bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and Cytotoxicity of Cyanoborane Adducts ofN6‐Benzoyladenine and 6‐Triphenylphosphonylpurine
Authors: Scarlett Tanya C. , Durham Richard W. , Hall Iris H. , Crosswicks Richard J. , Berkowitz Joshua D. , Burnham Bruce S.
Published: March 2007

N6‐Benzoyladenine‐cyanoborane (2), and 6‐triphenylphosphonylpurine‐cyanoborane (3) were selected for
investigation of cytotoxicity in murine and human tumor cell lines, effects on human HL‐60 leukemic
metabolism and DNA strand scission to determine the feasibility of these compounds as clinical
antineoplastic agents. Compounds 2 and 3 both showed effective cytotoxicity based on ED50 values less than
4 μg/ml for L1210, P388, HL‐60, Tmolt3, HUT‐78, HeLa‐S3 uterine, ileum HCT‐8, and liver Hepe‐2.
Compound 2 had activity against ovary 1‐A9, while compound 3 was only active against prostate PL and
glioma UM. Neither compound was active against the growth of lung 549, breast MCF‐7, osteosarcoma
HSO, melanoma SK2, KB nasopharynx, and THP‐1 acute monocytic leukemia. In mode of action studies in
human leukemia HL‐60 cells, both compounds demonstrated inhibition of DNA and protein syntheses after
60 min at 100 μM. These compounds inhibited RNA synthesis to a lesser extent. The utilization of the DNA
template was suppressed by the compounds as determined by inhibition of the activities of DNA polymerase
α, m‐RNA polymerase, r‐RNA polymerase and t‐RNA polymerase, which would cause adequate inhibition
of the synthesis of both DNA and RNA. Both compounds markedly inhibited dihydrofolate reductase
activity, especially in compound 2. The compounds appeared to have caused cross‐linking of the DNA
strands after 24 hr at 100 μM in HL‐60 cells, which was consistent with the observed increased in ct‐DNA
viscosity after 24 hr at 100 μM. The compounds had no inhibitory effects on DNA topoisomerase I and II
activities or DNA‐protein linked breaks. Neither compound interacted with the DNA molecule itself through
alkylation of the nucleotide bases nor caused DNA interculation between base pairs. Overall, these antineoplastic
agents caused reduction of DNA and protein replication, which would lead to killing of cancer
cells.
Solution Equilibria between Aluminum(III) Ion and L‐histidine orL‐tyrosine
Authors: Djurdjevic Predrag , Jelic Ratomir , Dzajevic Dragana , Cvijovic Mirjana
Published: March 2007

Toxic effects due to high aluminum body loads were observed in a number of conditions following
ingestion of Al‐containing antacids. Bio‐availability of aluminum depends not only on the solubility of the
ingested salt but also on the physico‐chemical properties of the soluble Al complexes formed in body fluids.
Amino acids may, upon interaction with Al‐salts, form absorbable Al‐complexes. Hence, complex formation
equilibria between Al3+
and either, L‐ histidine or L‐tyrosine were studied by glass electrode potentiometric
(0.1 mol/L LiCl ionic medium, 298 K), proton NMR and uv spectrophotometric measurements. Non linear
least squares treatment of the potentiometric data indicates that in the concentration ranges: 0.5 ≤ CAl ≤ 2.0
; 1.0 ≤ CHis ≤ 10.0
; 2.5 ≤ PH ≤ 6.5 , in Al3+ + His solutions, the following complexes (with log overall stability constants given in parenthesis) are formed: Al(HHis) 3+(12.21  ±  0.08) ; Al(His) 2+ , (7.25  ±  0.08); and Al(HHis)His2+
, (20.3  ±  0.1)
. In Al3+ + Tyr solutions in the concentration range 1.0 ≤  CTyr ≤ 3.0
mmol/L and
ligand to metal concentration ratio from 2:1 to 3:1, in the pH interval from 3.0 to 6.5 the formation of the
following complexes was detected: Al(HTyr) 2+
, (12.72  ±  0.09); Al(Tyr) 2+
, (10.16  ±  0.03)
and Al(OH) 2Tyr
, (2.70  ±  0.05)
. Proton NMR data indicate that in Al(His) 2+
complex histidine acts as a monodentate ligand but
its bidentate coordination is possible with carboxylate oxygen and imidazole 1‐nitrogen as donors. In
Al(HTyr) 3+
complex tyrosine is a monodentate ligand with carboxylate oxygen as donor. The mechanism of
the formation of complexes in solution is discussed as well as their possible role in aluminum toxicity.
Apoptosis Induced by Metal Complexes and Interaction withDexamethasone
Authors: Kim Jung Sun , Barros José Carlos Almeida , Zyngier Szulim Ber
Published: March 2007

Apoptosis induced by rhodium II amidate, rhodium II propionate, cisplatin and interactions with
dexamethaxone were studied on some human leukemia cell lines Raji, Jurkat and U937. Apoptosis was
studied by flow cytometry, agarose gel electrophoresis and morphological analysis. Rhodium II propionate
induced apoptosis in all the three cell lines, Rhodium II amidate, in the lymphoid cell lines Jurkat and Raji,
and cisplatin, only in the Jurkat, a T lymphoid cell line. It has also been observed that the addition of
dexamethasone enhances the apoptosis index only in U937, a monocytic line with a glucocorticoid receptor
bearing.
Cerebroprotective Effects of Dimeric Copper(II)Bis(o‐acetoxybenzoate) on Ischemia‐reperfusion Injury in Gerbils
Authors: Li Ling , Shen Zhiqiang , Yang Weimin , Wu Wanling , Liu Weiping , Chen Zhihe
Published: March 2007

The cerebroprotective effects of copper aspirinate [dimeric copper(II) bis(o‐acetoxybenzoate)] were
investigated in gerbils subjected to 10‐min global cerebral ischemia followed b 60‐min reperfusion. The
results showed that intragastric copper aspirinate (7.5, 15.0 and 30.0 mg Kg−1
) markedly promoted the
recovery of the electroencephalogram amplitude, attenuated the increase of lipid peroxide content and the
decrease of superoxide dismutase activity in the cortex during ischemia‐reperfusion injury. It suggested that
copper aspirinate possesses potential neuroprotective properties, the mechanism of which might be related to
an increase of the activity of endogenous superoxide dismutase.
Synthesis and Biological Activity of OrganothiophosphorylPolyoxotungstates
Authors: Sun Zhengang , Liu Jutao , Ma Jianfang , Liu Jingfu
Published: March 2007

Organothiophosphoryl polyoxotungstates
,
,
, (X = P, Si, Ge, B or Ga; R = PhP(S), C6H11P(S)) have been prepared from lacunary polyoxoanions and PhP(S)Cl2
or C6H11P(S)Cl2. The products were characterized by elemental analysis, IR,  31P
and  183W
NMR spectroscopy. According to
spectroscopic observations, the hybrid anions consist of a lacunary anion framework on which are grafted
two equivalent C6H5P(S)
or C6H11P(S)
groups through P‐O‐W bridges. Some of the title compounds showed
the antigerm activity.
Synthesis, Characterization and Biological Activity of DimethyltinDicarboxylates Containing Germanium
Authors: Choudhary M. A. , Mazhar M. , Ali S. , Song X. , Eng G.
Published: March 2007

A series of diorganotin dicarboxylates of the general formula
where
,
,
, R2 = C6H5
, H, CH3
, P‐CH3OC6H4
, P‐ClC6H4
, P‐CH3C6H4
, R3 = CH3
and H, have been synthesized by the reaction of dimethyltin oxide with germanium substituted
propionic acid in 1:2 molar ratio in toluene. The H2O
formed was removed azeotropically using a Dean and
Stark apparatus. All the compounds have been characterized by IR, multinuclear ( 1H
,  13C
,  119Sn
) NMR, mass
and Mössbauer spectroscopies. All compounds were found to have potential activity against bacteria.
Antifungal Activity of Solventlessly Synthesized Organomercurials
Authors: Kidwai M. , Venkataramanan R. , Dave B.
Published: March 2007

A series of new barbituryl/thiobarbituryl substituted organomercurial derivatives 3a‐i have been
synthesised from pyrimidine derivatives 1a‐c and arylmercuric chloride 2a‐c over K2CO3
under microwave
irradiations (MWI). This solventless synthesis apart from eliminating organic solvent from workup step,
also gave improved yield as compared to the conventional heating, with reaction time reduced from hours
to minutes. The prepared compounds were tested against
and for their antifungal
activity and were found to posses good activity.
Txicological Aspects of Newly Designed Macrocyclic Complexes ofIron(II)
Authors: Chaudhary Ashu , Singh R. V.
Published: March 2007

Brine shrimp lethality of a new series of 16 to 26‐membered macrocycles of iron(II) containing
tetraaza groups and prepared by the template condensation reaction of diacarboxylic acids (malonic, succinic,
glutaric or adipic) with 2,6‐diaminopyridine and diethylenetriamine in 1:2:2 molar ratios have been studied.
Structures and bonding of the macrocyclic complexes have been proposed based on elemental analyses, IR,
electronic, X‐ray and mass spectral studies. An octahedral geometry for these complexes has been proposed
as the binding sites are the nitrogen atoms of the macrocycles. The formation of the complexes as [Fe(Ln)Cl2]

has been established on the basis of the chemical composition. The complexes have also been screened
against several microbes.
Growth Effects of Some Platinum(II) Complexes with Sulfur‐Containing Carrier Ligands on MCF7 Human Breast Cancer Cell Line upon Simultaneous Administration with Taxol
Authors: Bogdanović Gordana , Kojić Vesna , Srdić Tatjana , Jakimov Dimitar , Djuran Miloš I. , Bugarčić Živadin D. , Baltić Mirjana , Baltić Vladimir V.
Published: March 2007

The platinum (II)complexes, cis‐[PtCl2(CH3SCH2CH2SCH3)] (Pt1), cis‐[PtCl2(dmso)2] (dmso is
dimethylsulfoxide; Pt2) and cis‐ (cisplatin), and taxol (T) have been tested at different
equimolar concentrations. Cells were exposed to complexes for 2 h and left to recover in fresh medium for
24, 48 or 72 h. Growth inhibition was measured by tetrazolium WST1 assay Analyses of the cell cycle, and
apoptosis were performed by flow cytometry, at the same exposure times. The IC50 value of each
platinum(II) complex as well as combination index (CI; platinum(II) complex + taxol) for various
cytotoxicity levels were determined by median effects analysis.

MCF7 cells were found to be sensitive to both Pt1 and Pt2 complexe These cisplatin analogues
influenced the cell growth more effectively as compared to cisplatin. Cytotoxic effect was concentration and
time‐dependent. Profound growth inhibitory effect was observed for Pt1 complex, across all its
concentrations at all recovery periods. A plateau effect was achieved three days after treatment at Pt1
concentrations ≤ 1 μM. Pt2, however, decreased MCF7 cells survival only for the first 24 h ranging between
50‐55%. Pt2 cytotoxicity sharply decreased thereafter, approaching 2 h ‐ treatment cytotoxicity level. The
median IC50 values for Pt1 and Pt2 were similar (0.337 and 0.3051 μM, respectively) but only for the first 24 h. The IC50 values for Pt1 strongly depend on the recovery period. On simultaneos exposure of cells to
taxol and platinum(II) complexes no consistent effect was found. The Cls for combinations of taxol with Pt1
or Pt2 revealed cytotoxic effects that were in most Cases synergistic (Pt1) or less than addtiive (Pt2). Flow
cytometry analysis has shown that each platinum(II) complex induced apoptosis in MCF7 cells. The level of
apoptosis correlated with cytotoxicity level for the range concentrations. Both cisplatin analogues, at IC50
concentrations, increased the number of MCF7 cells in G0G1 phase of cell cycle. Pt2‐treated cells remained
arrested in G0G1 phase up to 72 h after treatment. Combination of Pt2 and taxol caused further arrest of cells
in G0G1 phase (24 h) in parallel with strong decrement of G2M phase cells.
Metal–5‐Fluorouracil–Histamine Complexes: Solution, Structural,and Antitumour Studies
Authors: Tyagi Sadhna , Singh Sukh Mahendra , Gencaslan Sujan , Sheldrick W. S. , Singh Udai P.
Published: March 2007

Solution studies were performed pH‐metrically to study the interaction of Co(II), Ni(II), Cu(II), Zn(II) and
Cd(II) metal ions with 5‐fluorouracil (5FU) and histamine (Hm) separately (binary) and in the presence of
each other (ternary) at 25 ± 0.1  °C
temperature and a constant ionic strength of 0.1 M NaNO3
in aqueous
solution. The ternary complexes have been found to be more stable than the corresponding binary complexes
as shown by the positive value of Δlog⁡K. The species distribution curves have been obtained using the
computer programme BEST. On the basis of species distribution results, efforts were also made to prepare
some mixed complexes of Co(II), Ni(II), Cu(II), Zn(II) and Cd(II) ions by performing the reaction of their
metal nitrates, 5FU and Hm in aqueous ethanol medium at suitable pH. The isolated solid complexes were
characterized by different physico‐chemical method in order to suggest the possible binding site of the
ligands and the structure of the resultant complexes. All these complexes were checked for their antitumour
activity by injecting in Dalton′s lymphoma (DL) and Sarcoma‐180 (S‐180) bearing C3H/He mice. The results indicate that some complexes have good antitumour activity both in vivo and in vitro.
Antimicrobial, Antifertility and Antiinflammatory Approach toTetradentate Macrocyclic Complexes of Iron(II) and Manganese(II)
Authors: Chaudhary Ashu , Jaroli D. P. , Singh R. V.
Published: March 2007

Some antifertility inhibitors of 18 to 24‐membered tetraazamacrocyclic complexes of iron(II) and
manganese(II) have been synthesised by the template condensation using 1,3‐phenylenediamine with
malonic acid, succinic acid, glutaric acid and adipic acid. The reaction proceed smoothly to completion. The
complexes were characterized by elemental analyses, molecular weight determinations, infrared, electronic,
magnetic moment, mössbaur and mass spectral studies. The elemental analyses are consistent with the
formation of the complexes [M(N4Ln)Cl2]
(M = Fe(lI) or Mn(II)). All these complexes are stable and
monomeric in nature as indicated by the molecular weight determinations. The spectral studies confirm the
octahedral geometry around the central metal atom. The complexes have been screened in vitro against a number of fungi and bacteria to assess their growth inhibiting potential. The testicular sperm density and
testicular sperm morphology, sperm motility, density of cauda epididymal spermatozoa and fertility in
mating trials and biochemical parameters of reproductive organs have been examined and discussed.
Nematicidal, Fungicidal and Bactericidal Activities of Manganese (II) Complexes with Heterocyclic Sulphonamide Imines
Authors: Jain Mukta , Nehra Sampat , Trivedi P. C. , Singh R. V.
Published: March 2007

Some manganese(II) complexes derived from different sulphadrugs and heterocyclic ketones have been
prepared. These complexes have been characterized on the basis of elemental analyses, molecular weight
determinations, conductivity measurements, infrared, ESR and magnetic measurements. The spectral data
suggest that the ligands act in a monobasic, bidentate manner coordinating through nitrogen atom. A high
spin tetrahedral geometry around this metal has been proposed on the basis of magnetic and spectral studies. The isolated products are coloured solids, soluble in DMSO, DMF and MeOH. All the complexes are
monomeric in nature as indicated by their molecular weight determinations and conductivity measurements
in dry DMF show them to be non‐electrolytes. All the ligands and their corresponding complexes have been
screened for their fungicidal, bactericidal and nematicidal activities.
Facile Synthesis of cis‐Dichloro‐(1,4,7‐Triazacyclononane) Platinum(II) and its Screening Against Human Ovarian Cancer (SK‐OV‐3) and Leukemia (K‐562) Cell Lines
Authors: Haines Robert I. , Murnaghan Aleisha M.
Published: March 2007

A simple method for the preparation of cis‐dichloro(1,4,7‐triazacyclononane)platinum(II), cis‐Pt(tacn)Cl2 is presented, together with the results of screening the compound against the K‐562 (leukemia) and SK‐OV‐3
(ovarian) human cancer cell lines. While the compound shows no activity against K‐562 cells, there is
evidence for some cytotoxicity against SK‐OV‐3. The compound is much less effective than cisplatin, and its
limited solubility restricts the useable concentration range.
Quantification and Localization of Intracellular FreeMg2+ in Bovine Chromaffin Cells
Authors: Montezinho Liliana P. , Fonseca Carla P. , Geraldes Carlos F. G. C. , Castro M. Margarida C. A.
Published: March 2007

Magnesium is an essential element for all living systems. The quantification of free intracellular Mg2+
concentration () is of utmost importance since changes in its basal value may be an indication of
different pathologies due to abnormalities of Mg2+ metabolism. In this work we used  31P NMR and
fluorescence spectroscopy to determine the resting in bovine chromaffin cells, a neuron‐like cellular
model, as well as confocal laser scanning microscopy to study the free Mg2+ spatial distribution in these cells.
 31P NMR spectroscopy did not prove to be effective for the determination of in this particular case
due to some special morphological and physiological properties of this cell type. A basal value of
0.551 ± 0.008 mM was found for these cells using fluorescence spectroscopy and the Mg2+‐sensitive probe
furaptra; this value falls in the concentration range reported in the literature for neurons from different
sources. This technique proved to be an accurate and sensitive tool to determine the .

lntraceilular free Mg2+ seems to be essentially localized in the nucleus and around it, as shown by
confocal microscopy with the Mg2+‐sensitive probe Magnesium Green. It was not possible to derive any
conclusion about free Mg2+ localization inside the chromaffin granules and/or in the cytoplasm due to the
lack of sufficient spatial resolution and to probe compartmentalization.
Synthesis of New Five Coordinated Copper(II) and Nickel(II) Complexes of L‐Valine and Kinetic Study of Copper(II) with Calf Thymus DNA
Authors: Tak Aijaz Ahmad , Arjmand Farukh , Tabassum Sartaj
Published: March 2007

Five coordinated novel complexes of CuII and NiII have been synthesized from benzil and 1,3‐
diaminopropane‐CuII/NiII complex and characterized by elemental analysis, i.r., n.m.r., e.p.r, molar
conductance and u.v‐vis, spectroscopy. The complexes are ionic in nature and exhibit pentaeoordinated
geometry around the metal ion. The reaction kinetics of C25H36N5O2CuCl with calf thymus DNA was studied
by u.v‐vis, spectroscopy in aqueous medium. The complex after interaction with calf thymus DNA shows
shift in the absorption spectrum and hypochromicity indicating an intercalative binding mode. The Kobs values
have been calculated under pseudo‐first order conditions. The redox behaviour of complex C25H36N5O2CuCl
in the presence and in the absence of calf thymus DNA in the aqueous solution has been investigated by
cyclic voltammetry. The cyclic voitammogram exhibits one quasi‐reversible redox wave corresponding to
CuII/CuI redox couple with E1/2 values of ‐0.377 and ‐0.237 V respectively at a scan rate of 0.1Vs-1 .On
interaction with calf thymus DNA, the complex C25H36N5O2CuCl exhibits shifts in both Ep as well as in E1/2
values, indicating strong binding of the complex to the calf thymus DNA.
Synthesis, In vitro Antifungal and Antitumour Activity of Some Triorganotin(IV) N,C,N‐Chelates
Authors: Dostál Libor , Růžička Aleš , Jambor Roman , Buchta Vladimír , Kubanová Petra , Holoček Jaroslav
Published: March 2007

The in vitro antifungal activity of compounds 1‐3 (R2SnX; (where X=Cl, R=n‐Bu
for 1, X=Br, R=n‐Bu for 2 and x=PF6, R=n=Bu for 3)) was estimated with the help of a modified
microdilution format of the M27‐A guidelines and was compared with in vitro activity of their
diphenyltin(IV) analogues 4 and 5 (where X=Br, R=Ph for 4 and X=PF6, R=Ph for 5), and of drugs currently
in clinical use (ketoconazole, fluconazole and amphotericin B). It was found that in coordinating solvents the
more soluble derivative 2 is less active than the phenyl one (4), and compounds 1 and 3 are even inactive.

In this paper, the in vitro antitumour activity of ionic diphenyltin(IV) complexes 4 and 5 against seven
tumoural cell lines of human origin is also reported. The preparation and characterization ( 1H,  13C and  119Sn
NMR spectroscopy and electrospray ionization mass spectrometry) of the novel compound 3 is mentioned too.
Effect of hydrocortisone on interleukin‐6 production in human ,peripheral blood rnononuclear ceils
Authors: Hirooka Y. , Mitsuma T. , Nogimori T. , Ishizukis Y.
Published: March 2007

The effect of hydrocortisone on the production of interleukin‐6 (IL‐6) in human peripheral blood mononuclear
cells was studied. Using our newly developed radioimmunoassay
system for IL‐6 of which specificity, reproducibility,
sensitivity and usefulness have been demonstrated.
IL‐6 production in peripheral blood mononuclear
cells of ten normal subjects revealed that in lipopolysaccharide
(LPS, 10μg/ml)‐stimulation, the mean ± SD
of IL‐6 was 2.71 ± 0.85 ng/ml. No detectable amount of
IL‐6 was observed in the absence of LPS and in
the presence of hydrocortisone alone. Hydrocortisone
(10−10 M to 10−3 M) inhibited LPS‐stimulated IL‐6 production
in a dose‐dependent manner. However, there was
a wide variation in the response to hydrocortisone, namely,
ranging from steroid‐sensitive to steroid‐resistant. Based
on the concentration required to inhibit 50% of LPS‐stimulated
IL‐6 production, three of ten subjects were at
10−6 M, three at 10−5 M and the rest at
10−4 M, respectively.
The dramatic anti‐inflammatory and immunosuppressive
effects of glucocorticosteroids can be life‐saving
in autoimmune diseases. The present findings suggested
that there existed the differences in susceptibility to glucocorticosteroids
even among normal subjects, providing some implications for the drug treatment, and also gave
further evidence that there may exist an immunoregulatory feedback circuit
between the immune and neuroendocrine systems.
Mediators of increased blood flow in porcine skin
Authors: Moore H. D. , Cunningham F. M.
Published: March 2007

Nicotinates and benzalkonium chloride (B.Cl) cause inflammatory changes in human skin, thought to be dependent upon prostaglandin formation. This study has examined the effects of hexyl‐nicotinate (HN) and B.Cl on blood flow in porcine skin. The role of prostaglandins and interleukin (IL)‐1 in the blood flow response has been investigated. Blood flow was increased by both HN and B.Cl, the response to B.Cl being more protracted. Cyclooxygenase inhibitor pretreatment reduced these responses. IL‐1‐like biological activity was identified in normal porcine epidermis and the amounts recovered from inflamed skin were similar. Thus prostaglandin formation in HN or B.Cl‐induced inflammation, if IL‐1 dependent, is not associated with the loss of significant amounts of the cytokine from the epidermis.
Stimulation of neutrophil functions by C5adesArg: an in vitro model of haemodialysis
Authors: Eckle I. , Kolb G. , Martin E. Martinez , Havemann K.
Published: March 2007

Cuprophane membranes during haemodialysis significantly increase the plasma levels of C5adesArg (maximal 55 μg C5aadesArg/1 blood after 30 min) whereas Hemophane or Polysulphonemembranes induce only low plasma levels of C5adesArg. C5adesArg generated in vitro by yeast incubation of autologous plasma stimulates PMN chemotaxis and oxidative metabolism but has no effect on enzyme release. Preincubation of whole blood with C5adesArg causes aggregation and changed oxidative burst activity of the isolated PMN. These changes are similar to those found in cells from patients after haemodialysis with cuprophane membranes. So the elevated plasma levels of C5adesArg after haemodialysis explain some of the changes in PMN functions, but additional mechanisms have to be assumed.
IL‐7 and IL‐8 inhibit gamete interaction in the zona‐free hamster egg sperm penetration assay
Authors: Lambert H. , Collazo I. , Steinleitner A.
Published: March 2007

Current thought in reproductive endocrinology suggests hat endometriosis‐associated subfertility may be the result of an adverse influence of activated immunocompetent cells on fertilization and embryo development. Inflammatory ediators such as interleukin‐1 and tumour necrosis actor have been implicated in the pathophysiology of this process. The purpose of this study was to assess the effect of two recently characterized cytokines, interleukin‐7 (IL‐7 ) and interleukin‐8 (IL‐8), on gamete interaction in the perm penetration assay (SPA). Donor sperm were preincubated or 4 h with 0.5, 5, 50, or 500 ng ml-1 of human ecombinant IL‐7 or IL‐8. Sperm penetration was determined by an experienced gametologist by the presence of decondensed sperm heads or pronuclei formation. A dose‐dependent inhibition of gamete interaction was observed following coincubation with either IL‐7 or IL‐8. These data offer the possibility that IL‐7 and IL‐8 may play a role in the pathogenesis of immunocompetent cell‐associated subfertility.
ICAM‐1 expression on chondrocytes in rheumatoid arthritis: induction by synovial cytokines
Authors: Davies M. E. , Sharma H. , Pigott R.
Published: March 2007

The intercellular adhesion molecule‐1 (ICAM‐1) was found by immunostaining chondrocytes in cartilage from three patients with rheumatoid arthritis. Expression of ICAM‐1 was restricted to chondrocytes in areas of erodedcartilage adjacent to the invading synovial tissue. Toluidine blue staining of these areas demonstrated severe depletion of the cartilage extracellular matrix. In areas of undamaged cartilage there was no ICAM‐1 expression. Since ICAM‐1 is not constitutively expressed on normal human articular cartilage, but could be induced in vitro by exogenous IL‐1α, TNFα and IFNγ or by co‐culturing cartilage with inflammatory rheumatoid synovium, we conclude that the induction of ICAM‐1 on rheumatoid chondrocytes results from the synergistic action of a variety of cytokines produced by the inflammatory cells of the invading pannus.
Assay of phospholipases A2 and their inhibitors by kinetic analysis in the scooting mode
Authors: Jain Mahendra Kumar , Yu Bao-Zhu , Gelb Michael H. , Berg Otto G.
Published: March 2007

Several cellular processes are regulated by interfacial catalysis on biomembrane surfaces. Phospholipases A2 (PLA2) are interesting not only as prototypes for interfacial catalysis, but also because they mobilize precursors for the biosynthesis of eicosanoids and platelet activating factor, and these agents ultimately control a wide range of secretory and inflammatory processes. Since PLA2 carry out their catalytic function at membrane surfaces, the kinetics of these enzymes depends on what the enzyme ‘sees’ at the interface, and thus the observed rate is profoundly influenced by the organization and dynamics of the lipidwater interface (‘quality of the interface’). In this review we elaborate the advantages of monitoring interfacial catalysis in the scooting mode, that is, under the conditions where the enzyme remains bound to vesicles for several thousand catalytic turnover cycles. Such a highly processive catalytic turnover in the scooting mode is useful for a rigorous and quantitative characterization of the kinetics of interfacial catalysis. This analysis is now extended to provide insights into designing strategy for PLA2 assays and screens for their inhibitors.
Synthesis of a new biological response modifier thyrnosin β4 analogue and its restorative effect on depressed
Authors: Abiko Takashi , Sekino Hiroshi
Published: March 2007

Thymosin β4 is a polypeptide isolated from thymosin fraction 5. This peptide exhibits important activities in the regulation and differentiation of thymus‐dependent lymphocytes. An analogue of thymosin β4, [Phe(4F)12] deacetyl‐ thymosin β4, was synthesized by a solution method, followed by deprotection with 1 M trifluoromethanesulphonic acid (TFMSA)‐thioanisole (molar ratio, 1:1) in trifluoroacetic acid (TFA) in the presence of dimethlselenium. Finally, the deprotected peptide was incubated with dithiothreitol to reduce sulphoxide on the methionine side chain. The synthetic [Phe(4F)12]deacetyl‐thymosin β4 was found to have a restoring effect on the impaired blastogenic response of T‐lymphocytes isolated from uraemic patients with recurrent infectious diseases. This analogue exhibited stronger restorative activity than that of our synthetic deacetyl‐thymosin β4.
Intestinal inflammation in TNBS sensitized rats as a model of chronic inflammatory bowel disease
Authors: Selve N. , Wöhrmann T.
Published: March 2007

An enteritis, based on a delayed‐type hypersensitivity reaction, was induced in TNBS (2,4,4‐trinitrobenzenesulphonic acid) sensitized rats by multiple intrajejunal challenge with TNBS via an implanted catheter. This treatment induced chronic inflammation of the distal small intestine characterized by intense hyperaemia, oedema and gut wall thickening as assessed by macroscopic scoring and weighing a defined part of the dissected intestine. Histologically, the inflammatory response included mucosal and submucosal cell infiltration by lymphocytes and histiocytes, transmural granulomatous inflammation with multinucleated cells and activated mesenteric lymph nodes. Ex vivo stimulated release of the inflammatory mediator LTB4 in the dissected part of the intestine was increased following TNBS treatment. Drug treatment with sulphasalazine or 5‐aminosalicylic acid improved the enteritis score and attenuated TNBS induced oedema formation and LTB4 production. The applicability and relevance of this new model are discussed with respect to drug development and basic research of inflammatory bowel diseases.
Interaction between PAF and human platelet membranes: a fluorescence study
Authors: Kantar Ahmad , Giorgi Pier Luigi , Curatola Giovanna , Fiorini Rosamaria
Published: March 2007

The interaction between PAF and human platelet membranes was investigated by measuring the steadystate fluorescence anisotropy and fluorescence decay of 1 (4‐trimethylammoniumphenyl)‐6‐phenyl‐1,3,5‐hexatriene (TMA‐DPH) incorporated in platelet plasma membranes. PAF induced a time‐limited and significant increase of the lipid order in the exterior part of the membrane and a decrease in membrane heterogeneity. These changes were blocked in the presence of the PAF antagonists, L‐659,989 and 1‐O‐hexadecyl‐2‐acetyl‐sn‐glycero‐3‐phospho(N,N,N‐trimethyl)hexanolamine.H2O. These results indicate that the observed changes in the physico‐chemical properties of the membrane are attributed to the PAF–receptor interaction and signal transduction.
The in vitro free radical scavenging activity of tenidap, a new dual cyclo‐oxygenase and 5‐1ipoxygenase inhibitor
Authors: Lau C. S. , Belch J. J. F.
Published: March 2007

Tenidap, a new anti‐inflammatory drug, is presently undergoing clinical studies as a treatment for rheumatoid arthritis (RA). Early pilot work has shown it to be of some benefit. Tenidap is a dual inhibitor of cyclo‐oxygenase and 5‐lipoxygenase enzymes. It has also been shown to modify white blood cell behaviour such as interleukin‐1 production, monocyte differentiation and neutrophil degranulation. As free radicals (FRs) have been implicated in the pathogenesis of RA, we used an in vitro assay system developed by Misra and Fridovich to assess if tenidap has FR scavenging effects. Our study shows, for the first time, that tenidap has general FR scavenging effects although no effect on the superoxide anion () could be demonstrated. This effect occurred in a dose‐dependent manner at concentrations above 20 μg/ml (p < 0.005, Mann‐Whitney U‐test). As the therapeutic range of tenidap in serum is between 15 and 30 μg/ml such FR scavenging activity may be clinically relevant in the treatment of RA. Ex vivo confirmation of this possibility is underway.
Mechanism of action of 5‐arninosalicylic acid
Authors: Punchard N. A. , Greenfield S. M. , Thompson R. P. H.
Published: March 2007

5‐Aminosalicylic Acid (5‐ASA) has been used for over 50 years in the treatment of inflammatory bowel disease in the pro‐drug form sulphasalazine (SASP). SASP is also used to treat rheumatoid arthritis. However whether the therapeutic properties of SASP are due to the intact molecule, the 5‐ASA or sulphapyridine components is unknown. Several mechanisms of action have been proposed for 5‐ASA and SASP including interference in the metabolism of arachidonic acid to prostaglandins and leukotrienes, scavenging,of reactive oxygen species, effects on leucocyte function and production of cytokines. However, it is unlikely that the anti‐inflammatory properties of SASP and 5‐ASA are due to several different properties but more likely that a single property of 5‐ASA explains the theraapeutic effects of 5‐ASA and SASP. Reactive oxygen species (ROS) are involved in the metabolism of prostaglandins and leukotrienes and can act as second messengers, and so the scavenging of ROS may be the single mechanism of action of 5‐ASA that gives rise to its antiinflammatory effects in both inflammatory bowel disease and rheumatoid arthritis.
Involvement of serotonin and eicosanoids in the rat paw oedema response to the essential oil of Pilocarpus spicatus
Authors: Silva J. C. R. , Rao V. S. N.
Published: March 2007

Subplantar injection of Pilocarpus spicatus essential oil (PSEO), induced rat hindpaw oedema in a dose‐dependent manner. The time course study revealed that when compared to carrageenan‐induced oedema, the oedema response to PSEO was greater at 1 h post‐injection, and thereafter remained relatively constant until 5 h post‐injection. By 24 h, it was still at almost the 50% level. This effect of PSEO was characterized using several inhibitors of oedema formation. Pretreatment with the H1‐receptor antagonist chlorpheniramine did not affect this response, while a significant reduction of paw oedema was achieved with the serotonin antagonist methysergide, but only 1 h and 2 h after injection of PSEO. The oedemagenic activity of PSEO was also suppressed by pretreating the rats with the eicosanoid synthesis inhibitors, phenylbutazone, EP 10161 and dexamethasone. This last drug showed the greatest potency. These findings suggested a probable injury to dermal mast cells and liberation of arachidonate metabolites and eicosanoids at the late phase of oedema induced by PSEO.
Interactions between platelet activating factor and eicosanoids during endotoxic shock in anaesthetized pigs
Authors: Mózes T. , Zijlstra F. J. , Heiligers J. P. C.
Published: March 2007

The effects of platelet activating factor (PAF) on eicosanoid release during endotoxic shock was investigated in anaesthetized pigs receiving 5 μg kg−1 Escherichia coli endotoxin (LPS) into the superior mesenteric artery over a 60 min period, by measuring plasma levels of a variety of mediators. Fifteen of the 31 animals infused with LPS and not treated with BN 52021, a PAF receptor antagonist, died within 30 min after the commencement of LPS infusion (non‐survivors), while the other 16 survived the experimental period of 3 h, though in a state of shock (survivors). No alterations were observed in plasma concentrations of eicosanoids in the non‐survivors. A significant, though transient, increase in eicosanoid concentrations occurred only in the survivors. Treatment with BN 52021 (4 mg kg‐1, i.v.) injected 5 min prior to LPS infusion, failed to exert any effect on the survival rate. However, pretreatment with BN 52021 prevented circulatory collapse in the survivors and reduced the concentration of cyclooxygenase enzyme products, without affecting LTB4 release. Exogenous administration of PAF (0.01 μg kg−1) caused hypotension and increased TXB2 levels although 6‐keto PGF1α and LTB4 concentrations were unchanged. The data suggest that prostanoid formation may be secondary to PAF release in circulatory collapse evoked by LPS infusion in survivors, and give further support to the suggestion that PAF prostanoid interaction is important during endotoxic shock. However, their role in early death seems to be negligible, indicating the importance of other mediators.
Tumour necrosis factor‐α mediates blood—brain barrier damage in HIV‐1 infection of the central nervous system
Authors: Sharief M. K. , Ciardi M. , Thompson E. J. , Sorice F. , Rossi F. , Vullo V. , Cirelli A.
Published: March 2007

The pathogenesis of brain inflammation and damage by human immunodeficiency virus (HIV) infection is unclear. Because blood–brain barrier damage and impaired cerebral perfusion are common features of HIV‐1 infection, we evaluated the role of tumour necrosis factor‐α (TNF‐α) and interleukin‐1β (IL‐1β) in mediating disruption of the blood–brain barrier. Levels of TNF‐α were more elevated in cerebrospinal fluid (CSF) than in serum of HIV‐1 infected patients and were mainly detected in those patients who had neurologic involvement. Intrathecal TNF‐α levels correlated with signs of blood–brain barrier damage, manifested by high CSF to serum albumin quotient, and with the degree of barrier impairment. In contrast, intrathecal IL‐1β levels did not correlate with blood‐brain barrier damage in HIV‐1 infected patients. TNF‐α seems to be related to active neural inflammation and to blood–brain barrier damage. The proinflammatory effects of TNF‐α in the nervous system are dissociated from those of IL‐1β.
Induction of circulating phospholipase A2 by intravenous administration of recombinant human tumour necrosis factor
Authors: Pruzanski Waldemar , Sherman Matthew L. , Kufe Donald W. , Vadas Peter
Published: March 2007

We have examined the effects of intravenous infusion of recombinant human tumour necrosis factor (rh‐TNF) on serum activity of phospholipase A2 (PLA2) in patients with malignancies. Nine patients received a 24 h continuous intravenous infusion ranging from 1.0 × 105 U/m2 to 3.0 × 105 U/m2; 14 patients received a 5 day continuous intravenous infusion ranging from 0.5 × 105 U/m2/day to 3.0 105 U/m2/day. Twenty one of 23 patients responded with marked increases in serum PLA2 activity that were detectable 3 h after the beginning of the rh‐TNF infusion and reached maximum levels at 18 h with a mean increase of 16.2‐fold. In patients receiving a 5 day rh‐TNF infusion, the highest levels of PLA2 were observed after the first day of infusion. Serum PLA2 activity declined continuously to 2.9‐fold above baseline at the end of the infusion. A significant correlation was noted between the dose of infused rh‐TNF and the maximum increase in PLA2 activity. To our knowledge, this is the first time that an association between intravenous TNF administration and induction of circulating PLA2 in man has been established.
Selective inhibition by antiflamrnin‐2 of thromboxane B2 release from isolated and perfused guinea‐pig lung
Authors: Sautebin Lidia , Cirino Giuseppe , Rosa Massimo Di
Published: March 2007

Antiflammin‐2 (AF2) is a nonapeptide corresponding to the amino acid residues 246–254 of lipocortin‐1 showing anti‐inflammatory activity both in vitro and in vivo. The effect of AF2 on the thromboxane B2 (TXB2) and histamine release from isolated and perfused guinea‐pig lungs has been studied. AF‐2 (10–100 nM) inhibited leukotriene C4‐ (LTC4) (3 ng) and antigen‐induced (ovalbumin, 1 mg) TXB2 release in normal and sensitized lungs, respectively. In contrast AF‐2 (100 nM) did not modify TXB2 release induced by histamine (5 μg) or bradykinin (5 μg) in normal lungs. Antigen‐induced histamine release was not affected by 100 nM AF‐2 infusion. When tested in chopped lung fragments AF‐2 (0.1–25 μM) did not modify the release of histamine and TXB2 induced by antigen (ovalbumin, 10 μg ml−1) or calcium ionophore A 23187 (1 μM). Our results show that the inhibitory effect of AF‐2 on TXB2 release is selective and depends on the stimulus applied. In this respect AF‐2 mimics, at least in part, the actions of both glucocorticoids and lipocortin‐1.
Cyclic‐AMP mediated drugs: differential or global reduction of eicosanoid synthesis in the isolated rat lung?
Authors: Post Mark J. , Biesebeek Jan Dirk te , Wemer Johan , Rooij Hans H. van , Zijlstra Freek J. , Porsius Arijan J.
Published: March 2007

In this study the question was addressed whether cAMP mediated drugs induce a differential reduction of branches of the arachidonic acid metabolism rather than a global reduction of eicosanoid synthesis. The isolated lungs of actively sensitized rats were employed to study prostaglandin and leukotriene release in the presence and absence of the cAMP mediated drugs theophylline, milrinone, sulmazole, isobutyl‐methylxanthine and salbutamol. The release of eicosanoids as measured by RIA was predominantly basal and continuous, with a mild antigen induced stimulation only for TXB2 and the leukotrienes. All drugs reduced eicosanoid release globally. It is concluded that cAMP mediated drugs interfere with arachidonic acid metabolism at a site proximal to the branching into lipoxygenase and cyclo‐oxygenase pathways.
Bacterial lipopolysaccharide potentiates type II collagen‐induced arthritis in mice
Authors: Caccese Robert G. , Zimmerman John L. , Carlson Richard P.
Published: March 2007

Collagen‐induced arthritis (CIA) is an immunologically relevant animal model of human rheumatoid arthritis. Studies comparing the disease incidence in genetically susceptible male and female DBA/1LacJ mice demonstrated that under low density/low stress housing conditions, female mice had earlier onset (day 35) and higher disease incidence (25%) than the male mice (17% at day 49) when immunized with bovine type II collagen. A single subcutaneous or intraperitoneal injection of bacterial lipopolysaccharide (LPS) 17–24 days after collagen immunization greatly potentiated this standard CIA model in a dose related manner. 20–40 μg of LPS accelerated the onset of disease from day 35 to day 21 and exacerbated the clinical severity score from 0.27 to 2.00 at day 42. A similar administration of 6 μg of recombinant interleukin‐β produced a comparable potentiated CIA model. The acute phase protein, serum amyloid P (SAP), was elevated in the serum at day 26 to 440 μg ml−1 for the LPS potentiated CIA mice compared to 65 μg ml−1 in the non‐potentiated immunized CIA mice. There was a significant correlation (r = 0.78) between SAP levels and disease expression in the LPS treated CIA mice. The rapidity and uniformity of disease expression in this LPS potentiated CIA model will allow more and different drugs to be evaluated with a smaller number of animals.
Interactions between rnacrophage cytokines and eicosanoids in expression of antitumour activity
Authors: Ben-Efraim Shlomo
Published: March 2007

Cytokines and eicosanoid products of macrophages play an essential role in expression of antitumour activity of macrophages either in a cell‐to‐cell contact system between the effector and the target cell or as cell‐free soluble products. In this review the relationship between three main monokines, namely TNF‐α, IL‐1 and IL‐6 and the interrelationship between these monokines and eicosanoids (PGE2, PGI2, LTB4, LTC4) in their production and in expression of antitumour activity is discussed. Emphasis is given to the effect of tumour burden on production of the monokines and of the eicosanoids and on the production of these compounds by the tumour cells. Finally, the therapeutic implications drawn from animal studies and clinical trials is discussed.
Receptor mechanisms of PAF mediated lymphatic constriction in the canine forelimb
Authors: Dobbins D. E.
Published: March 2007

Platelet activating factor (PAF) is a potent inflammatory lipid. In this study we assessed the ability of PAF to impact lymphatic vessel function by altering prenodal lymphatic resistance. Intralymphatic PAF (7.47 × 10−6, 7.47 × 10−5 and 7.47 × 10−4 M) increased lymphatic perfusion pressure at the two highest infusion rates. PAF mediated lymphatic constriction was not altered by the intra‐arterial infusion of phentolamine but was blocked by the intra‐arterial infusion of the PAF receptor antagonist WEB 2170. These data indicate that in addition to PAF′s effects on microvascular permeability, this agent may also impact the ability of the lymphatics to transport fluid through alterations in lymphatic smooth muscle tone. PAF mediated lymphatic constriction is not mediated by α‐receptors but rather through PAF receptor mediated mechanism.
Release of tumour necrosis factor alpha into bronchial alveolar lavage fluid following antigen challenge in passively sensitized guinea‐pigs
Authors: Kelly D. E. , Denis M. , Biggs D. F.
Published: March 2007

Five groups of ten female guinea‐pigs were passively sensitized against ovalbumin (OA) (n = 9) or control guinea‐pig serum (n = 1). 24 h later, they received mepyramine (0.5 mg/kg, i.p.) and 30 min later inhaled aerosols of: (A) OA (2 in 0.9% saline, 8 min, n = 4/9); (B) saline (40 min, n = 4/9); (C) LPS (40 min, Escherichia coli 0111:B4, 150 ng/kg in PBS, n = 1/9); and (D) the control animal was treated as in (C) (n = 1). Their tracheas were cannulated under pentobarbital anaesthesia and bronchial alveolar lavage (BAL) was performed with 2 × 5 ml PBS containing BSA (1%) (n = 1 group), or BSA (1%) and aprotinin (1000 KIU/ml) (n = 4 groups), at 30, 60, 90 or 120 min post‐inhalations. BAL fluids recovered were centrifuged, the supernatants recovered and frozen until assayed for tumour necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1) and interleukin‐6 (IL‐6). No TNF‐α could be detected unless aprotinin was present in the lavaging solution. BAL fluid from OA‐sensitized and control animals that had inhaled LPS contained high levels of TNF‐α that peaked at 90 min. BAL fluid from OA sensitized animals that inhaled OA aerosols contained no detectable TNF‐α at 30 min, but it was found in increasing amounts at 60, 90 and 120 min; TNF‐α was not detected in fluid from any of the animals that inhaled saline. As BAL fluids were toxic to the cells used in the assays, neither IL‐1 nor IL‐6 could be measured. We conclude that the monokine TNF‐α is released into BAL fluid following anaphylactic challenge of passively sensitized guinea‐pigs. The presence of the antiprotease, aprotinin, in the lavaging solution is essential for the detection and measurement of TNF‐α in BAL fluid.
Formation of 4‐hydroxynonenal and further aldehydic mediators of inflammation during bromotrichlorornethane treatment of rat liver cells
Authors: Sommerburg Olaf , Grune Tilman , Klee Sabine , Ungemach Fritz R. , Siems Werner G.
Published: March 2007

Bromotrichloromethane (CBrCl3) treatment is a model for studies on molecular mechanisms of haloalkane toxicity with some advantages compared with CCl4 treatment. The formation of 4‐hydroxynonenal and similar aldehydic products of lipid peroxidation, which play a role as mediators of inflammatory processes, was clearly demonstrated in rat hepatocytes treated with CBrCl3. It may be assumed that haloalkane toxicity is connected with the biological effects of those inflammation mediatory aldehydic compounds.
The effect of tumour necrosis factor‐α (TNF‐α) muteins on human neutrophils in vitro
Authors: Tchorzewski H. , Zeman K. , Kantorski J. , Paleolog E. , Kahan M. , Feldmann M. , Kwinkowski M. , Guga P. , Szymanska B. , Parniewski P. , Wilk A. , Jarosz J.
Published: March 2007

Tumour necrosis factor‐α (TNF‐α) has been implicated as an important inflammatory mediator. In vitro, TNF‐α is reported to activate human polymorphonuclear neutrophils (PMN), inducing responses such as phagocytic activity, degranulation and oxidative metabolism. Biological responses to TNF‐α are initiated by its binding to specific cell surface receptors, and various studies have shown that the major TNF receptor species on PMN is the 75 kDa receptor. To verify the suggestion that the receptor binding domain includes the region close to the N‐terminus of the TNF‐α molecule, four TNF‐α derivatives termed muteins were constructed, using a synthetic cDNA fragment substituting the N‐terminal 3–7 selected hydrophilic or hydrophobic amino acids in the original TNF‐α genomic DNA. Binding of muteins to PMN was assessed using monoclonal antibodies recognizing either the 55 kDa (p55) or the 75 kDa (p75) TNF receptor subtypes. Blocking by muteins of anti‐p75 antibody binding to PMN was as expected from their N‐terminal amino acid composition and hydrophilic properties. Hydrophilic muteins competed well with anti‐TNF receptor antibodies for binding to the p75 receptor. In contrast, hydrophobic muteins were unable to block anti‐p75 binding. Similarly, degranulation, chemiluminescence or enhancement of the PMN response to specific stimuli by the muteins correlated with the hydrophilic properties of the muteins. The significance of these observations in relation to the molecular structure of TNF‐α is discussed.