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Abstract: We investigated nitric oxide ( NO)-mediated proteosomal activation in bovine aortic endothelial cells (BAEC) treated with varying fluxes of hydrogen peroxide (H2O2) generated from glucose/glucose oxidase (Glu/GO). Results revealed a bell-shaped NO signaling response in BAEC treated with Glu/GO (2–20 mU/ml). GO treatment (2 mU/ml) enhanced endothelial nitric oxide synthase (eNOS) phosphorylation and NO release in BAEC. With increasing GO concentrations, phospho eNOS and NO levels decreased. Bell-shaped responses in proteasomal function and NO induction were observed in BAEC treated with varying levels of GO (2–10 mU/ml). Proteosomal activation induced in GO-treated BAEC was inhibited by N ω-nitro-l-arginine-methyl ester pretreatment, suggesting that NO mediates proteasomal activation. Intracellular NO induced by H2O2 was detected by isolating the 4,5-diaminoflourescein (DAF-2)/ NO/O2-derived “green fluorescent product” using the high-performance liquid chromatography–fluorescence technique, a more rigorous and quantitative methodology for detecting the DAF-2/ NO/O2 reaction product. Finally, the relationships between H2O2 flux, proteasomal activation/inactivation, endothelial cell survival, and apoptosis are discussed. [Copyright &y& Elsevier]

Abstract: Nitric oxide ( NO) was shown to stimulate the proteasomal function and the ubiquitin-proteasome pathway and to ameliorate endothelial apoptotic signaling induced by oxidants. Understanding the regulatory mechanisms by which NO stimulates proteasomes and affords cytoprotection in endothelial cells has therapeutic implications, as many vascular diseases are characterized by a deficiency in NO. Here we report that NO/cGMP/cAMP-induced immunoproteasome subunit expression is responsible for the increased proteasomal activities. Cells pretreated with protein kinase G and protein kinase A inhibitors markedly attenuated NO-dependent proteasome activation. Results show that the NO/cGMP/cAMP signaling mechanism enhanced the phosphorylation of the transcription factor cAMP-response element-binding protein, elevated the cAMP-response element-promoter activity and induced the expression of immunoproteasomal subunits (LMP2 and LMP7). NO-dependent proteasomal activity was abrogated in cells transfected with antisense LMP2 and LMP7 oligonucleotides. Lower levels of LMP2 and LMP7 were detected in aorta of iNOS−/− mice compared to wild-type controls, suggesting that endogenous production of NO is important in the basal regulation of immunoproteasome. The NO/cGMP/cAMP signaling pathway mitigates transferrin-iron-mediated oxidative stress and apoptosis through induction of immunoproteasomes. These results provide new insights on the regulatory mechanisms by which the NO-mediated immunoproteasome signaling pathway affords cytoprotection in endothelial cells. [Copyright &y& Elsevier]

Abstract: In this study, we investigated the molecular mechanism of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes parkinsonism in experimental animals and humans. Using wild-type and human neuronal nitric oxide synthase (nNOS) stably transfected neuroblastoma cells (SH-SY5Y), we showed that nNOS overexpression in SH-SY5Y cells greatly enhanced proteasome activity and mitigated MPP+-induced apoptosis. During MPP+-induced oxidative stress, intracellular BH4 levels decreased, resulting in nNOS “uncoupling” (i.e., switching from nitric oxide to superoxide generation). Increasing the intracellular BH4 levels by sepiapterin supplementation restored the nNOS activity, inhibited superoxide formation, increased proteasome activity, decreased protein ubiquitination, and attenuated apoptosis in MPP+-treated cells. Implications of BH4 depletion in dopaminergic cells and sepiapterin supplementation to augment the striatal nNOS activity in the pathogenesis mechanism and treatment of Parkinson disease are discussed. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to test the hypothesis whether Mito-carboxy proxyl (Mito-CP), a mitochondria-targeted nitroxide, inhibits peroxide-induced oxidative stress and apoptosis in bovine aortic endothelial cells (BAEC). Glucose/glucose oxidase (Glu/GO)-induced oxidative stress was monitored by dichlorodihydrofluorescein oxidation catalyzed by intracellular H2O2 and transferrin receptor-mediated iron transported into cells. Pretreatment of BAECs with Mito-CP significantly diminished H2O2- and lipid peroxide-induced intracellular formation of dichlorofluorescene and protein oxidation. Electron paramagnetic resonance (EPR) studies confirmed the selective accumulation of Mito-CP into the mitochondria. Mito-CP inhibited the cytochrome c release and caspase-3 activation in cells treated with peroxides. Mito-CP inhibited both H2O2- and lipid peroxide-induced inactivation of complex I and aconitase, overexpression of transferrin receptor (TfR), and mitochondrial uptake of 55Fe, while restoring the mitochondrial membrane potential and proteasomal activity. In contrast, the “untargeted” carboxy proxyl (CP) nitroxide probe did not protect the cells from peroxide-induced oxidative stress and apoptosis. However, both CP and Mito-CP inhibited superoxide-induced cytochrome c reduction to the same extent in a xanthine/xanthine oxidase system. We conclude that selective uptake of Mito-CP into the mitochondria is responsible for inhibiting peroxide-mediated Tf-Fe uptake and apoptosis and restoration of the proteasomal function. [Copyright &y& Elsevier]

The mitochondria-targeted drugs mitoquinone (Mito-Q) and mitovitamin E (MitoVit-E) are a new class of antioxidants containing the triphenylphosphonium cation moiety that facilitates drug accumulation in mitochondria. In this study, Mito-Q (ubiquinone attached to a triphenylphosphonium cation) and MitoVit-E (vitamin E attached to a triphenylphosphonium cation) were used. The aim of this study was to test the hypothesis that mitochondria-targeted antioxidants inhibit peroxide-induced oxidative stress and apoptosis in bovine aortic endothelial cells (BAEC) through enhanced scavenging of mitochondrial reactive oxygen species, thereby blocking reactive oxygen species-induced transferrin receptor (TfR)-mediated iron uptake into mitochondria. Glucose/glucose oxidase-induced oxidative stress in BAECs was monitored by oxidation of dichlorodihydrofluorescein that was catalyzed by both intracellular H2O2 and transferrin iron transported into cells. Pretreatment of BAECs with Mito-Q (1 μM) and MitoVit-E (1 μM) but not untargeted antioxidants (e.g. vitamin E) significantly abrogated H2O2- and lipid peroxide-induced 2′,7′-dichlorofluorescein fluorescence and protein oxidation. Mitochondria-targeted antioxidants inhibit cytochrome c release, caspase-3 activation, and DNA fragmentation. Mito-Q and MitoVit-E inhibited H2O2- and lipid peroxide-induced inactivation of complex I and aconitase, TfR overexpression, and mitochondrial uptake of 55Fe, while restoring the mitochondrial membrane potential and proteasomal activity. We conclude that Mito-Q or MitoVit-E supplementation of endothelial cells mitigates peroxide-mediated oxidant stress and maintains proteasomal function, resulting in the overall inhibition of TfR-dependent iron uptake and apoptosis. [ABSTRACT FROM AUTHOR]

In this study, we investigated the molecular mechanisms of toxicity of 1-methyl-4-phenylpyridinium (MPP+), an ultimate toxic metabolite of a mitochondrial neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, that causes Parkinson-like symptoms in experimental animals and humans. We used rat cerebellar granule neurons as a model cell system for investigating MPP+ toxicity. Results show that MPP+ treatment resulted in the generation of reactive oxygen species from inhibition of complex I of the mitochondrial respiratory chain, and inactivation of aconitase. This, in turn, stimulated transferrin receptor (TfR)-dependent iron signaling via activation of the iron-regulatory protein/iron-responsive element interaction. MPP+ caused a time-dependent depletion of tetrahydrobiopterin (BH4) that was mediated by H2O2 and trans-ferrin iron. Depletion of BH4 decreased the active, dimeric form of neuronal nitric-oxide synthase (nNOS). MPP+-mediated ’uncoupling’of nNOS decreased NO and increased superoxide formation. Pretreatment of cells with sepiapterin to promote BH4 biosynthesis or cell-permeable iron chelator and TfR antibody to prevent ironcatalyzed BH4 decomposition inhibited MPP+ cytotoxicity. Preincubation of cerebellar granule neurons with nNOS inhibitor exacerbated MPP+-induced iron uptake, BH4 depletion, proteasomal inactivation, and apoptosis. We conclude that MPP+-dependent aconitase inactivation, Tf-iron uptake, and oxidant generation result in the depletion of intracellular BH4, leading to the uncoupling of nNOS activity. This further exacerbates reactive oxygen species-mediated oxidative damage and apoptosis. Implications of these results in unraveling the molecular mechanisms of neurodegenerative diseases (Parkinson's and Alzheimer's disease) are discussed. [ABSTRACT FROM AUTHOR]

The cytoprotective effects of redox-active metalloporphyrins (e.g., FeTBAP and MnTBAP) were generally attributed to their ability to scavenge reactive oxygen and nitrogen species. In this study, we evaluated the pro- and antiapoptotic potentials of different metalloporphyrins containing iron, cobalt, zinc, and manganese in adult rat cardiomyocytes exposed to doxorubicin (DOX), an anticancer drug that forms superoxide and hydrogen peroxide via redox-cycling of DOX semiquinone in the presence of molecular oxygen. We used electron spin resonance/spin trapping and cytochrome c reduction to assess the scavenging of superoxide anion by metalloporphyrins. Superoxide anion was effectively scavenged by FeTBAP and MnTBAP but not by CoTBAP and ZnTBAP. FeTBAP efficiently scavenged H2O2. Both CoTBAP and FeTBAP inhibited DOX-induced cardiomyocyte apoptosis. These findings implicate that mechanisms other than oxy-radical scavenging may account for their antiapoptotic property. In addition, CoTBAP and FeTBAP induced heme oxygenase-1 more potently than did MnTBAP and ZnTBAP. Inhibition of heme oxygenase abolished the protective effect of CoTBAP and reduced the protection by FeTBAP against DOX-induced cardiomyocyte apoptosis. We propose that metalloporphyrins can inhibit apoptosis either by inducing heme oxygenase-1 and antiapoptotic protein signaling or by scavenging reactive oxygen species. [Copyright &y& Elsevier]

Lipids are responsible for the atheromatous plaque formation during atherosclerosis by their deposition in the subendothelial intima of the aorta, leading to infarction. Sterol regulatory element-binding protein 2 (SREBP2), regulating cholesterol homeostasis, is suggested to play a pivotal role during the early incidence of atherosclerosis through dysregulation of lipid homeostasis. Here we demonstrate that oxidative stress stimulates SREBP2-mediated cholesterol uptake via low density lipoprotein receptor (LDLR), rather than cholesterol synthesis, in mouse vascular aortic smooth muscle cells (MOVAS) and THP-1 monocytes. The enhancement of mature form of SREBP2 (SREBP2-M) during oxidative stress was associated with the inhibition of AMP-activated protein kinase (AMPK) activation. In contrast, inhibition of either SREBP2 by fatostatin or LDLR by siLDLR resulted in decreased cholesterol levels during oxidative stress. Thereby confirming the role of SREBP2 in cholesterol regulation via LDLR. Metformin-mediated activation of AMPK was able to significantly abrogate cholesterol uptake by inhibiting SREBP2-M. Interestingly, although metformin administration attenuated angiotensin (Ang)-II-impaired lipid homeostasis in both aorta and liver tissues of ApoE -/- mice, the results indicate that SREBP2 through LDLR regulates lipid homeostasis in aorta but not in liver tissue. Taken together, AMPK activation inhibits oxidative stress-mediated SREBP2-dependent cholesterol uptake, and moreover, metformin-induced prevention of atheromatic events are in part due to its ability to regulate the SREBP2-LDLR axis. [ABSTRACT FROM AUTHOR]

An abstract of the article "Nitric Oxide, Proteasomal Function, and Iron Homeostasis--Implications in Aging and Neurodegenerative Diseases," by Srigiridhar Kotamraju and colleagues is presented.

Age is a dominant and independent risk factor for the development of atherosclerosis, a major cardiovascular disease, and if left untreated leads to myocardial infarction and death. Mitochondria-targeted anti-oxidants are evolving as a new class of compounds that can alter the pathophysiology of age-related diseases, including atherosclerosis, where mitochondrial dysfunction plays a critical role in disease progression. We recently synthesized an alkyl TPP + -tagged esculetin (mitochondria-targeted esculetin or Mito-Esc). Apoe −/− mice were chronically (14 months) administered with Mito-Esc to investigate its efficacy in the mitigation of atherosclerosis in the setting of aging. We monitored BP, and performed various biochemical assays, histopathology, immunohistochemistry, inflammatory factors, qPCR, and Western blotting. Simultaneously, human aortic endothelial cells (HAECs) were used as a model system to study the mechanistic aspects. A chronic low-dose administration of Mito-Esc to Apoe −/− mice greatly prevented alterations in lipid profile, blood pressure, and atherosclerotic plaque formation in the setting of aging. Mito-Esc administration significantly reduced vascular senescence and pro-inflammatory cytokines levels and prevented dysregulation of mitochondrial biogenesis markers in aortic tissue. Further, Mito-Esc treatment prevented replicative and stress-induced premature senescence (SIPS) in HAEC. Importantly, Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. Moreover, Mito-Esc treatment by altering miR-19b and miR-30c via a SIRT1 activation significantly inhibited the increase in PAI-1 levels in HAEC as well as in the serum of Apoe −/− mice. In addition, Mito-Esc treatment improved mitochondrial function in late passage (aged) HAECs by enhancing the oxygen consumption rate (OCR). Furthermore, Mito-Esc administration counteracted the decline in GSH and nitrite levels in Apoe −/− mice and in HAECs. Overall, Mito-Esc alleviates atherosclerosis in the setting of aging by delaying vascular senescence and pro-inflammatory processes, and by improving mitochondrial biogenesis and function. [Display omitted] • Mito-Esc treatment preserved mitochondrial function in the aged endothelial cells. • Mito-Esc treatment delayed endothelial cell senescence by increasing human telomerase reverse transcriptase (hTERT) levels via SIRT1 activation. • Mito-Esc treatment inhibited the increase in PAI-1 levels through SIRT1 activation. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX), a widely used chemotherapeutic agent, exhibits cardiotoxicity as an adverse side effect in cancer patients. DOX-mediated cardiomyopathy is linked to its ability to induce apoptosis in endothelial cells and cardiomyocytes by activation of p53 protein and reactive oxygen species. We evaluated the potential roles of H2O2 and p53 in DOX-induced apoptosis in normal bovine aortic endothelial cells and adult rat cardiomyo. cytes and in tumor cell lines PA-1 (human ovarian teratocarcinoma) and MCF-7 (human breast adenocareinoma). Time course measurements indicated that activation of caspase-3 preceded the stimulation of p53 transcriptional activity in endothelial cells. In contrast, DOX caused early activation of p53 in tumor cells that was followed by caspase-3 activation and DNA fragmenta. tion. These findings suggest that the transcriptional activation of p53 in DOX-induced apoptosis in endothelial cells may not be as crucial as it is in tumor cells. Further evidence was obtained using a p53 inhibitor, pifithrin-α. Pifithrin-α completely suppressed DOX-induced activation of p53 in both normal and tumor cell lines and prevented apoptosis in tumor cell lines but not in endothelial cells and cardiomyocytes. In contrast, detoxification of H2O2, either by redox-active metalloporphyrin or overexpression of glutathione peroxidase, decreased DOX-induced apoptosis in endothelial cells and cardiomyocytes but not in tumor cells. This newly discovered mechanistic difference in DOX-induced apoptotic cell death in normal versus tumor cells will be useful in developing drugs that selectively mitigate the toxic side effects of DOX without affecting its antitumor action. [ABSTRACT FROM AUTHOR]

1-Methyl-4-phenylpyridinium (MPP+) is a neurotoxin that causes Parkinson's disease in experimental animals and humans. Despite the fact that intracellular iron was shown to be crucial for MPP+-induced apoptotic cell death, the molecular mechanisms for the iron requirement remain unclear. We investigated the role of transferrin receptor (TfR) and iron in modulating the expression of α-synuclein (α-syn) in MPP+-induced oxidative stress and apoptosis. Results show that MPP+ inhibits mitochondrial complex-1 and aconitase activities leading to enhanced H2O2 generation, TfR expression and α-syn expression/aggregation. Pretreatment with cellpermeable iron chelators, TfR antibody (that inhibits TfR-mediated iron uptake), or transfection with glutathione peroxidase (GPx1) enzyme inhibits intracellular oxidant generation, α-syn expression/aggregation, and apoptotic signaling as measured by caspase-3 activation. Cells overexpressing α-syn exacerbated MPP+ toxicity, whereas antisense α-syn treatment totally abrogated MPP+-induced apoptosis in neuroblastoma cells without affecting oxidant generation. The increased cytotoxic effects of α-syn in MPP+-treated cells were attributed to inhibition of mitogen-activated protein kinase and proteasomal function. We conclude that MPP+induced iron signaling is responsible for intracellular oxidant generation, α-syn expression, proteasomal dysfunction, and apoptosis. Relevance to Parkinson's disease is discussed. [ABSTRACT FROM AUTHOR]

Endothelial senescence in conjunction with mitochondrial dysfunction orchestrates age-associated cardiovascular disorders. In this study we investigated the causal link between these two processes and studied the molecular mechanisms by which metformin acts to coordinate the delay of endothelial senescence via enhancing mitochondrial biogenesis/function. AMPK activators metformin and AICAR delayed endothelial senescence via SIRT1-mediated upregulation of DOT1L, leading to increased trimethylation of H3K79 (H3K79me3). Treatment of cells with either siAMPK or siSIRT1 repressed DOT1L-mediated enhancement of H3K79me3. Moreover, the increase in SIRT3 expression and mitochondrial biogenesis/function by AMPK activators was H3K79me-dependent as H3K79N mutant or siDOT1L abrogated these effects. This was confirmed by the enrichment of H3K79me3 in the SIRT3 promoter with AMPK activation. Intriguingly, enhanced PGC-1α expression by SIRT3 via AMPK activation was responsible for increased hTERT expression and delayed endothelial senescence. In contrast, SIRT3 knockdown caused increased oxidative stress and premature senescence, possibly by depleting hTERT expression. Furthermore, a chronic low dose administration of metformin significantly attenuated vascular aging and inhibited age-associated atherosclerotic plaque formation in ApoE −/− mice. Overall, the results of this study show a novel regulation of mitochondrial biogenesis/function, and cellular senescence by H3K79me acting through SIRT3, thus providing a molecular basis for metformin-mediated age-delaying effects. [ABSTRACT FROM AUTHOR]

Monocyte-to-macrophage differentiation promotes an inflammatory environment within the arterial vessel wall that causes a mal-adaptive immune response, which contributes to the progression of atheromatous plaque formation. In the current study, we show that resveratrol, a well-known antioxidant, dose-dependently attenuated phorbol myristate acetate (PMA)-induced monocyte-to-macrophage differentiation, as measured by cell adhesion, increase in cell size, and scavenger receptor expression in THP-1 monocytes. Also, resveratrol significantly inhibited PMA-induced pro-inflammatory cytokine/chemokine and matrix metalloprotease (MMP-9) production. This inhibitory effect of resveratrol on monocyte differentiation results from its ability to restore intracellular glutathione (GSH) status, as resveratrol in the presence of buthionine sulfoximine (BSO) failed to affect monocyte differentiation. Furthermore, PMA-induced monocyte differentiation and inflammation was greatly inhibited when cells were co-treated with N-Acetyl- l -cysteine (NAC), a GSH precursor, while the presence of BSO aggravated these processes. These results also show that resveratrol mediated up-regulation of GSH is due to AMP-activated protein kinase (AMPK)-α activation, as compound C (AMPK inhibitor) treatment drastically depleted intracellular GSH and exacerbated PMA-induced monocyte differentiation and pro-inflammatory cytokine production. More importantly, chronic administration of resveratrol efficiently prevented monocyte infiltration and markedly diminished angiotensin (Ang)-II-induced atheromatous plaque formation in apolipoprotein-E knockout (ApoE −/− ) mice. We conclude that, intracellular GSH status plays a critical role in regulating monocyte-to-macrophage differentiation and inflammation and resveratrol, by restoring GSH levels, inhibits these processes. Taken together, these results suggest that resveratrol can attenuate atherosclerosis, at least, in part, by inhibiting monocyte differentiation and pro-inflammatory cytokines production. [ABSTRACT FROM AUTHOR]

An efficient three-component protocol is described for the synthesis of benzo[6,7]cyclohepta[1,2- b ]pyridine derivatives using β-chloroacroleins, 1,3-dicarbonyls and ammonium acetate under catalyst free conditions by using ethanol as reaction media. The mild reaction conditions, operational simplicity and high yields are the advantages of this protocol and the broad scope of this one-pot reaction makes this procedure promising for practical usages. All the final compounds were screened for anti-inflammatory activity. Among the compounds tested, the compounds 5a , 5b , 5c , 5d , 5f , and 5k exhibited significant inhibition of IL-1β and MCP-1 secretion as a measure of anti-inflammatory activity. [ABSTRACT FROM AUTHOR]

A novel series of coumarin substituted thiazolyl-3-aryl-pyrazole-4-carbaldehydes ( 4a – o ) were synthesized via an efficient, one-pot multicomponent approach involving 3-(2-bromoacetyl)coumarins ( 1a – g ), thiosemicarbazide ( 2 ) and substituted acetophenones ( 3a – c ) utilizing Vilsmeier–Haack reaction condition with good yields. The title compounds structure was elucidated by spectroscopic data (IR, NMR and Mass) and elemental analysis. All the synthesized compounds were screened for their in vitro cytotoxic activity against MCF-7, DU-145 and HeLa cell lines and studied detailed about molecular interaction of probable target protein human microsomal cytochrome CYP450 2A6 using docking simulation. These coumarin derivatives were exhibiting moderate to appreciable cytotoxic activities. The compounds 4m and 4n exhibited significant cytotoxic activity with IC 50 values having 5.75 and 6.25 μM against HeLa cell line. Similarly compound 4n also exhibiting good anti cancer property and antibacterial activity against DU-145 cell line and Gram negative bacterial strains. [ABSTRACT FROM AUTHOR]

A series of new 3,6-diphenylimidazo[2,1- b ]thiazole derivatives ( 4a – l ) are synthesized and evaluated for their anticancer activity. Some of the synthesized compounds have shown potent anti-proliferative activity against HeLa, MDA-MB-231, A549 and THP1 human cancer cell lines. Among the active compounds, 3-(3-trifluoromethylphenyl)-6-phenylimidazo[2,1- b ]thiazole ( 4j ) has caused significant cytotoxicity in HeLa cells, with IC 50 as low as 6.5 μM. Compound 4j has induced caspase-3 and caspase-8 activation, leading to an apoptotic cell death. FACS analysis has revealed that compound 4j arrests cells in G0/G1 phase. The presence of 3-(3-trifluoromethylphenyl)- or 3-(3-chlorophenyl)-substituent, in that order, on the 6-phenylimidazo[2,1- b ]thiazole impacts more positively than other aryl-substituents, on the anti-proliferative properties of these compounds. [ABSTRACT FROM AUTHOR]

Abstract: A series of novel 1,2,3-triazole substituted N-phenyl nitrone derivatives 5a–e were prepared in three steps starting from 1-substituted-1,2,3-triazole-4-carbaldehydes 2 via Schiff's base formation, reduction followed by oxidation. Similarly, 1,2,3-triazole substituted N-alkyl nitrone derivatives 6a–p were prepared in single step starting from compound 2 on reaction with N-alkyl hydroxylamine hydrochlorides. All the final compounds were screened for anti-inflammatory and anticancer activity against various cancer cell lines. Among the compounds tested, the compounds 5a, 5d, 6a, 6b, 6m and 6o exhibited significant inhibition of IL-1β secretion as a measure of anti-inflammatory activity. Compound 5b, 5c, 6h, 6i and 6o exhibited significant activity against all the cell lines (A549, COLO 205, MDA-MB 231 and PC-3) at IC50 values of <15 μM. [Copyright &y& Elsevier]

Abstract: A series of novel 1,2-benzothiazine 1,1-dioxide-3-ethanone oxime N-aryl acetamide ether derivatives 7a–h and 9a–h were synthesized starting from sodium salt of saccharin 1 in series of steps. Final compounds 7a–h and 9a–h were evaluated for the anti-inflammatory activity and their ability to inhibit monocyte-to-macrophage transformation. Compounds 7e, 9b, 9e and 9h showed impressive anti-inflammatory activities (TNF-α, IL-8 and MCP-1) at micro molar concentration which was found to be better than positive control i.e., piroxicam. Compound 9e marginally and compound 9h significantly inhibited PMA-induced MMP-9 gelatinase activity. Also compounds 9e and 9h greatly inhibited the PMA-induced monocyte-to-macrophage transformation, a pre-requisite step in the formation of atheroma. [Copyright &y& Elsevier]

Abstract: A series of novel N-(4-aryl-1,3-thiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamides (4a–k) and N-(1,3-benzothiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamide derivatives (4l–o) are synthesized and evaluated for their anti-inflammatory and antioxidant activity (DPPH radical scavenging, superoxide anion scavenging, lipid peroxide inhibition, erythrocyte hemolytic inhibition). Compounds 4k and 4l have exhibited good antioxidant activity in four assays, while compounds 4c, 4d, 4m, 4n and 4o have shown good DPPH radical scavenging efficacy. Compounds 4a, 4h, 4i, 4k, 4m and 4n have possessed excellent anti-inflammatory activity. N-[4-(o-methoxyphenyl)-1,3-thiazol-2-yl]-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamide (4k) and N-(6-nitro-/methoxy-1,3-benzothiazol-2-yl)-2-(2,4-dioxo-1,3-thiazolidin-5-yl)acetamide (4m and 4n) have exhibited both antioxidant and anti-inflammatory activities. [Copyright &y& Elsevier]