Hypericum species are known for their phytochemical richness and diverse pharmacological activities; however, the biological potential and underlying mechanisms of Hypericum triquetrifolium remain unclear. This study aimed to investigate the phytochemical profile and bioactivities of Hypericum triquetrifolium hydroalcoholic extract (HTE). Plant samples collected from Gelibolu (Çanakkale, Türkiye) were analyzed by HPTLC, revealing the presence of rutin, hyperoside, chlorogenic acid, neochlorogenic acid, and hypericin. Antioxidant activity was evaluated using DPPH, CUPRAC, and FRAP assays, demonstrating strong activity across all tests. Anti-inflammatory effects were assessed in LPS-stimulated RAW264.7 macrophages. HTE significantly reduced nitrite, PGE2, IL-6, ROS, and MDA levels, with the most pronounced effect observed at 0.5 mg/mL (p < 0.05). Cytotoxic and anticancer activities were evaluated in MIA PaCa-2 pancreatic cancer cells and healthy human dermal fibroblasts. The extract exhibited selective cytotoxicity toward cancer cells (IC50 = 0.16 mg/mL), with approximately fivefold lower toxicity in healthy cells. Cell cycle analysis demonstrated G0/G1 arrest, while the Annexin V assay revealed dose-dependent apoptosis (p < 0.0001). DNA damage analysis further supported its anticancer potential. Overall, HTE exhibits potent antioxidant, anti-inflammatory, and selective anticancer activities by reducing oxidative stress, inducing cell cycle arrest, and promoting apoptosis, highlighting its potential as a therapeutic agent.

AimThis study investigated the effects of tryptophan (TRP) metabolism, kynurenine pathway (KP) and neopterin levels in heroin use disorder (HUD) in relation to neurotoxicity, treatment processes and psychiatric recovery.MethodThe study groups consisted of patients with HUD who sought treatment at the hospital and received treatment, and a healthy control (C) group. The levels of neopterin, tryptophan and kynurenine in the participants’ serum were determined, and the pre- and post-treatment results in the groups were compared with the controls.ResultsNeopterin levels, reflecting immune system activation, were observed to decrease in HUD group after treatment (p = 0.021). Similarly, a decrease in levels of tumor necrosis factor-alpha (TNF-α), a pro-inflammatory cytokine, was also detected after treatment (p < 0.05). However, changes in interleukin-6 (IL-6) and interferon-gamma (IFN-γ) levels were not found to be significant (p > 0.05). The total scores of the Addiction Profile Index (API-K), which measures the severity of addiction, decreased significantly after treatment (p < 0.001). At the same time, improvement was observed in the general symptom level (GSI) and all subscales (including depression, anxiety, obsessive-compulsive disorders, and somatization) of the Symptom Checklist-90-Revised (SCL-90-R) scale, which assesses general psychopathology. Regression analyses revealed that the two strongest factors negatively affecting treatment success in the HUD group were duration of use (p = 0.028) and high neopterin levels (p = 0.020).ConclusionThis study highlights the critical role of immunological and neuroinflammatory processes in the success of HUD treatment. The findings indicate that biochemical recovery progresses in parallel with psychiatric recovery during treatment, and that changes in the KYN/TRP ratio and IL-6 levels have strong diagnostic and prognostic value. Neopterin, kynurenine, and tryptophan, on the other hand, have moderate prognostic value.

Polycyclic aromatic hydrocarbons (PAHs) are common environmental pollutants generated from the incomplete combustion of organic materials and represent an important source of occupational and environmental exposure. Aside from their carcinogenic properties, PAHs are known to exert immunomodulatory and proinflammatory effects. Immune activation is closely associated with alterations in pteridine metabolism and activation of the kynurenine pathway; however, evidence linking PAH exposure to these immune-inflammatory pathways in humans remains limited. This study aimed to investigate the systemic biological effects of occupational exposure to PAHs from asphalt fumes in road construction workers, with a particular focus on alterations in pteridine metabolism and activation of the kynurenine pathway, using a combined panel of exposure and mechanistic biomarkers. Routine clinical parameters remained within normal ranges while urinary 1-hydroxypyrene, a well-established biomarker of internal PAH exposure, was significantly elevated, confirming substantial PAH exposure. Key findings revealed profound alterations in two critical metabolic pathways: (i) Pteridine metabolism was shifted, with increased neopterin and decreased biopterin levels, indicating activation of cell-mediated immunity and reduced cofactor availability; (ii) the kynurenine pathway was concurrently activated, as reflected by elevated kynurenine, reduced tryptophan, and increased estimated indoleamine 2,3-dioxygenase activity. These findings indicate that low-level but chronic PAH exposure induces sustained Th1-type immune activation and metabolic disturbances in the absence of overt clinical pathology, representing a state of subclinical biological adaptation.

Gold nanoparticles (AuNPs) are used in biomedical applications. Due to data gap for safety of them, this research aimed to evaluate both AuNPs and oligonucleotide coated AuNPs (O-AuNPs) at 100, 500, and 2500 & micro;g/kg doses in rats. The synthesized AuNPs were characterized by Ultraviolet/Visible (UV/Vis) spectroscopy, Dynamic Light Scattering (DLS), and Transmission Electron Microscopy (TEM). The hydrodynamic diameter of the particles was about 13 nm and showed a characteristic peak around 520 nm in the UV/Vis spectrum. AuNPs coated with oligonucleotide were analyzed by UV/Vis and DLS. No UV/Vis peak shift was observed after coating, only a decreased optical density. DLS measurements detected an increase of about 2 nm in hydrodynamic diameter. Oxidative stress parameters, cytokines, 3-Nitrotyrosine, and metallothionein levels were also measured. There were significant changes in catalase, superoxide dismutase, and malondialdehyde in erythrocyte, liver, kidney, and brain tissues of rats. Liver metallothionein decreased in the lowest dose AuNPs, lowest and mid-dose O-AuNPs. As a result, AuNPs seem to have some adverse effects on oxidative stress parameters. Further researches are needed to elucidate the safety of AuNPs and O-AuNPs.

Background/Objectives: This study aimed to develop and formulation-design curcumin-loaded buccal films using a green deep eutectic solvent (DES) to improve drug solubility and support localized mucosal delivery, with the help of a Design of Experiments (DoE) approach. Methods: Various DESs with different components and molar ratios were prepared, characterized, and the optimal DES was selected. Curcumin-loaded buccal films were prepared by solvent casting, employing the optimal DES as the solvent system. A three-factor and five-level central composite design was applied to systematically investigate the amounts of HPMC K100, Kollicoat® IR, and DES in buccal films, and mucoadhesive strength, elongation (%), swelling index, swelling time, and thickness were identified as critical responses. Based on these responses, characterization, in vitro release, ex vivo permeation, and in vitro biological activity studies were performed on the model-predicted optimal formulations. Results: Choline chloride: propylene glycol (1:4 molar ratio) was selected as the optimal DES due to its viscosity, pH, organoleptic properties, and the highest curcumin solubility (11.90 ± 0.15 mg/mL). While DES increased curcumin solubility, buccal films were successfully obtained. Six formulations identified through model-based DoE optimization were advanced to detailed experimental evaluation. The drug release exhibited sustained curcumin release profiles over 24 h, and ex vivo studies showed <2% mucosal permeation. The lead formulations demonstrated in vitro cell compatibility, anti-inflammatory and antioxidant activities, and enhanced wound-healing-related bioactivity. Conclusions: Curcumin-loaded buccal films containing DES and developed using a DoE-guided formulation strategy successfully demonstrated the acceptable formulation properties and screening-level in vitro biological activities, offering a promising formulation platform for localized buccal delivery applications.

Butyric acid (a short-chain fatty acid) has anti-inflammatory and wound-healing potential but its direct use is limited by instability, odor, and irritancy. This study asked whether loading calcium butyrate (CAB) into a bioadhesive hydrogel suited for dermal delivery would yield acceptable physicochemical performance, sustained release, cytocompatibility, anti-inflammatory activity, pro-migratory/wound-closure effects, and non-irritancy. Hydrogels were prepared with carboxymethyl cellulose, xanthan gum, glycerin, and rose water, generating a blank matrix (F1) and a CAB-loaded system (F1-CAB). Formulations were characterized for pH, viscosity, CAB conten in the formulationt, texture/spreadability, rheology/thermal behavior, and in-vitro release kinetics. Biological evaluations followed ISO 10,993 principles using L929 fibroblasts, RAW 264.7 macrophages, and reconstructed human epidermis models. Endpoints included cell viability (cytotoxicity), nitrite inhibition (anti-inflammatory activity) versus CAB alone, fibroblast migration/wound-closure assays, and in-vitro irritation (tissue viability). CAB incorporation increased viscosity, bioadhesion, and viscoelastic strength. F1-CAB exhibited shear-thinning behavior and superior thermal stability, consistent with Ca²⁺-mediated crosslinking. CAB release was sustained. The formulation showed excellent cytocompatibility with viability > 70

In this study, Poloxamer based in situ gels were developed and characterized to formulate a successful dressing and to give a new impulse to wound treatment. These gels were formulated with 2 % Gallic acid (GA), using Poloxamer 407 (P407), Poloxamer 188 (P188), and sodium alginate with cold method in various concentrations to develop thermoresponsive and bioadhesive gels utilizing the healing effect of GA. The in situ gels with the suitable gelation temperature were selected for further studies. They underwent a thorough evaluation, including clarity, gelling capacity, pH, drug content, viscosity, spreadability, mechanical properties, bioadhesion, and in vitro release studies. Notably, the F8 (20 % P407, 5 % P188, 1 % sodium alginate) demonstrated the highest adhesiveness (37.22 +/- 8.65 g s) value in mechanical examination, which is one of the most important factors of bioadhesive formulations, corresponding required strength as well as preventing leakage at the same time. It was also supported by ex vivo bioadhesion (0.23 +/- 0.29 N) results among the formulations. The in vitro release studies revealed that each formulation was capable of releasing GA up to 100 % within 4 h. Following these results, further ex vivo permeation, penetration studies, and biological assays were examined. F8 stood out, showing superior performance in wound healing, nitric oxide (NO) measurement, analgesic activity, and IL-6 release, all while displaying no cytotoxic effects. In vivo experiments further confirmed the efficacy of GA loaded in situ gels, showing the lowest inflammatory cell concentration, the thickest granulation tissue, the highest level of epidermal regeneration, and the densest collagen and new vessel formation compared to other groups. These findings suggest that new in situ gels hold great promise for safe and effective wound treatment.

Helper T (Th) 1 inflammatory cytokines, like interferon gamma, play a role in the active inflammatory phase of ocular allergic diseases in addition to Th2-type cytokines, which are actively involved in the pathogenesis of allergies. Allergic conjunctivitis is one of the most common syndromes in ocular disorders, with a prevalence of 5–22% in the general population. The goal of this study was to evaluate the serum neopterin and immunoglobulin E (IgE) levels, as well as the kynurenine (Kyn)/tryptophan (Trp) ratio as an indicator of indoleamine 2,3-dioxygenase activation, in 44 pediatric patients with seasonal AC (SAC) in comparison with values from 33 healthy children. We also assessed the correlations between these biomarkers and symptom and sign scores. Serum neopterin levels were significantly higher in patients with SAC than in healthy controls (p = 0.018) and were significantly correlated with all parameters except the sign score among the patients. Serum IgE was also higher (p < 0.001) and Trp levels were significantly lower (p = 0.017) among patients, while Kyn levels and the Kyn/Trp ratio did not differ between the groups. In conclusion, our study indicated that both Th1 and Th2 responses are active in SAC, confirming the complex involvement of both cytokines in this pathology.

Novel alkyl α ‐hydroxymethacrylate‐based prodrugs are prepared to improve bioavailability, decrease toxicity, and control drug release. First, an ibuprofen (IBU)‐functionalized methacrylate (TBMA‐IBU) is synthesized from the reaction of tert ‐butyl α ‐bromomethacrylate with IBU. The free radical homopolymerization and copolymerization with poly(ethylene glycol) methyl ether methacrylate ( M n = 300), cleavage of tert ‐butyl ester groups of the homopolymer and a copolymer with trifluoroacetic acid (TFA) gave new polymer prodrugs ( p ‐TBMA‐IBU, p ‐TBMA‐IBU ‐co ‐PEGMA, p ‐MA‐IBU, and p ‐MA‐IBU ‐co ‐PEGMA), with IBU linked through ester bonds on the side chain. The release studies showed extended‐release of IBU (20–60% in 15 d), which can be triggered under the stimulation of lipase. The in vitro studies indicate that the representative polymers are effective in relieving inflammatory responses in RAW264.7 macrophage cells without any cytotoxicity. These results suggest that the synthesized polymers with controllable functionality can be promising IBU prodrugs.

As a result of anti-inflammatory activity-guided fractionation, 16 secondary metabolites from the underground parts of Valeriana phu L. were obtained, including five new ones belonging to iridoid (1, 2, and 5), phenylpropanoid (6) and neolignan (7) chemical classes. Their structures were elucidated by 1D and 2D NMR analyses as well as HRESIMS. The in vitro anti-inflammatory activities of the extract, fractions and isolates were evaluated through NO inhibition assay on LPS-induced RAW 264.7 cells. Compounds 1-3, 7-9, 11, 13, and 16 which significantly inhibited the nitrite release (IC50 14.94-94.81 mu M) were also assessed for their reducing capacity on TNF-alpha, IL-1 beta, IL-6, PGE2 and COX-2 production. Compounds 3, 8, and 16 inhibited LPS induced iNOS expression levels in Western blotting. Molecular docking studies for the active compounds targeting iNOS, TNF-alpha and COX-2 were also carried out. Moreover, compounds with remarkable anti-inflammatory activities were tested for their potential cytotoxicity against breast (MCF-7 and MDA-MB-231), glioblastoma (U87 and A172), pancreas (MIA PaCa-2 and PANC-1), hepatocellular (Mahlavu and Hep3B) cancer cell lines by WST-8. Compounds, 7, 8, and 16 showed significant cytotoxicity against A172 and PANC-1 cell lines (IC50 18.3-21.8 mu M) via causing cell cycle arrest, especially in the G2/M phase and triggering the apoptotic pathway.

Valeriana tuberosa L. yielded four new iridoids, valtuberoside I-IV (1-3 and 15), along with 13 known secondary metabolites via activity-directed fractionation. Compounds were characterized by NMR and HRESIMS. EtOH extract, fractions, and isolates were evaluated for their inhibition on nitric oxide (NO) release in LPS-induced RAW 264.7 cells. Compounds 3, 4, 6, 8, 9, 11, 13, 16, and 17 exhibited anti-inflammatory activity by inhibiting the release of NO (IC50 43.44-95.71 μM), and their mode of actions were elucidated by ELISA, Western blot, qPCR, immunostaining techniques and supported by molecular modelling studies. Compounds 8, 9, 11, 13, and 17 showed significant reduction in TNF-α, IL-1β, IL-6, PGE2, and COX-2 enzyme production, while 9 and 13 decreased iNOS protein expression in RAW 264.7 cells. Compound 13 exhibited remarkable inhibition on pro-inflammatory markers, cox-2 gene expression and translocation of NF-κB to the nuclear region. Moreover, it had the most favourable interaction (ds: -6.46 kcal/mol) with iNOS in in silico analyses. The cytotoxic activities of the most active isolates against MCF-7, MDA-MB-231, U87, A172, MIA PaCa-2, PANC-1, Mahlavu, and Hep3B cancer cell lines were assessed using CCK8 assay and their cell death mechanisms were unveiled via Apoptosis/Necrosis Assay Kit. Compound 8 had significant cytotoxic activity against MIA PaCa-2 (IC50 23.7 μM) and Hep3B (IC50 25.4 μM) cancer cell lines, via arresting cell cycle especially in G2/M phase and triggering the apoptotic pathway. These findings indicated that 8 and 13 deserve further in vivo assays on the way to discover new potential drug leads.

This study aimed to develop in situ gel formulations containing vanillic acid to enhance patient compliance and accelerate wound healing. Vanillic acid-loaded in situ gels were prepared, and their physicochemical properties were evaluated through in vitro release and ex vivo permeation studies. Additionally, antioxidant capacity, cytotoxicity, wound healing, prostaglandin E2 levels, IL-6 inhibition, and skin irritation tests were conducted. The optimized IN3-VA formulation exhibited a gelling temperature of 32.394 ± 0.842, a pH value of 4.780 ± 0.010 and a viscosity of 2473.33 ± 11.54 cP. It demonstrated specific mechanical properties, including hardness of 27.94 ± 1.30 g and adhesiveness of -97.00 ± 14.60 g.mm. The IN15-VA formulation showed improved parameters, with a hardness of 38.84 ± 3.33 g, adhesiveness of -126.35 ± 22.78 g.mm, pH value of 4.870 ± 0.010, viscosity of 3853.33 ± 30.55 cP, and a gelling temperature of 31.854 ± 0.345. Both formulations demonstrated sustained release behavior, releasing 60% of the medication in vitro over 6 h with no cytotoxic effects. They also decreased copper ion reduction and the release of nitric oxide, with cellular proliferation rates of 63% for IN3-VA and 73% for IN15-VA. Moreover, IN15-VA significantly reduced prostaglandin E2 levels, controlled IL-6 increase, and exhibited non-irritating properties. The results suggest that these vanillic acid-loaded in situ gels hold promising potential in wound treatment due to their sustained release over 48 h.

BackgroundGlucocorticoids are associated with withdrawal syndrome, but specific glucocorticoid types that cause severe conditions remain unclear.ObjectivesThis study identified glucocorticoids that exhibit significant pharmacovigilance signals for withdrawal, directly comparing the different types to determine those that exhibit a higher risk. We also aimed to investigate the routes of administration for glucocorticoids that are most likely to cause glucocorticoid withdrawal syndrome (GWS) and identify the age, sex, and regional groups among which GWS is more common.MethodsWe extracted the region, severity, age group, sex, and indications from VigiBase reports on GWS from January 2013 to December 2023.ResultsAmong 343,296 adverse drug reactions, 1,713 were withdrawal syndrome, with a higher prevalence among females (60%). Prednisone accounted for 28% of the cases, followed by hydrocortisone (17%) and betamethasone (14%). Case numbers tended to peak in 2021, with the highest incidence between ages 18-44 (36%) and significant regional variations for different glucocorticoids. Most cases (77%) were serious, with 18% requiring prolonged hospitalization. Predominant administration routes were topical for betamethasone, triamcinolone, and hydrocortisone; oral for prednisone and prednisolone; and intravenous for methylprednisolone. Disproportionality signals indicated that hydrocortisone exhibited the highest association with GWS (reporting odds ratio [ROR]: 4.04, 95% confidence interval [CI]: 3.59-4.53), followed by betamethasone (ROR: 3.81, 95% CI: 3.35-4.32), triamcinolone (ROR: 2.15, 95% CI: 1.83-2.52), and cortisone (ROR: 1.57, 95% CI: 0.99-2.50).ConclusionAbrupt withdrawal of glucocorticoid therapy may cause GWS. Healthcare providers should inform patients about the potential risks of withdrawal, particularly when prescribing topical hydrocortisone and betamethasone, topical and nasal triamcinolone, and oral and topical cortisone, to promote safer practices.

Osteoarthritis is characterized by persistent pain and dysfunction in the joints due to joint deformity and degradation. This study intended to develop a new microemulsion formulation of hyaluronic acid incorporating cetyl myristoleate for intra-articular administration and pain control related to arthritis. A titration method was utilized to formulate the microemulsions. The formulations were assessed for clarity, pH, droplet size, polydispersity index, zeta potential, and in vitro release analysis. Additionally, CHON-001 healthy human cartilage fibroblast cells were assessed for cytocompatibility. The chosen formulation was examined in vivo in rats. The characterisation investigations revealed that the droplet diameters of the blank, hyaluronic acid loaded and both hyaluronic acid and cetyl myristoleate added as an excepient to the formulation used in in vivo studies were found 25.23 f 3.14 nm, 36.35 f 2.10 nm and 78.8 f 0.4 nm, respectively. PDI values of the mentioned formulations were 0.298 f 0.035, 0.232 f 0.006 and 0.250 f 0.032. The drug concentration in the formulations varied from 9.7 f 0.2 to 9.9 f 0.2 mg/mL. Cell culture tests demonstrated that the formulations had cytocompatible profiles. In vivo studies, Mankin scoring was performed to both show the occurrence of osteoarthritis and to demonstrate improvement. At the end of the study, it was observed that the hyaluronic acid-loaded cetyl myristoleate added formulation statistically significantly increased the improvement compared to the control group and the market product. MMP3 and caspase-3 positive cells were examined by immunohistochemical method. In the results obtained, the addition of cetyl myristoleate as an excipient to the formulation loaded with hyaluronic acid showed a synergistic effect and decreased MMP3 expression in a statistically significant way. However, the number of Caspase-3 positive cells was also significantly reduced in the group to which the formulation was applied. Transmission electron microscope images revealed that in the osteoarthritis animal group, cell integrity were disrupted, microvilli structures degenerated and vacuolization was detected in the cytoplasm of the chondrocytes. The cells showed normal morphology when compared with the patient in the animal groups.In conclusion, the created microemulsion technology may provide a more effective and prolonged therapy of hyaluronic acid in the treatment of osteoarthritis compared to conventional medications.

This study investigated the anti-cancer effects of the chemically characterized Tilia species (linden) on MIA PaCa-2 cells by analyzing various cancer-triggering mechanisms, including oxidative stress and inflammation status. Extracts from the flowers, bracts, and inflorescences of T. cordata, T. platyphyllos, T. rubra, and T. tomentosa were evaluated for antioxidant activity; subsequently, their ability to mitigate inflammation was assessed through in vitro nitrite assays in LPS-induced RAW264.7 cells. The anticancer potentials of the extracts against MIA PaCa-2 pancreatic cancer cells were investigated in 2D (cytotoxic effect) and 3D (effect on spheroid growth) models in vitro. All investigated Tilia species displayed remarkable antioxidant activity and significantly inhibited LPS-induced nitrite, IL-6, and PGE2 production. Extract from T. rubra bracts showed the highest cytotoxic activity against MIA PaCa-2 cells with an IC50 value of 0.16 mg/mL, as well as the most significant delay on spheroid growth, which was further confirmed through the arrest in cell cycle. In the Annexin V cell death assays of T. rubra, cells treated with the flower extract exhibited the highest rate of necrotic population with 66.53%. Overall, our results highlight a potential use for Tilia extracts, particularly T. rubra, in pancreatic cancer treatment by modulating cell death.

Acetaminophen (APAP) is one of the most widely used analgesic and antipyretic agents for the management of mild to moderate pain. Though clinically safe at therapeutic doses, excessive use causes severe toxicity due to reactive metabolites inducing oxidative stress and hepatotoxicity. Sideritis congesta, has been traditionally utilized for its anti-inflammatory, anti-ulcer, antioxidant, and antimicrobial properties. In the present study, we aimed to investigate the potential protective effects of S. congesta aqueous and hydroalcoholic extract against APAP-induced cytotoxicity and oxidative stress in HepG2 cell line. The anti-inflammatory and anti-mutagenic activities of S. congesta AE has been evaluated. Moreover, bioactive compounds were further analyzed using in silico methodologies to predict biological activities. Our findings revealed that APAP treatment significantly reduced SOD and CAT activity along with GSH level, whereas pretreatment with S.congesta extracts effectively restored their activities. Additionally, APAP-induced elevated MDA levels, was significantly mitigated by S. congesta extracts. Moreover, its extracts demonstrated potent antimutagenic activity. These findings show that S. congesta has strong hepatoprotective effects against APAP-induced oxidative stress and cytotoxicity. Its ability to modulate antioxidant defense systems, inhibit lipid peroxidation, and exert anti-inflammatory and anti-mutagenic effects underscores its potential as a natural therapeutic candidate for mitigating APAP-induced toxicity.

The use of ocular inserts (OS) as vehicles for the delivery of antimicrobial agents to the eye is rapidly growing. In fact, the intraOS can deliver the antibiotics to the ocular surface after ophthalmic surgeries i.e., cataract. This was a rational progress of pharmaceutical field given that the conventional dosage forms i.e., drops present many limitations. Considering this fact, in this study novel nanofibrous inserts based on poly(epsilon-caprolactone) and poly(lactic acid) prepared via electrospinning process and used to load an antibiotic drug, moxifloxacin. The used aliphatic polyesters are biocompatible but do not present mucoadhesion which is essential for ocular drug delivery. Therefore, two known mucoadhesive agents, hyaluronic acid and xanthan gum, were blended in various concentrations (0.1 and 0.2%) and used for the coating of the fibers. The fibrous inserts have mean diameters in the range 500-1000 nm. The inserts showed stability over time, improved water uptake and improved mechanical properties. In vitro cytotoxicity studies revealed the biocompatibility of the structures. From in vitro release studies, a controlled release rate was depicted while the inserts demonstrated desirable antimicrobial properties. It can be concluded that the coated OS can be potent ocular delivery carriers of moxifloxacin battling against eye infections. [GRAPHICS] .

Due to the serious gastrointestinal side effects associated with prolonged use of current anti-inflammatory therapies, various strategies such as the regulation of nitric oxide (NO) and prostaglandin E2 (PGE2) production have been explored in the field of anti-inflammatory drug development. In this study, a series of disubstituted 1,3,4-oxadiazoles (3a-f and 4a-f) and their cyclized 1,2,4-triazole derivatives (5a-e and 6a-e) were synthesized and tested for their NO, PGE2, and interleukin-6 (IL-6) releasing inhibition ability. All of the compounds were observed to reduce lipopolysaccharide (LPS)-induced nitrite production in a concentration-dependent manner. Moreover, compounds 3b (50 μM) and 6d (1 μM) exhibited 63% and 49% inhibition, respectively, while indomethacin showed 52% at 100 μM. Based on a preliminary NO inhibition assay, 10 of the compounds (3a, 3b, 3e, 4b, 4d, 6a-e) were selected to be evaluated for in vitro PGE2, IL-6, and inducible nitric oxide synthase (iNOS) inhibition. Notably, compound 6d proved to be the most active of the series with the lowest dose (1 µM), in comparison to the other further tested compounds (5-100 µM) and the reference drug indomethacin (100 µM). The inhibitory activity of the compounds was supported by docking simulations into the binding site of the iNOS protein receptor (Protein Data Bank [PDB]ID: 3E7G). The data showing that 4d reduced iNOS levels the most can be explained by the H-bond with Tyr347 through oxadiazole and π-halogen interactions through the p-bromo, in addition to aromatic interactions with protoporphyrin IX.

In this work, a series of phenyl-derivatives of spirofuran-triazolo[1,5-a]pyrimidine (5 a-i) were evaluated for their anti-inflammatory and analgesic activities, including SAR and molecular docking studies. The cytotoxicity of compounds was studied in RAW 264.7 murine macrophage cell line by MTT assay. Then, those with cell viability higher than 70 % were tested for their anti-inflammatory activity at their non-toxic doses by evaluating the nitrite level of the cell supernatants with the Griess reagent. Compounds 5 b, 5 d, 5 e, and 5 g demonstrated significant inhibition of nitrite production by 49 %, 59 %, 63 % respectively at 100 mu M (p<0.05), whereas 56 % inhibition was seen with 50 mu M of 5 g. According to the inhibition of PGE(2), compound 5 b showed the most notable effect compared to control. All tested compounds, particularly 5 b, 5 d, 5 e and 5 f reduced the PGE(2) level and showed potential analgesic activity. Seven heterocycles 5 a-g showed moderate to significant anti-inflammatory and analgesic activities. Molecular docking predicts modest or no inhibition of 5 a-i with COX-1. Instead, the modelling results also show that these molecules can effectively bind to the enzymes COX-2 and mPGES-2. However, the simulation distinguished the key role of the 2-OH group in stabilizing the inhibitor-target complex only in the case of binding to COX-2.

Two novel ibuprofen cystamine salts (IBU-CYS 1 and IBU-CYS 2) are synthesized by coupling the anion of ibuprofen with cystamine dihydrochloride in 1 : 1 and 2 : 1 ratio to improve the solubility and bioavailability of ibuprofen. The salts are characterized by 1H NMR, FT-IR and UV-Vis spectroscopy, differential scanning calorimetry (DSC), thermogravimetry (TGA, DTA) and X-ray diffraction measurements. IBU-CYS 1 and IBU-CYS 2 show higher solubility (6.11 and 7.81 mg/mL) compared to ibuprofen (0.04 mg/mL) in water. IBU-CYS2 was encapsulated into 2-hydroxyethyl methacrylate: poly (ethylene glycol) acrylate hydrogels for enhanced delivery. The in vitro studies in PBS (pH 7.4) indicate that the salts are effective in relieving inflammatory responses induced by lipopolysaccharide in RAW264.7 macrophage cells (nitrite inhibition percentages of IBU-CYS 1, IBU-CYS 2 and ibuprofen: approximately 34.29, 27.03 and 31.50 respectively) while indicating no cytotoxicity. Therefore, these salts may be promising candidates for the development of effective formulations of this drug.