Marine Natural Product for Pesticide Candidate: Pulmonarin Alkaloids as Novel Antiviral and Anti-Phytopathogenic-Fungus Agents.

Plant diseases are seriously endangering agricultural production. The emergence of drug resistance has brought great challenges to the prevention and control of plant diseases. There is an urgent need for the emergence of new drug candidates. In this work, we achieved the efficient synthesis of pulmonarins A and B in 64% and 59% overall yield, respectively. Pulmonarins A and B were found to have good antiviral activities against tobacco mosaic virus (TMV) for the first time. A series of pulmonarin derivatives were designed, synthesized, and evaluated for their antiviral and fungicidal activities systematically. Most compounds displayed higher anti-TMV activities than commercial ribavirin. Compounds 6a, 6c, and 6n with better inactivation effects than ningnanmycin emerged as new antiviral candidates. We selected 6c for further antiviral mechanism research, which revealed that it could inhibit virus assembly by interacting with TMV coat protein (CP). The molecular docking results further confirmed that these compounds could interact with CP through hydrogen bonding. These compounds also displayed broad spectrum fungicidal activities. Especially compound 6u with prominent antifungal activity emerged as a new fungicidal candidate for further research. The current work provides a reference for understanding the application of pulmonarin alkaloids in plant protection.

Mild temperature photothermal assisted anti-bacterial and anti-inflammatory nanosystem for synergistic treatment of post-cataract surgery endophthalmitis.

Rationale: Endophthalmitis, which is one of the severest complications of cataract surgeries, can seriously threaten vision and even lead to irreversible blindness owing to its complicated microenvironment, including both local bacterial infection and severe inflammation. It is urgent to develop a comprehensive treatment for both anti-bacterial and anti-inflammatory effects. Methods: Herein, we developed AuAgCu2O-bromfenac sodium nanoparticles (AuAgCu2O-BS NPs), which was designed to combine anti-bacterial and anti-inflammatory effects for integrated therapy of endophthalmitis after cataract surgery. The AuAgCu2O-BS NPs could eradicate methicillin-resistant Staphylococcus aureus (MRSA) bacterial strain relied on their photodynamic effects and the release of metal ions (Ag+ and Cu+) by the hollow AuAgCu2O nanostructures mediated mild photothermal effects. The anti-inflammatory drug, bromfenac sodium, released from the nanoparticles were able to significantly reduce the local inflammation of the endophthalmitis and promote tissue rehabilitation. In vivo bacterial elimination and anti-inflammation were confirmed by a postcataract endophthalmitis rabbit model. Results: Excellent antibacterial ability of AuAgCu2O-BS NPs was verified both in vitro and in vivo. Ophthalmological clinical observation and pathologic histology analysis showed prominent treatment of inflammatory reaction. Importantly, the mild temperature photothermal effect not only promoted the release of metal ions and bromfenac sodium but also avoided the thermal damage of the surrounding tissues, which was more suitable for the practical application of ophthalmology due to the complex structure of the eyeball. Moreover, superior biocompatibility was approved by the preliminary toxicity investigations, including low cytotoxicity, negligible damage to major organs, and stable intraocular pressure. Conclusions: Our studies of nanosystem provide a promising synergic therapeutic strategy for postcataract endophthalmitis treatment with favorable prognosis and promise in clinical translations.

Protective effect of bromfenac sodium on femtosecond laser­assisted cataract surgery via modulating cyclooxygenase­2 expression.

Cataract is a blinding­caused disease and affects millions of individuals worldwide. Although conventional phacoemulsification (CPCS) has been widely used for treatment of cataract, the incidence of cataract­caused blindness still increased year by year. Recently, femtosecond laser technology has been expanded to variety of clinical applications, including cataract surgery. The present study evaluated the curative effect of bromfenac sodium (BS) after femtosecond laser­assisted cataract surgery (FLACS) and analyzed the mechanism of action. A total of 90 patients were randomly divided into five groups: Group I, conventional phacoemulsification treatment (CPCS) + dexamethasone (DEX)/tobramycin (TOB); group II, CPCS + bromfenac sodium (BS); group III, Femtosecond laser­assisted cataract surgery (FLACS) + DEX/TOB; group IV, FLACS + BS; and group V, FLACS + pranoprofen. Aqueous humor was collected from these patients post­surgery. For in vitro studies, SRA01/04 cells were irradiated using UV, followed by the collection of culture media and cell lysate. Prostaglandin E2 (PGE2) levels, an indicator of inflammation, were measured using ELISA both in vivo and in vitro. In addition, cyclooxygenase (COX) and cleaved caspase­1 p20 expression levels were analyzed using western blotting. The findings suggested that BS was more effective and safer compared with glucocorticoids (GCs) after cataract surgery. BS can protect against post­operative inflammation by inhibiting PGE2 production. Under in vitro conditions BS prevented the SRA01/04 cells from undergoing apoptosis after UV treatment and also suppressed PGE2 release from UV­irradiated SRA01/04 cells by modulating COX­2 expression. Furthermore, BS may have an inhibitory effect on the inflammatory form of cell death. Overall, these results indicated that BS could replace existing GCs as a reliable drug for a perioperative period of cataract surgery. It was also identified that the inhibitory effect of BS on PGE2 production was mediated via the regulation of COX­2.

CX-F9, a novel RSK2 inhibitor, suppresses cutaneous melanoma cells proliferation and metastasis through regulating autophagy.

Approximately 60% of melanoma have BRAF mutation which leads to the abnormal activation of MAPK signaling pathway. Therefore, targeting these signaling pathways is particularly important for melanoma therapy. Ribosomal S6 Kinase 2 (RSK2) is a downstream target of ERK1/2 in MAPK/ERK pathway and inhibition of RSK2 suppresses the tumorigenesis and metastasis of neoplasm. We investigated whether CX-F9, a novel RSK2 inhibitor predicted by computer, inhibits the malignant phenotype of melanoma cells. In this study, we found knockdown of RSK2 expression in melanoma cells induces autophagy and inhibits its proliferation, migration and invasion. CX-F9 directly binds to RSK2 and inhibits the kinase activity. CX-F9 significantly suppressed cell proliferation, induced autophagy, apoptosis and cycle arrest, as well as inhibited migration and invasion in SK-MEL-5 and SK-MEL-28 cells. Western blotting revealed that CX-F9 declined the activation of p-CREB. Moreover, CX-F9 inhibited tumor formation and metastasis in vivo. Furthermore, CX-F9 suppressed cell proliferation, migration, invasion in BRAF inhibitor resistant melanoma cells. These findings reveal a new RSK2 inhibitor CX-F9 could significantly suppressed malignant phenotype of melanoma in vitro and in vivo, which provide a novel strategy for melanoma treatment in clinic.

Bromfenac Inhibits TGF-ß1-Induced Fibrotic Effects in Human Pterygium and Conjunctival Fibroblasts.

Purpose: Nonsteroidal anti-inflammatory drugs (NSAIDs) have shown antifibrotic effects on several diseases. The aims of the present in vitro study were to investigate the antifibrotic effects of bromfenac (a kind of NSAID) on primary human pterygium fibroblasts (HPFs) and primary human conjunctival fibroblasts (HConFs), as well as to explore the possible mechanisms of these effects. Methods: The cells used in this study were primary HPFs and HConFs, and profibrotic activation was induced by transforming growth factor-beta1 (TGF-ß1). Western blot, quantitative real-time PCR, and immunofluorescence (IF) assays were used to detect the effects of TGF-ß1 and bromfenac on the synthesis of fibronectin (FN), type III collagen (COL3), and alpha-smooth muscle actin (α-SMA) in HPFs and HConFs; the changes of signaling pathways were detected by Western blot; cell migration ability was detected by wound healing assay; cell proliferation ability was detected by CCK-8 assay; and pharmaceutical inhibitions of the downstream signaling pathways of TGF-ß1 were used to assess their possible associations with the effects of bromfenac. Results: Bromfenac suppressed the TGF-ß1-induced protein expression of FN (0.59 ± 0.07 folds, P = 0.008), COL3 (0.48 ± 0.08 folds, P = 0.001), and α-SMA (0.61 ± 0.03 folds, P = 0.008) in HPFs. Bromfenac also attenuated TGF-ß1-induced cell migration (0.30 ± 0.07 folds, P < 0.001), cell proliferation (0.64 ± 0.03 folds, P = 0.002) and the expression levels of p-AKT (0.66 ± 0.08 folds, P = 0.032), p-ERK1/2 (0.69 ± 0.11 folds, P = 0.003), and p-GSK-3ß-S9 (0.65 ± 0.10 folds, P = 0.002) in HPFs. PI3K/AKT inhibitor (wortmannin) and MEK/ERK inhibitor (U0126) reduced the TGF-ß1-induced synthesis of FN, COL3, and α-SMA in HPFs. All the results were similar in HConFs. Conclusions: Bromfenac protects against TGF-ß1-induced synthesis of FN, α-SMA, and COL3 in HPFs and HConFs at least in part by inactivating the AKT and ERK pathways.

Inhibition of Copper Transport Induces Apoptosis in Triple-Negative Breast Cancer Cells and Suppresses Tumor Angiogenesis.

Treatment of advanced breast cancer remains challenging. Copper and some of the copper-dependent proteins are emerging therapeutic targets because they are essential for cell proliferation and survival, and have been shown to stimulate angiogenesis and metastasis. Here, we show that DCAC50, a recently developed small-molecule inhibitor of the intracellular copper chaperones, ATOX1 and CCS, reduces cell proliferation and elevates oxidative stress, triggering apoptosis in a panel of triple-negative breast cancer (TNBC) cells. Inhibition of ATOX1 activity with DCAC50 disrupts copper homeostasis, leading to increased copper levels, altered spatial copper redistribution, and accumulation of ATP7B to the cellular perinuclear region. The extent and impact of this disruption to copper homeostasis vary across cell lines and correlate with cellular baseline copper and glutathione levels. Ultimately, treatment with DCAC50 attenuates tumor growth and suppresses angiogenesis in a xenograft mouse model, and prevents endothelial cell network formation in vitro Co-treatment with paclitaxel and DCAC50 enhances cytotoxicity in TNBC and results in favorable dose reduction of both drugs. These data demonstrate that inhibition of intracellular copper transport targets tumor cells and the tumor microenvironment, and is a promising approach to treat breast cancer.

Total Synthesis of Pulmonarin B and Design of Brominated Phenylacetic Acid/Tacrine Hybrids: Marine Pharmacophore Inspired Discovery of New ChE and Aß Aggregation Inhibitors.

A marine natural product, pulmonarin B (1), and a series of related tacrine hybrid analogues were synthesized and evaluated as cholinesterase (ChE) inhibitors. The in vitro ChE assay results revealed that 1 showed moderate dual acetylcholinesterase (AChE)/ butyrylcholinesterase (BChE) inhibitory activity, while the hybrid 12j proved to be the most potent dual inhibitor among the designed derivatives, being almost as active as tacrine. Molecular modeling studies together with kinetic analysis suggested that 12j interacted with both the catalytic active site and peripheral anionic site of AChE. Compounds 1 and 12j could also inhibit self-induced and AChE-induced Aß aggregation. In addition, the cell-based assay against the human hepatoma cell line (HepG2) revealed that 1 and 12j did not show significant hepatotoxicity compared with tacrine and donepezil. Taken together, the present study confirmed that compound 1 was a potential anti-Alzheimer's disease (AD) hit, and 12j could be highlighted as a multifunctional lead compound for anti-AD drug development.

Unfolding of the myosin head by purealin in glycerol.

Purealin is a small bioactive compound obtained from the marine sponge. The compound modulates various types of ATPase activity of myosin from skeletal muscle, cardiac muscle, and smooth muscle. To elucidate the structural basis of these effects of purealin on myosin ATPases, we examined the effect of purealin on the conformation of skeletal muscle myosin in aqueous solution and in glycerol. Analysis of the circular dichroism spectrum of subfragment 1, a single-headed fragment of myosin, revealed that in 10% glycerol purealin decreased the ß-sheet content of S1, but in aqueous solution it had little effect on the secondary structure of S1. A myosin monomer conforms to two pear-like globular heads attached to a long tail. Electron microscopy observations with rotary shadowing revealed that purealin unfolded each globular head to an extended single strand. The tips of the unfolded strand bound each other and formed a ring in one molecule. These results suggest that binding of purealin affects the critical parameters of myosin folding.

[Comparison of the effects of 0.1% bromfenac sodium eye drops and corticosteroids after small incision lenticule extraction].

Objective: To study the safety, efficacy and tolerability of the usage of 0.1% bromfenac sodium eye drops in small incision lenticule extraction (SMILE). Methods: Prospective case control study. Three groups were observed, including 60 patients (60 eyes) undergoing SMILE for myopia. After surgery, 20 patients (20 eyes) were treated with 0.1% bromfenac sodium eye drops twice daily for 10 days, 20 patients (20 eyes) were treated with topical compound tobramycin eye drops 4 times daily for 10 days, and 20 patients (20 eyes) were treated with topical compound tobramycin eye drops 4 times daily for 3 days and 0.1% bromfenac sodium eye drops twice daily thereafter for 7 days. All of the patients were examined preoperatively and at 1 day, 10 days, 1 month and 3 months postoperatively, including visual acuity, intraocular pressure, topography and adverse reactions. The differences among the 3 groups were analyzed by the single factor analysis of variance. Results: There was no significant difference among the 3 groups in the uncorrected visual acuity at 10 days, 1 month and 3 months postoperatively (F=0.77, 0.30, 0.36. P=0.47, 0.75, 0.69) . The intraocular pressure in the dexamethasone group at 10 days, 1 month and 3 months postoperatively was higher than the other two groups with no significant difference (F=0.56, 0.98, 0.63. P=0.57, 0.38, 0.54) . The surface asymmetry index of patients was 0.33±0.10, 0.50±0.17 and 0.55±0.21 in the bromfenac sodium group, 0.33±0.08, 0.49±0.16 and 0.60±0.37 in the dexamethasone-bromfenac sodium group, and 0.31±0.12, 0.52±0.23 and 0.55±0.19 in the dexamethasone group; preoperatively and at 1 and 3 months, respectively. There was no significant difference among the 3 groups in the surface asymmetry index at 1 and 3 months postoperatively (F=0.09, 0.21. P=0.91, 0.81) . The surface regularity index of patients was 0.15±0.12, 0.34±0.18 and 0.40±0.18 in the bromfenac sodium group, 0.18±0.17, 0.33±0.26 and 0.33±0.26 in the dexamethasone-bromfenac sodium group, and 0.30±0.25, 0.41±0.28 and 0.34±0.29 in the dexamethasone group preoperatively and at 1 and 3 months, respectively. There was no significant difference among the 3 groups in the surface regularity index at 1 and 3 months postoperatively (F=0.74, 0.39. P= 0.48, 0.68) . In the bromfenac sodium group, one patient complained of binocular visual fatigue at 10 days, and one patient complained of dryness in one eye at 1 and 3 months. Conclusion: Bromfenac sodium eye drops can be used to replace corticosteroids after SMILE procedure with high safety and good tolerance. Satisfactory recovery of visual acuity, intraocular pressure and ocular surface could be achieved. (Chin J Ophthalmol, 2017, 53: 18-22).

Topical 0.1% Bromfenac Sodium for Intraoperative Miosis Prevention and Prostaglandin E2 Inhibition in Femtosecond Laser-Assisted Cataract Surgery.

PURPOSE: The purpose of this study was to evaluate the effect of topical 0.1% bromfenac sodium, a nonsteroidal anti-inflammatory drug (NSAID), on intraoperative pupil dilation maintenance and prostaglandin E2 (PGE2) inhibition during femtosecond laser-assisted cataract surgery. METHODS: Sixty patients (30 each in study and control groups) were included in this study. The patients received 0.1% bromfenac ophthalmic solution or control placebo twice a day for 3 days before surgery. Pupil size was measured at the initiation of femtosecond laser pretreatment and phacoemulsification. Aqueous humor was collected at the beginning of routine cataract surgery. PGE2 levels were measured with an enzyme-linked immunoassay. Laser flare photometry was measured preoperatively and at 1 day postoperatively. RESULTS: Compared with untreated patients, the change in pupil size and postoperative day 1 aqueous flare were significantly reduced throughout the operation in the patients treated with 0.1% bromfenac (P < 0.001). Mean PGE2 concentrations were also significantly decreased by treatment with 0.1% bromfenac (P < 0.001). The reduction of the pupil area and postoperative day 1 aqueous flare were significantly correlated with PGE2 levels (P < 0.001). CONCLUSION: NSAID treatment, when administered before femtosecond laser-assisted cataract surgery, was effective in maintaining intraoperative pupil dilation, preventing miosis, and reducing PGE2 levels.

Synthesis and cytotoxic activity of novel hexahydropyrrolo[2,3-b]indole imidazolium salts.

A series of novel hexahydropyrrolo[2,3-b]indole-1H-imidazolium salts were synthesized and evaluated in vitro against a panel of human tumor cell lines. The results suggest that the 5,6-dimethyl-benzimidazole ring, and substitution of the imidazolyl-3-position with a 2-bromobenzyl or 2-naphthylmethyl group, were important for the cytotoxic activity. Notably, Compound 43, bearing a 2-bromobenzyl substituent at position-3 of 5,6-dimethyl-benzimidazole, was found to possess the most potent derivative against five human tumor cell lines with IC50 values below 2.68µM and more selective towards SMMC-7721, A549 and SW480 cell lines. Compounds 25 and 39 were more selective to HL-60 and MCF-7 cell lines with IC50 values of 0.47 and 1.46µM.

The Effects of Two Non-Steroidal Anti-Inflammatory Drugs, Bromfenac 0.1% and Ketorolac 0.45%, on Cataract Surgery.

PURPOSE: To compare the additive effects of two types of non-steroidal anti-inflammatory drugs (NSAIDs), bromfenac 0.1% or ketorolac 0.45%, relative to topical steroid alone in cataract surgery. MATERIALS AND METHODS: A total 91 subjects scheduled to undergo cataract operation were randomized into three groups: Group 1, pre/postoperative bromfenac 0.1%; Group 2, pre/postoperative preservative-free ketorolac 0.45%; and Group 3, postoperative steroid only, as a control. Outcome measures included intraoperative change in pupil size, postoperative anterior chamber inflammation control, change in macular thickness and volume, and ocular surface status after operation. RESULTS: Both NSAID groups had smaller intraoperative pupil diameter changes compared to the control group (p<0.05). There was significantly less ocular inflammation 1 week and 1 month postoperatively in both NSAID groups than the control group. The changes in central foveal subfield thickness measured before the operation and at postoperative 1 month were 4.30±4.25, 4.87±6.03, and 12.47±12.24 µm in groups 1 to 3, respectively. In the control group, macular thickness and volume increased more in patients with diabetes mellitus (DM), compared to those without DM. In contrast, in both NSAID groups, NSAIDs significantly reduced macular changes in subgroups of patients with or without DM. Although three ocular surface parameters were worse in group 1 than in group 2, these differences were not significant. CONCLUSION: Adding preoperative and postoperative bromfenac 0.1% or ketorolac 0.45% to topical steroid can reduce intraoperative miosis, postoperative inflammation, and macular changes more effectively than postoperative steroid alone.

Bioactive secondary metabolites from the Red Sea marine Verongid sponge Suberea species.

In a continuation of our efforts to identify bioactive compounds from Red Sea Verongid sponges, the organic extract of the sponge Suberea species afforded seven compounds including two new dibrominated alkaloids, subereamollines C and D (1 and 2), together with the known compounds aerothionin (3), homoaerothionin (4), aeroplysinin-1 (5), aeroplysinin-2 (6) and a revised subereaphenol C (7) as ethyl 2-(2,4-dibromo-3,6-dihydroxyphenyl)acetate. The structures of the isolated compounds were assigned by different spectral data including optical rotations, 1D (1H and 13C) and 2D (COSY, multiplicity-edited HSQC, and HMBC) NMR and high-resolution mass spectroscopy. Aerothionin (3) and subereaphenol C (7) displayed potent cytotoxic activity against HeLa cell line with IC50 values of 29 and 13.3 µM, respectively. In addition, aeroplysinin-2 (6) showed potent antimigratory activity against the human breast cancer cell line MDA-MB-231 with IC50 of 18 µM. Subereamollines C and D are new congeners of the previously reported compounds subereamollines A and B with methyl ester functionalities on the side chain. These findings provide further insight into the biosynthetic capabilities of members of the genus Suberea and the chemical diversity as well as the biological activity of these compounds.

Trabecular meshwork bradykinin receptors: mRNA levels, immunohistochemical visualization, signaling processes pharmacology, and linkage to IOP reduction.

PURPOSE: To localize mRNA and protein of bradykinin (BK) receptors, BK precursor polypeptide (kininogen) mRNA, and to study functional biochemical pharmacology of the signal transduction processes mediated by B2-receptors in isolated human trabecular meshwork (h-TM) cells. Intraocular pressure (IOP) lowering effects of 2 kinins were also investigated. METHODS: Previously documented procedures were utilized throughout these studies. RESULTS: Kinninogen mRNA was most abundant in TM, ciliary body (CB), and optic nerve head and appeared elevated in glaucomatous h-TM tissue. High levels of B2-receptor mRNA were found in the sclera, iris, TM, and CB. B2-receptor subtype protein was localized in cells of the monkey and h-TM, and the treatment of isolated h-TM cells with transforming growth factor-ß2 (5 ng/mL) caused significant (P<0.04) downregulation of B2-receptor mRNA. In isolated primary h-TM cells, BK (EC50=0.8±0.2 nM; n=19) and Met-Lys-BK (EC50=6.5±1.5 nM) mobilized intracellular Ca(2+) and induced the release of prostaglandins (PGs) that was blocked by 2 B2-receptor antagonists [HOE-140; (S)-WIN-64338]. The cyclooxygenase inhibitor, bromfenac, abolished BK-induced PGs production. BK concentration dependently increased cell impedance, and it significantly (P<0.05) decreased h-TM cell volume in vitro. Intravitreal (ivt) administration of BK (50 µg), but not a B1-agonist (Sar-[D-Phe(9)]-Des-Arg(9)-BK; also at 50 µg), efficaciously lowered IOP (22.9% to 37% from baseline) of Dutch-Belted rabbits that naturally have high IOPs (27-28 mmHg). CONCLUSIONS: BK activates multiple signal transduction pathways in h-TM cells via B2-receptors that also mediate IOP reduction as observed in rabbits following ivt administration of BK. These ocular hypotensive effects of BK may be physiologically important and suggest a novel therapeutic potential of BK-related B2-agonists.

In vitro and in vivo antioxidant and antimutagenic activities of polyphenols extracted from hops (Humulus lupulus L.).

BACKGROUND: Hops (Humulus lupulus L.) contain 40-140 mg g(-1) polyphenols. The objective of this study was to determine the phenolic composition of a high-purity (total phenolic content = 887 mg g(-1) ) hop polyphenol extract (HPE) and evaluate its antioxidant activities in vivo and in vitro and its antimutagenic activity. The antioxidant activity of HPE was compared with the activity of green tea polyphenols. RESULTS: The phenolic compositions of HPE were more than 55% proanthocyanidins and more than 28% flavonoid glycosides. In vitro, HPE effectively scavenged α,α-diphenyl-ß-picrylhydrazyl, hydroxyl and superoxide anion radicals, and inhibited DNA oxidative damage. In vivo, oral HPE at a polyphenol dose of 200-800 mg kg(-1) body weight significantly prevented a bromobenzene-induced decrease in liver superoxide dismutase and glutathione peroxidase activity, and decreased levels of liver thiobarbituric acid reactive substances in bromobenzene-treated mice. An oral dose of 20-80 mg kg(-1) body weight HPE significantly reduced the frequency of bone marrow micronuclei induced by cyclophosphamide. The antioxidant activities of hop polyphenols in vitro and in vivo were higher than green tea polyphenols at the same concentration. CONCLUSION: Hop polyphenols had the same or higher antioxidant activity than tea polyphenols. Hop polyphenols might be useful as natural antioxidants and antimutagens.

Identification of PPARγ ligands with One-dimensional Drug Profile Matching.

INTRODUCTION: Computational molecular database screening helps to decrease the time and resources needed for drug development. Reintroduction of generic drugs by second medical use patents also contributes to cheaper and faster drug development processes. We screened, in silico, the Food and Drug Administration-approved generic drug database by means of the One-dimensional Drug Profile Matching (oDPM) method in order to find potential peroxisome proliferator-activated receptor gamma (PPARγ) agonists. The PPARγ action of the selected generics was also investigated by in vitro and in vivo experiments. MATERIALS AND METHODS: The in silico oDPM method was used to determine the binding potency of 1,255 generics to 149 proteins collected. In vitro PPARγ activation was determined by measuring fatty acid-binding protein 4/adipocyte protein gene expression in a Mono Mac 6 cell line. The in vivo insulin sensitizing effect of the selected compound (nitazoxanide; 50-200 mg/kg/day over 8 days; n = 8) was established in type 2 diabetic rats by hyperinsulinemic euglycemic glucose clamping. RESULTS: After examining the closest neighbors of each of the reference set's members and counting their most abundant neighbors, ten generic drugs were selected with oDPM. Among them, four enhanced fatty acid-binding protein/adipocyte protein gene expression in the Mono Mac 6 cell line, but only bromfenac and nitazoxanide showed dose-dependent actions. Induction by nitazoxanide was higher than by bromfenac. Nitazoxanide lowered fasting blood glucose levels and improved insulin sensitivity in type 2 diabetic rats. CONCLUSION: We demonstrated that the oDPM method can predict previously unknown therapeutic effects of generic drugs. Nitazoxanide can be the prototype chemical structure of the new generation of insulin sensitizers.

Cytotoxic psammaplysin analogues from a Suberea sp. marine sponge and the role of the spirooxepinisoxazoline in their activity.

Seventeen bromotyrosine-derived metabolites, including eight new compounds, were isolated from a Micronesian sponge of the genus Suberea. Four of the new compounds were psammaplysin derivatives (10-13), and the other four were ceratinamine derivatives (14-17). Of the compounds obtained, the psammaplysins exhibited cytotoxicity against human cancer cell lines (GI50 values down to 0.8 µM), while the ceratinamine and moloka'iamine analogues showed almost no activity. These results suggest that the spirooxepinisoxazoline ring system is a requirement for cytotoxicity and, therefore, may serve as an attractive molecular scaffold for the development of a potent anticancer agent.

A new curcumin analogue exhibits enhanced antitumor activity in nasopharyngeal carcinoma.

The aim of the present study was to evaluate the antitumor effects of the curcumin analogue GL63 on radioresistant nasopharyngeal carcinoma (NPC) CNE2R cells and parental CNE2 cells. The cell viability and proliferation of NPC cells were detected by MTT assay and colony formation assay. The suppressive effect on tumor growth was examined using in vivo subcutaneously inoculated NPC tumor models using nude mice. The cell cycle distribution was detected using flow cytometry. Apoptosis was examined by Hoechst 33342 and Annexin V/PI staining assay. The protein expression of endoplasmic reticulum (ER) stress pathway markers, XBP-1, ATF-4 and CHOP, were examined by western blotting. A growth inhibitory effect was observed following treatment with GL63 in a dose-dependent manner and was more potent when compared to curcumin. GL63 at 5 µM induced significant G2/M arrest and apoptosis in NPC. The tumor-suppressive activity of GL63 in NPC xenograft models was more potent when compared to curcumin. Furthermore, GL63 induced an ER stress response, upregulation of CHOP, XBP-1 and ATF-4 expression, while the same concentration of curcumin had no effect on ER stress. These results suggest that GL63 has more potent antitumor activity than curcumin, which is associated with activation of ER stress, induction of G2/M arrest and apoptosis in NPC cells.

Attenuation of high-glucose-induced inflammatory response by a novel curcumin derivative B06 contributes to its protection from diabetic pathogenic changes in rat kidney and heart.

There is increasing evidence indicating that inflammatory processes are involved in the development and progression of diabetic complications. However, effective anti-inflammatory treatments for patients who have diabetic complications have yet been practically identified. Curcumin is a main component of Curcuma longa with numerous pharmacological activities. Previously, we synthesized a novel curcumin analogue (B06) that exhibited an improved pharmacokinetic and enhanced anti-inflammatory activity compared to curcumin. The present study aimed to test the hypothesis that B06 may reduce high-glucose-induced inflammation and inflammation-mediated diabetic complications. In vitro, pretreatment with B06 at a concentration of 5 µM significantly reduced the high-glucose-induced overexpression of inflammatory cytokines in macrophages. This anti-inflammatory activity of B06 is associated with its inhibition of c-Jun N-terminal kinase/nuclear factor κB activation. In vivo, despite that B06 administration at 0.2 mg · kg(-1) · d(-1) for 6 weeks did not affect the blood glucose profile of diabetic rats, the B06-treated animals displayed significant decreases in inflammatory mediators in the serum, kidney, and heart and renal macrophage infiltration. This was accompanied with an attenuation of diabetes-induced structural and functional abnormalities in the kidney and heart. Taken together, these data suggest that the novel derivative B06 might be a potential therapeutic agent for diabetic complications via an anti-inflammatory mechanism and support the potential application in diabetic complication therapy via anti-inflammatory strategy.

Prostaglandin E2 inhibition of ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% in patients undergoing phacoemulsification.

INTRODUCTION: We compared the prostaglandin E(2) (PGE(2)) inhibition of three topical nonsteroidal antiinflammatory drugs (NSAIDs): ketorolac 0.45%, bromfenac 0.09%, and nepafenac 0.1% at peak dosing levels in patients previously scheduled to undergo phacoemulsification. METHODS: This was a single-center, double-masked observational study of 121 patients randomized to one of three NSAID treatment arms. Patients were instructed to take the NSAID per on-label dosing (twice daily [b.i.d.] for ketorolac 0.45% and bromfenac 0.09%, three times a day [t.i.d.] for nepafenac 0.1%) for 1 day before surgery, and were to instill one drop the morning of surgery. Each patient received an additional four doses 1 hour prior to undergoing phacoemulsification. After completion of the paracentesis site with a super blade, aqueous humor (0.15 mL) was collected through the peripheral clear cornea with a 30 G needle attached to a tuberculin (TB) syringe. Aqueous humor samples were stored at -40°C prior to analysis, and diluted 1:10 with diluent. Assays were conducted on multiple plates in duplicate (seven standards per plate). RESULTS: The mean (±SD) PGE(2) concentrations were 224.8±164.87 pg/mL for ketorolac 0.45% (n=42), 288.7±226.05 pg/mL for bromfenac 0.09% (n=41), and 320.4±205.6 pg/mL for nepafenac 0.1% (n=38). The difference between ketorolac 0.45% and nepafenac 0.1% was statistically significant (P=0.025). The difference between bromfenac 0.09% and nepafenac 0.1% was not significantly different (P=0.516). CONCLUSIONS: Ketorolac 0.45% achieved the greatest inhibition of PGE(2) compared to nepafenac 0.1% and bromfenac 0.09%. Ketorolac 0.45% may be more efficacious at controlling inflammation at the time of cataract surgery versus nepafenac 0.1% and bromfenac 0.09%.