoid tumor treated by COX-2 inhibitor-a case report.

BACKGROUND: Desmoid tumors (DTs) are non-metastatic, locally aggressive neoplasms with high postoperative recurrence rates. The pancreas is an extremely rare location for DTs. The local control of DTs is challenging. Surgery and radiotherapy are currently the principal treatment modalities for DTs; however, some resections might not be radical, and radiotherapy has several drawbacks. Therefore, many studies have been focusing on the molecular pathways involved in DTs in order to develop molecular-targeted therapies or chemotherapy. Cyclooxygenase-2 (COX-2) has been demonstrated to play a role in the growth of DTs, and the pharmacologic blockade of COX resulted in decreased cell proliferation in desmoid cell cultures in vitro. CASE PRESENTATION: Herein, we report a 57-year-old woman who presented with recurrent epigastric pain and weight loss. An abdominal computed tomography scan showed an approximately 10-cm mass over the pancreatic head region and dilatation of the pancreatic duct. Tumor biopsy and bypass surgery were performed. A DT was confirmed on pathologic analysis. After resection, we prescribed treatment with the COX-2 inhibitor celecoxib. The patient showed complete remission and there was no local recurrence or distant metastasis within the 24-month follow-up period. CONCLUSIONS: The outcome of this case study is encouraging, and long-term follow-up studies are required to establish the effect of treatment with celecoxib on the prognosis of DTs.

Novel strategy for cystitis glandularis: Oral treatment with cyclooxygenase-2 inhibitor.

Cystitis glandularis, a proliferative disease of the bladder, is resistant to antibiotics, non-steroidal anti-inflammatory drugs, anti-allergy drugs and transurethral resection. Cystectomy or partial cystectomy is occasionally required for refractory cystitis glandularis. It has not been defined if cystitis glandularis is a premalignant lesion. We experienced a case of remission from cystitis glandularis after combination of oral treatment with selective cyclooxygenase-2 inhibitor, celecoxib and transurethral resection. Immunohistochemistry showed positive signals of cyclooxygenase-2 in the epithelium of pretreatment specimens, suggesting the pathophysiological role of cyclooxygenase-2 in cystitis glandularis. Here, we show the effectiveness of celecoxib against cystitis glandularis for the first time. Celecoxib could be one of the therapeutic strategies for cystitis glandularis.

Safety and Efficacy Study of the Cyclooxygenase-2 Inhibitor Parecoxib Sodium Applied for Postoperative Analgesia After Endo-Nasal Operation.

OBJECTIVE: To evaluate the safety and efficacy of the cyclooxygenase-2 inhibitor parecoxib sodium after endo-nasal operation. METHODS: Patients aged 18 to 55 years with body mass index (BMI) ≤25 and ASAI~II who were undergoing endo-nasal operation were randomly allocated to receive either i.v. parecoxib sodium 40 mg or i.v. placebo (saline) 2 mL 15 minutes before induction of anesthesia. The magnitude of pain was measured using the visual analogue scale (VAS) and recorded on awakening, then at interval of 1, 2, 4, 6, 8, 12, and 24 hours after operation. Safety evaluation including nausea, vomiting, dry mouth, drowsiness, urinary retention, respiratory depression, surgical site bleeding, and so on was assessed. The patients' satisfaction of the postoperative analgesia was recorded and compared between the 2 groups. RESULTS: A total of 64 patients were enrolled in the study, including 31 in parecoxib group and 33 in placebo group. The VAS scores at 1, 2, 4, 6, 8 hours after operation were significantly lower in parecoxib group than in placebo group (P < 0.05). The P values were 0.002, <0.001, 0.001 at 2, 4, 6 hours after operation, respectively. The percentage of the patients who considered the postoperative analgesia "good" or "excellent" was 45.2% in parecoxib group and 9.1% in placebo group. There were no serious side effects in both groups. CONCLUSIONS: Parecoxib sodium was effective and safe when used for postoperative analgesia in endo-nasal operation.

Synergistic effect of simvastatin plus NS398 on inhibition of proliferation and survival in hepatocellular carcinoma cell line.

BACKGROUND AND AIMS: NS398, a selective cyclooxygenase-2 inhibitor, and simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, both exert an anticancer effect on hepatocellular carcinoma cells, but the effect of co-administration of the two drugs remains unknown. We aimed to investigate the synergistic in vitro anticancer effect of co-administration of NS398 and simvastatin and its mechanism. METHODS: The Hep3B and Huh-7 cell lines were cultured. Cells were treated with simvastatin, NS398, or a combination. 5-bromo-2'-deoxyuridine ELISA assay, flow cytometry, Western blot analyses, and immunofluorescence assay were performed. RESULTS: In both cell lines, co-administration of simvastatin and NS398 resulted in a greater effect on proliferation and apoptosis. In Hep3B cells, co-administration of the two drugs resulted in a greater decrease in procaspase 3 and Bcl-2 and an increase in cleaved caspase 9 than that noted with monotherapy. In Huh-7 cells, co-administration of the two drugs resulted in a greater decrease in procaspase 3 and cyclin D1 and an increase in cleaved caspase 9. Expression of NF-κB and Akt were also decreased to a greater extent when the two drugs were co-administered in both cell lines. Immunofluorescence assay showed suppression of the nuclear localization of NF-κB by simvastatin or NS398. The effect was greater by co-administration. CONCLUSIONS: The co-administration of NS398 and simvastatin produced greater antiproliferative and proapoptotic effects against Hep3B cells and Huh-7 cells. Inhibition of the NF-κB and Akt pathway and activation of caspase cascade, which are considered as the major mechanism of synergistic anticancer properties, were observed in both cell lines.

The impact of cyclooxygenase inhibitor use on urinary prostaglandin metabolites in preterm infants.

BACKGROUND: There is limited evidence on the association between the clinical course of patent ductus arteriosus (PDA) and prostaglandin (PG) metabolites. This study aimed to determine the influence of PDA treatment on urinary PG metabolite excretion in very-low-birth-weight (VLBW) infants. METHODS: Urine samples were collected from 25 VLBW infants at 1, 3, and 7 days of age. Infants were separated into two groups: a PDA-treated group that received a cyclooxygenase-2 (COX) inhibitor (n = 12) and a control group that did not receive a COX inhibitor during the first 7 days after birth (n = 13). Urinary PG metabolite tetranor prostaglandin E2 metabolite (t-PGEM) and tetranor prostaglandin D2 metabolite (t-PGDM) levels were analyzed using liquid chromatography-tandem mass spectrometry. RESULTS: Urinary t-PGEM excretion levels were not significantly different between the groups at 1, 3, and 7 days of age. Urinary t-PGDM excretion levels at 1 day of age were higher in PDA-treated infants than in control infants (median [interquartile range]: 5.5 [2.6, 12.2] versus 2.1 [1.0, 3.9] ng/mg creatinine; p = 0.017); however, among PDA-treated infants, the levels were significantly lower at 3 and 7 days than at 1 day of age (5.5 [2.6, 12.2] versus 3.4 [1.7, 4.5] and 4.0 [1.7, 5.3] ng/mg creatinine, respectively; p < 0.05). The urinary t-PGDM excretion level in the control group did not significantly differ among the time points. CONCLUSION: PDA and COX inhibitor administration affected PG metabolism in VLBW infants. Our results indicated that urinary t-PGDM excretion was significantly associated with PDA-treatment in preterm infants.

Preoperative oral treatment with cyclooxygenase-2 inhibitor for cystitis glandularis.

Introduction: A previous report has shown that cyclooxygenase-2 inhibitors can prevent the recurrence of cystitis glandularis postoperatively. Herein, we present a case of cystitis glandularis in which the tumor volume was markedly reduced by preoperative oral administration of a cyclooxygenase-2 inhibitor. Case presentation: A 45-year-old man with voiding difficulty and lower abdominal pain during urination was referred to our hospital. Cystoscopy revealed multiple cystitis glandularis-like edematous masses on the trigone and the neck of the bladder, completely involving the bilateral ureteral orifices. Cyclooxygenase-2 inhibitor was orally administered at the patient's request. Six weeks later, the tumor volume was markedly reduced, bilateral ureteral orifices were identified, and the voiding difficulty and pain on urination disappeared. Complete transurethral resection of the residual tumor was performed, and the pathological diagnosis was intestinal-type cystitis glandularis. Conclusion: Cyclooxygenase-2 inhibition can be considered a useful therapeutic strategy for cystitis glandularis.

Meloxicam as an adjuvant to peginterferon-α-2a and ribavirin treatment for genotype 1 chronic hepatitis C: A randomized trial.

AIM: In this multicenter, randomized trial, we evaluated the effectiveness of meloxicam - a non-steroidal anti-inflammatory drug - as an adjuvant for enhancing antiviral efficacy and preventing neutropenia during the treatment of patients with genotype 1 chronic hepatitis C using peginterferon and ribavirin. METHODS: A total of 60 patients were randomly assigned, in a 1:1 ratio, to either the meloxicam or the control group after stratification by neutrophil count. Both groups received weekly peginterferon-α-2a (180 µg) and a weight-based dose of ribavirin for 48 weeks. The meloxicam group received meloxicam (10 mg/day) for the first 8 weeks after initiation of treatment. RESULTS: Through intent-to-treat analysis, we found that the sustained virological response rate in the meloxicam group (19/30, 63.3%) was significantly higher than in the control group (11/30, 36.7%, P < 0.05). The relapse rate was more than twice as high (45%) in the control group than in the meloxicam group (19.0%); however, this difference was not statistically significant. The rate of neutrophil decrease, calculated by dividing the lowest value observed during the first 8 weeks by pretreatment count, was significantly smaller in the meloxicam group (55.1 ± 14.3%) than in the control group (62.3 ± 9.6%, P < 0.05). CONCLUSION: Meloxicam enhanced antiviral efficacy and reduced the decline in neutrophil counts for the peginterferon and ribavirin treatment of genotype 1 chronic hepatitis C. This drug could be a reasonable adjuvant for the treatment of patients with chronic hepatitis C. The present study including a small number of patients warrants larger clinical trials.

The Safety of Celecoxib as an Acute Treatment for Migraine: A Narrative Review.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first-line choice for the acute treatment of migraine attacks for decades; however, the safety of a particular NSAID is related to its treatment dose, duration, and mechanism of action. Although adverse event (AE) risks differ substantially among individual migraine treatments, increased or prolonged exposure to any NSAID elevates risks and severity of AEs. METHODS: For this narrative review, we conducted a literature search of PubMed until July 2022, focusing on the history, mechanism of action, and treatment guidelines informing the safety and efficacy of celecoxib oral solution for the acute treatment of migraine attacks. RESULTS: Here we discuss the mechanisms of action of nonselective NSAIDs vs. cyclooxygenase-2 (COX-2) inhibitors, and how these mechanisms underlie the AEs associated with these treatments. We review the clinical trials that influenced the regulatory history of NSAIDs, specifically COX-2 inhibitors, the role of traditional and new formulations of NSAIDs including celecoxib oral solution, and special considerations in the acute treatment of migraine attacks. CONCLUSIONS: Low-dose formulations of NSAIDs, such as celecoxib oral solution, provide acute migraine analgesia with similar or fewer associated cardiovascular and gastrointestinal events than previous formulations.