Female-biased embryonic death from inflammation induced by genomic instability.

Genomic instability can trigger cellular responses that include checkpoint activation, senescence and inflammation1,2. Although genomic instability has been extensively studied in cell culture and cancer paradigms, little is known about its effect during embryonic development, a period of rapid cellular proliferation. Here we report that mutations in the heterohexameric minichromosome maintenance complex-the DNA replicative helicase comprising MCM2 to MCM73,4-that cause genomic instability render female mouse embryos markedly more susceptible than males to embryonic lethality. This bias was not attributable to X chromosome-inactivation defects, differential replication licensing or X versus Y chromosome size, but rather to 'maleness'-XX embryos could be rescued by transgene-mediated sex reversal or testosterone administration. The ability of exogenous or endogenous testosterone to protect embryos was related to its anti-inflammatory properties5. Ibuprofen, a non-steroidal anti-inflammatory drug, rescued female embryos that contained mutations in not only the Mcm genes but also the Fancm gene; similar to MCM mutants, Fancm mutant embryos have increased levels of genomic instability (measured as the number of cells with micronuclei) from compromised replication fork repair6. In addition, deficiency in the anti-inflammatory IL10 receptor was synthetically lethal with the Mcm4Chaos3 helicase mutant. Our experiments indicate that, during development, DNA damage associated with DNA replication induces inflammation that is preferentially lethal to female embryos, because male embryos are protected by high levels of intrinsic testosterone.

Cytotoxicity and Bioimmunological Activity of Poly(2-Isopropenyl-2-oxazoline) Conjugates with Ibuprofen Using 3D Reconstructed Tissue Models.

Poly(2-isopropenyl-2-oxazoline) (PIPOx) represents a universal polymer platform with pendant 2-oxazoline groups, allowing the preparation of biomaterials for various biomedical applications. However, there is a lack of information on PIPOx concerning the effect of molar mass (Mn) on cytotoxicity and bioimmunological properties. Here, aqueous copper(0)-mediated reversible-deactivation radical polymerization (Cu0-RDPR) was used for the preparation of PIPOx with defined Mn and low dispersity. PIPOx of different Mn are used for the synthesis of conjugates with ibuprofen (5 mol %), the nonsteroidal anti-inflammatory drug. The release of ibuprofen at 37 °C and different pH values is monitored using high-performance liquid chromatography, where the rate of drug release increases with increasing pH and lower Mn. In vitro cytotoxicity and bioimmunological properties of PIPOx and drug conjugates are studied using 3D reconstructed tissue models of the human epidermis and intestinal epithelium. We demonstrate low cytotoxicity of PIPOx and conjugates with different Mn values on both 3D tissue models.

Pain-suppressed consumption of highly palatable liquid in rats.

This study determined whether consumption of a highly palatable liquid is a reliable measure of inflammatory pain and antinociception in male and female rats. After a 10-day acquisition period, the impact of intraplantar oil vs. complete Freund adjuvant (CFA) on consumption of vanilla-flavored Ensure was assessed, with a sipper tube height 12 or 19 cm above the floor. CFA significantly decreased Ensure consumption, which completely recovered within 4-7 days to levels in oil-treated controls; neither sex nor sipper tube height significantly influenced Ensure consumption. CFA also significantly suppressed Ensure consumption in rats not exposed to the 10-day acquisition period, but only in males. To test the predictive validity of Ensure consumption as a measure of pain, separate rats were pretreated with a vehicle, an opioid, a nonsteroidal anti-inflammatory drug, or a cannabinoid the day after CFA treatment. Morphine and ibuprofen significantly attenuated CFA-suppressed drinking in at least one sex, and tetrahydrocannabinol did not. Neither ibuprofen nor tetrahydrocannabinol significantly altered drinking in oil-injected, 'pain-free' controls, but morphine increased drinking. These results demonstrate that CFA decreases consumption of a highly palatable liquid regardless of previous exposure (training) to the consumption procedure, but only in males. Although standard analgesics attenuate CFA-suppressed drinking, nonspecific hyperphagic effects can confound the interpretation of results. Thus, consumption of a highly palatable liquid is not an optimal measure for candidate analgesic screening.

Synthesis and biological evaluation of new nicotinic acid derivatives as potential anti-inflammatory agents with enhanced gastric safety profile.

Two innovative series derived from nicotinic acid scaffold were synthesized and evaluated for their anti-inflammatory activity. Ibuprofen, celecoxib and indomethacin were used as standard drugs. All the newly synthesized compounds were in vitro screened for their anti-inflammatory activity adopting 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyltetrazolium bromide dye (MTT), as well as Griess assays. The results showed that all compounds exhibited significant anti-inflammatory activity without affecting the viability of the macrophages compared to ibuprofen. In addition, compounds 4d, 4f, 4g, 4h and 5b exhibited the most potent nitrite inhibition activity and consequently superior anti-inflammatory activity with MTT results ranging between values 86.109 ± 0.51 to 119.084 ± 0.09. The most active compounds were subjected to evaluation of TNF-α, IL-6, iNOS and COX-2 levels in LPS/INF γ-stimulated RAW 264.7 macrophage cells in comparison to ibuprofen as a reference compound. The five compounds showed comparable inhibition potency of these inflammatory cytokines compared to ibuprofen. Same compounds were further in vivo evaluated for their anti-inflammatory activity via carrageenan induced arthritis in rats. Regarding the ulcerogenic profile, compound 4h showed mild infiltration of gastric mucosa superb to compound 5b displayed severe gastritis. Molecular docking of 4h and 5b in the COX-2 active site was performed to evaluate their preferential COX-2 inhibitory potency. The docking results were in accordance with the biological findings.

Fenamates and ibuprofen as foundational components in the synthesis of innovative, targeted COX-2 anti-inflammatory drugs, undergoing thorough biopharmacological assessments and in-silico computational studies.

Cyclooxygenase-2 plays a vital role in inflammation by catalyzing arachidonic acid conversion toward prostaglandins, making it a prime therapeutic objective. Selective COX-2 inhibitors represent significant progress in anti-inflammatory therapy, offering improved efficacy and fewer side effects. This study describes the synthesis of novel anti-inflammatory compounds from established pharmaceutically marketed agents like fenamates III-V and ibuprofen VI. Through rigorous in vitro testing, compounds 7b-c, and 12a-b demonstrated substantial in vitro selective inhibition, with IC50 values of 0.07 to 0.09 µM, indicating potent pharmacological activity. In vivo assessment, particularly focusing on compound 7c, revealed significant anti-inflammatory effects. Markedly, it demonstrated the highest inhibition of paw thickness (58.62 %) at the 5-hr mark compared to the carrageenan group, indicating its potency in mitigating inflammation. Furthermore, it exhibited a rapid onset of action, with a 54.88 % inhibition observed at the 1-hr mark. Subsequent comprehensive evaluations encompassing analgesic efficacy, histological characteristics, and toxicological properties indicated that compound 7c did not induce gastric ulcers, in contrast to the ulcerogenic tendency associated with mefenamic acid. Moreover, compound 7c underwent additional investigations through in silico methodologies such as molecular modelling, field alignment, and density functional theory. These analyses underscored the therapeutic potential and safety profile of this novel compound, warranting further exploration and development in the realm of pharmaceutical research.

Design, optimization and pharmaceutical characterization of wound healing film dressings with chloramphenicol and ibuprofen.

OBJECTIVE: The aim of the present study was to develop and optimize a wound dressing film loaded with chloramphenicol (CAM) and ibuprofen (IBU) using a Quality by Design (QbD) approach. SIGNIFICANCE: The two drugs have been combined in the same dressing as they address two critical aspects of the wound healing process, namely prevention of bacterial infection and reduction of inflammation and pain related to injury. METHODS: Three critical formulation variables were identified, namely the ratios of Kollicoat SR 30D, polyethylene glycol 400 and polyvinyl alcohol. These variables were further considered as factors of an experimental design, and 17 formulations loaded with CAM and IBU were prepared via solvent casting. The films were characterized in terms of dimensions, mechanical properties and bioadhesion. Additionally, the optimal formulation was characterized regarding tensile properties, swelling behavior, water vapor transmission rate, surface morphology, thermal behavior, goniometry, in vitro drug release, cell viability, and antibacterial activity. RESULTS: The film was optimized by setting minimal values for the folding endurance, adhesive force and hardness. The optimally formulated film showed good fluid handling properties in terms of swelling behavior and water vapor transmission rate. IBU and CAM were released from the film up to 80.9% and 82.5% for 8 h. The film was nontoxic, and the antibacterial activity was prominent against Micrococcus spp. and Streptococcus pyogenes. CONCLUSIONS: The QbD approach was successfully implemented to develop and optimize a novel film dressing promising for the treatment of low-exuding acute wounds prone to infection and inflammation.

Comparing the efficacy of intravenous morphine versus ibuprofen or the combination of ibuprofen and acetaminophen in patients with closed limb fractures: a randomized clinical trial.

INTRODUCTION: This study aims to investigate the effectiveness of intravenous ibuprofen or intravenous ibuprofen plus acetaminophen compared to intravenous morphine in patients with closed extremity fractures. METHODS: A triple-blinded randomized clinical trial was conducted at a tertiary trauma center in Iran. Adult patients between 15 and 60 years old with closed, isolated limb fractures and a pain intensity of at least 6/10 on the visual analog scale (VAS) were eligible. Patients with specific conditions or contraindications were not included. Participants were randomly assigned to receive intravenous ibuprofen, intravenous ibuprofen plus acetaminophen, or intravenous morphine. Pain scores were assessed using the visual analog scale at baseline and 5, 15, 30, and 60 min after drug administration. The primary outcome measure was the pain score reduction after one hour. RESULTS: Out of 388 trauma patients screened, 158 were included in the analysis. There were no significant differences in age or sex distribution among the three groups. The pain scores decreased significantly in all groups after 5 min, with the morphine group showing the lowest pain score at 15 min. The maximum effect of ibuprofen was observed after 30 min, while the ibuprofen-acetaminophen combination maintained its effect after 60 min. One hour after injection, pain score reduction in the ibuprofen-acetaminophen group was significantly more than in the other two groups, and pain score reduction in the ibuprofen group was significantly more than in the morphine group. CONCLUSION: The study findings suggest that ibuprofen and its combination with acetaminophen have similar or better analgesic effects compared to morphine in patients with closed extremity fractures. Although morphine initially provided the greatest pain relief, its effect diminished over time. In contrast, ibuprofen and the ibuprofen-acetaminophen combination maintained their analgesic effects for a longer duration. The combination therapy demonstrated the most sustained pain reduction. The study highlights the potential of non-opioid analgesics in fracture pain management and emphasizes the importance of initiation of these medications as first line analgesic for patients with fractures. These findings support the growing trend of exploring non-opioid analgesics in pain management. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05630222 (Tue, Nov 29, 2022). The manuscript adheres to CONSORT guidelines.

Design, Synthesis, Anti-Inflammatory Activity, DFT Modeling and Docking Study of New Ibuprofen Derivatives.

A new ibuprofen derivative, (E)-2-(4-isobutylphenyl)-N'-(4-oxopentan-2-ylidene) propane hydrazide (IA), was synthesized, along with its metal complexes with Co, Cu, Ni, Gd, and Sm, to investigate their anti-inflammatory efficacy and COX-2 inhibition potential. Comprehensive characterization, including 1H NMR, MS, FTIR, UV-vis spectroscopy, and DFT analysis, were employed to determine the structural configurations, revealing unique motifs for Gd/Sm (capped square antiprismatic/tricapped trigonal prismatic) and Cu/Ni/Co (octahedral) complexes. Molecular docking with the COX-2 enzyme (PDB code: 5IKT) and pharmacokinetic assessments through SwissADME indicated that these compounds have superior binding energies and pharmacokinetic profiles, including BBB permeability and gastrointestinal absorption, compared to the traditional ibuprofen standalone. Their significantly lower IC50 values further suggest a higher efficacy as anti-inflammatory agents and COX-2 inhibitors. These research findings not only introduce promising ibuprofen derivatives for therapeutic applications but also set the stage for future validation and exploration of this new generation of ibuprofen compounds.

Medicinal Anti-Inflammatory Patch Loaded with Lavender Essential Oil.

Transdermal drug delivery offers a promising alternative for administering medications like ibuprofen, known for its analgesic and anti-inflammatory properties, with reduced gastrointestinal side effects compared to oral administration. This study explored the potential synergistic effects of combining ibuprofen with lavender essential oil (LEO) in transdermal patches. The composition of LEO was analyzed, revealing predominant compounds such as linalyl acetate and linalool, which are known for their analgesic and anti-inflammatory properties. The physicochemical properties of the patches were investigated, indicating improved cohesion with the addition of LEO. Additionally, thermal stability assessments demonstrated enhanced stability with LEO incorporation with an increase in onset decomposition temperature from 49.0 to 67.9 °C. The antioxidant activity of patches containing LEO was significantly higher with a free radical scavenging ability of 79.13% RSA compared to 60% RSA in patches without LEO. Release and permeation studies showed that patches with LEO exhibited an increased permeation of ibuprofen through the skin with 74.40% of the drug released from LEO-containing patches compared to 36.29% from patches without LEO after 24 h. Moreover, the permeation rate was notably faster with LEO, indicating quicker therapeutic effects. The inclusion of LEO in transdermal patches containing ibuprofen holds promise for enhancing drug delivery efficiency and therapeutic effectiveness, offering a potential strategy for improved pain management with reduced side effects.

Finding a Direct Method for a Dynamic Process: The DD (Direct and Dynamic) Cell-Tox Method.

The main focus of in vitro toxicity assessment methods is to assess the viability of the cells, which is usually based on metabolism changes. Yet, when exposed to toxic substances, the cell triggers multiple signals in response. With this in mind, we have developed a promising cell-based toxicity method that observes various cell responses when exposed to toxic substances (either death, division, or remain viable). Based on the collective cell response, we observed and predicted the dynamics of the cell population to determine the toxicity of the toxicant. The method was tested with two different conformations: In the first conformation, we exposed a monoculture model of blood macrophages to UV light, hydrogen peroxide, nutrient deprivation, tetrabromobisphenol A, fatty acids, and 5-fluorouracil. In the second, we exposed a coculture liver model consisting of hepatocytes, hepatic stellate cells, Kupffer cells, and liver sinusoidal endothelial cells to rifampicin, ibuprofen, and 5-fluorouracil. The method showed good accuracy compared to established toxicity assessment methods. In addition, this approach provided more representative information on the toxic effects of the compounds, as it considers the different cellular responses induced by toxic agents.

Silver and Copper Complexes with Ibuprofen and Caffeine-Preparation and Evaluation of Their Selected Biological Effects.

Several organometallic complexes based on more than twenty different metals have already been approved for medical applications. The aim of the presented research was to obtain complexes of silver and copper with the non-steroidal anti-inflammatory drugs ibuprofen and xanthine alkaloid caffeine and evaluate selected aspects of their bioactivity and biosafety in terms of their future possible applications. The obtained complexes were characterized by Fourier-transform infrared spectroscopy, thermogravimetry, UV-VIS spectroscopy, conductometry, elemental analysis, and bioassays. Cytotoxicity for normal human cells of the CCD-Co18 cell line was evaluated by determining the IC50 value, with metabolic and morphology assessments. It was observed that complexes containing ibuprofen and caffeine exhibited lower toxicity than those with ibuprofen only. Complexes with copper showed lower toxicity towards healthy human fibroblasts compared to silver-based compounds, with an IC50 above 140 µg mL-1. However, in the silver complexes, the presence of caffeine increased the potency of COX-2 inhibition. Antimicrobial effects against different Gram-positive and Gram-negative bacterial strains were evaluated by MIC determination with values less than 20 µg mL-1.

Ibuprofen inhibits anaplastic thyroid cells in vivo and in vitro by triggering NLRP3-ASC-GSDMD-dependent pyroptosis.

Pyroptosis is a novel type of proinflammatory programmed cell death that is associated with inflammation, immunity, and cancer. Anaplastic thyroid carcinoma (ATC) has a high fatality rate, and there is no effective or standard treatment. The disease progresses rapidly and these tumors can invade the trachea and esophagus, leading to breathing and swallowing difficulties. Hence, new treatment methods are greatly needed. Ibuprofen is a common drug that can exert antitumor effects in some cancers. In this study, we demonstrated in vitro and in vivo that ibuprofen can induce ATC pyroptosis. Hence, we treated C643 and OCUT-2C ATC cells with ibuprofen and found that several dying cells presented the characteristic morphological features of pyroptosis, such as bubble-like swelling and membrane rupture, accompanied by activation of ASC and NLRP3 and cleavage of GSDMD. Along with the increased release of LDH, ibuprofen treatment promoted apoptosis and inhibited viability, invasion, and migration. However, overexpression of GSDMD significantly inhibited ibuprofen-induced pyroptosis. In vivo, research has demonstrated that thyroid tumor growth in nude mice can be suppressed by ibuprofen-induced pyroptosis in a dose-dependent manner. In this research, we explored a new mechanism by which ibuprofen inhibits ATC growth and progression and highlighted its promise as a therapeutic agent for ATC.

Fluconazole-Loaded Ibuprofen In Situ Gel-Based Oral Spray for Oropharyngeal Candidiasis Treatment.

Oral candidiasis is a fungal infection affecting the oral mucous membrane, and this research specifically addresses on a localized treatment through fluconazole-loaded ibuprofen in situ gel-based oral spray. The low solubility of ibuprofen is advantageous for forming a gel when exposed to an aqueous phase. The 1% w/w fluconazole-loaded in situ gel oral sprays were developed utilizing various concentrations of ibuprofen in N-methyl pyrrolidone. The prepared solutions underwent evaluation for viscosity, surface tension, contact angle, water tolerance, gel formation, interface interaction, drug permeation, and antimicrobial studies. The higher amount of ibuprofen reduced the surface tension and retarded solvent exchange. The use of 50% ibuprofen as a gelling agent demonstrated prolonged drug permeation for up to 24 h. The incorporation of Cremophor EL in the formulations resulted in increased drug permeation and exhibited effective inhibition against Candida albicans, Candida krusei, Candida lusitaniae, and Candida tropicalis. While the Cremophor EL-loaded formulation did not exhibit enhanced antifungal effects on agar media, its ability to facilitate the permeation of fluconazole and ibuprofen suggested potential efficacy in countering Candida invasion in the oral mucosa. Moreover, these formulations demonstrated significant thermal inhibition of protein denaturation in egg albumin, indicating anti-inflammatory properties. Consequently, the fluconazole-loaded ibuprofen in situ gel-based oral spray presents itself as a promising dosage form for oropharyngeal candidiasis treatment.

Effects of Ibuprofen and Diclofenac Pre-Treatment on Viability and Apoptosis Processes in Human Dental Pulp Stem Cells.

Background and Objectives: Stem cell-based regeneration strategies have shown therapeutic efficacy in various fields of regenerative medicine. These include bone healing after bone augmentation, often complicated by pain, which is managed by using nonsteroidal anti-inflammatory drugs (NSAIDs). However, information is limited about how NSAIDs affect the therapeutic potential of stem cells. Materials and Methods: We investigated the effects of ibuprofen and diclofenac on the characteristics, morphology, and immunophenotype of human mesenchymal stromal cells isolated from the dental pulp (DPSCs) and cultured in vitro, as well as their effects on the expression of angiogenic growth factors (VEGFA and HGF) and selected genes in apoptosis signalling pathways (BAX, BAK, CASP3, CASP9, and BCL2). Results: Ibuprofen and diclofenac significantly reduced the viability of DPSCs, while the expression of mesenchymal stem cell surface markers was unaffected. Both ibuprofen and diclofenac treatment significantly upregulated the expression of HGF, while the expression of VEGFA remained unchanged. Ibuprofen significantly altered the expression of several apoptosis-related genes, including the upregulation of CASP9 and BCL2, with decreased CASP3 expression. BAK, CASP3, CASP9, and BCL2 expressions were significantly increased in the diclofenac-treated DPSCs, while no difference was demonstrated in BAX expression. Conclusions: Our results suggest that concomitant use of the NSAIDs ibuprofen or diclofenac with stem cell therapy may negatively impact cell viability and alter the expression of apoptosis-related genes, affecting the efficacy of stem cell therapy.

Vascular and pulmonary effects of ibuprofen on neonatal lung development.

BACKGROUND: Ibuprofen is a nonsteroidal anti-inflammatory drug that is commonly used to stimulate closure of a patent ductus arteriosus (PDA) in very premature infants and may lead to aberrant neonatal lung development and bronchopulmonary dysplasia (BPD). METHODS: We investigated the effect of ibuprofen on angiogenesis in human umbilical cord vein endothelial cells (HUVECs) and the therapeutic potential of daily treatment with 50 mg/kg of ibuprofen injected subcutaneously in neonatal Wistar rat pups with severe hyperoxia-induced experimental BPD. Parameters investigated included growth, survival, lung histopathology and mRNA expression. RESULTS: Ibuprofen inhibited angiogenesis in HUVECs, as shown by reduced tube formation, migration and cell proliferation via inhibition of the cell cycle S-phase and promotion of apoptosis. Treatment of newborn rat pups with ibuprofen reduced pulmonary vessel density in the developing lung, but also attenuated experimental BPD by reducing lung inflammation, alveolar enlargement, alveolar septum thickness and small arteriolar wall thickening. CONCLUSIONS: In conclusion, ibuprofen has dual effects on lung development: adverse effects on angiogenesis and beneficial effects on alveolarization and inflammation. Therefore, extrapolation of the beneficial effects of ibuprofen to premature infants with BPD should be done with extreme caution.

Differential effects of purines and prostaglandins on hypoxia induced dilatation of porcine retinal vessels at different branching level ex vivo.

The metabolic pathways leading from hypoxia to retinal vasodilatation can involve effects of both purines and prostaglandins, but the effects of these compounds at different vascular branching levels are unknown. The purpose of the present study was to investigate differential effects of purines and prostaglandins in hypoxia-induced dilatation of retinal arterioles, precapillary arterioles and capillaries ex vivo. Porcine hemiretinas were mounted in a tissue chamber while monitoring temperature, pH, and oxygen tension. The effect of hypoxia on the diameter of larger arterioles, precapillary arterioles and capillaries was studied in the presence of the ecto-nucleotidase inhibitor AOPCP, the nonselective P2 purinoreceptor antagonist PPADS, the A2B adenosine receptor antagonist MRS 1754, the A3 adenosine receptor antagonist MRS 1523, the EP1 receptor antagonist SC-19220, the EP2 receptor antagonist PF-04418948, the EP3 receptor antagonist L-798,106, the EP4 receptor antagonist L-161-982, the prostaglandin synthesis inhibitor ibuprofen, and ibuprofen combined with AOPCP or ATP. Hypoxia-induced dilatation in arterioles was reduced by the A2B adenosine receptor antagonist (p < 0.01) and increased by the EP2 and the EP3 receptor antagonists (p < 0.01 for both comparisons). In precapillary arterioles the dilatation was reduced by the EP2 receptor antagonist (p < 0.04) and increased by the EP1 receptor antagonist (p < 0.03), whereas in capillaries the dilatation was increased by both the A3 adenosine receptor antagonist (p < 0.01), by ibuprofen in combination with the unspecific ecto-nucleotidase inhibitor AOPCP (p = 0.04) and by the prostaglandin EP3 receptor antagonist. Hypoxia-induced dilatation of retinal vessels is influenced by adenosine A2B and A3 receptors, and by the prostaglandin EP1, EP2 and EP3 receptors. The effects mediated by these receptors differ at different branching levels of the resistance vessels.

3D Printed Flavor-Rich Chewable Pediatric Tablets Fabricated Using Microextrusion for Point of Care Applications.

Over the past few years, 3D printing technologies have gained interest in the development of medicinal products for personalized use at the point of care. The printing of drug products offers personalization and flexibility in dose, shape/design, and flavor, potentially enhancing acceptability in pediatric populations. In this study, we present the design and development of ibuprofen (IBU) chewable flavor-rich personalized dosage forms by using microextrusion for the processing of powdered blends. The optimization processing parameters such as applied pneumatic pressure and temperature resulted in high quality printable tablets of various designs with a glossy appearance. Physicochemical characterization of the printed dosages revealed that IBU was molecularly dispersed in the methacrylate polymer matrix and the formation of H bonding. A panelist's study demonstrated excellent taste masking and aroma evaluation when using strawberry and orange flavors. Dissolution studies showed very fast IBU dissolution rates of more than 80% within the first 10 min in acidic media. Microextrusion is a 3D printing technology that can be effectively used to generate pediatric patient centric dosage forms at the point of care.

Effects of non-steroidal anti-inflammatory drug (ibuprofen) in low and high dose on stemness and biological characteristics of human dental pulp-derived mesenchymal stem cells.

PURPOSE: The effect of ibuprofen, an NSAID, on biological characteristics such as proliferation, viability, DNA damage and cell cycle in dental pulp derived stem cells (DPSCs) can be important for regenerative medicine. Our aim is to investigate how low and high doses of ibuprofen affect stem cell characteristics in DPSCs. MATERIALS AND METHODS: DPSCs were isolated from human teeth and characterized by flow cytometry and differentiation tests. Low dose (0.1 mmol/L) and high dose (3 mmol/L) ibuprofen were administered to DPSCs. Surface markers between groups were analyzed by immunofluorescence staining. Membrane depolarization, DNA damage, viability and cell cycle analysis were performed between groups using biological activity test kits. Cellular proliferation was measured by the MTT and cell count kit. Statistical analyzes were performed using GraphPad Prism software. RESULTS: High dose ibuprofen significantly increased CD44 and CD73 expression in DPSCs. High-dose ibuprofen significantly reduced mitochondrial membrane depolarization in DPSCs. It was determined that DNA damage in DPSCs decreased significantly with high dose ibuprofen. Parallel to this, cell viability increased significantly in the ibuprofen applied groups. High-dose ibuprofen was found to increase mitotic activity in DPSCs. Proliferation in DPSCs increased in parallel with the increase in mitosis stage because of high-dose ibuprofen administration compared to the control and low-dose ibuprofen groups. Our proliferation findings appeared to support cell cycle analyses. CONCLUSION: High dose ibuprofen improved the immunophenotypes and biological activities of DPSCs. The combination of ibuprofen in the use of DPSCs in regenerative medicine can make stem cell therapy more effective.

Novel 1,2,4-triazoles derived from Ibuprofen: synthesis and in vitro evaluation of their mPGES-1 inhibitory and antiproliferative activity.

Some novel triazole-bearing ketone and oxime derivatives were synthesized from Ibuprofen. In vitro cytotoxic activities of all synthesized molecules against five cancer lines (human breast cancer MCF-7, human lung cancer A549, human prostate cancer PC-3, human cervix cancer HeLa, and human chronic myelogenous leukemia K562 cell lines) were evaluated by MTT assay. In addition, mouse embryonic fibroblast cells (NIH/3T3) were also evaluated to determine the selectivity. Compounds 18, 36, and 45 were found to be the most cytotoxic, and their IC50 values were in the range of 17.46-68.76 µM, against the tested cancer cells. According to the results, compounds 7 and 13 demonstrated good anti-inflammatory activity against the microsomal enzyme prostaglandin E2 synthase-1 (mPGES-1) enzyme at IC50 values of 13.6 and 4.95 µM. The low cytotoxicity and non-mutagenity of these compounds were found interesting. Also, these compounds significantly prevented tube formation in angiogenesis studies. In conclusion, the anti-inflammatory and angiogenesis inhibitory activities of these compounds without toxicity suggested that they may be promising agents in anti-inflammatory treatment and they may be supportive agents for the cancer treatment.

The effects of Ibuprofen and 1, 8- cineol on anxiety and spatial memory in hyperammonemic rats.

In hepatic encephalopathy, hyperammonemia (HA) causes cognitive impairment and anxiety by causing neuroinflammation. Ibuprofen and 1,8- cineol have anti-inflammatory and antioxidant properties, respectively. The aim of this study was to evaluate the effects of ibuprofen alone and in combination with 1,8- cineol on anxiety and oxidative stress in a HA rat animal model. For this purpose, 36 rats were divided into six groups (n = 6) including the HA (received intraperitoneally (IP) ammonium acetate 2.5 mg/kg for four week), ibuprofen (induced HA rats that received 15 mg/kg, IP), cineol (induced HA rats that received 5 and 10 mg/kg, IP), Ib + cineol (induced HA rats that received 15 and 10 mg/kg, respectively, IP), and the control groups (received normal saline, IP). Except the HA group, all other groups received the aforementioned treatment for two weeks.. The Morris water maze and elevated plus maze were used to assess cognitive function and anxiety in the animals, respectively. Superoxide dismutase (SOD) activity was measured to evaluate oxidative stress. The mRNA expression levels of interleukin (IL)-6 and IL-1ß was assessed by real-time PCR in the animal's brain. The results showed a significant improvement in spatial memory and anxiety of the Ib group compared to the HA group (P < 0.01), but no significant change was observed in SOD activity (P > 0.05). There was a significant improvement in spatial memory and anxiety as well as a significant increase in SOD activity in the Ib + cineol group (P < 0.01) compared to the HA group. These results indicate that the Ib + cineol, not only improve cognitive function and reduce anxiety, also reduce oxidative stress, therefore, the simultaneous use of these two compounds may be useful in improving HA-induced cognitive disorders and anxiety.