Wael M. El-Sayed

Prophylactic and therapeutic effects of taurine against aluminum-induced acute hepatotoxicity in mice

Aluminum is a well known neurotoxin and a possible candidate of hepatotoxins to humans. Using natural antioxidants against metal-induced hepatotoxicity is a modern approach. In the present study, Aluminum (AlCl(3)) intoxication (a single injection of 25mg Al(3+)/kg, i.p.) for 24h in mice resulted in elevations in serum alanine aminotransferase activity and serum tumor necrosis factor and hepatic malondialdehyde levels. Aluminum reduced the activities of glutathione peroxidase, glutathione S-transferase, quinone oxidoreductase, and catalase in liver. In addition, Al caused hepatic hemorrhage, cellular degeneration as well as necrosis of hepatocytes. Ultrastructure examination showed swelling of mitochondria, derangement of rough endoplasmic reticulum cisternae and pleomorphic nuclei with abnormal chromatin distribution. Taurine, a sulfur-containing amino acid was administered to mice daily for 5 days before (at 100mg/kg, i.p.) or 2h after (a single dose of 1g/kg, i.p.) aluminum administration. Treating mice with taurine at either dosing regimens, pre- or post-aluminum administration alleviated aluminum oxidative damaging effects. The rate of recovery was better when taurine was administered prior to Al. Taurine had anaphylactic and therapeutic activity against hepatotoxicity induced by aluminum in mice.

Antimutagenic and antioxidant activity of novel 4-substituted phenyl-2,2'-bichalcophenes and aza-analogs

Evaluation of the potential antimutagenic activities of new compounds by Ames assay has been of great interest for the development of novel therapeutics for many diseases including cancer. Ten novel bichalcophenes with in vitro and in vivo broad spectrum activities against various microbial strains were investigated throughout the present study for their cytotoxic, antioxidant, and antimutagenic potential in a Salmonella reverse mutation assay system against sodium azide (NaN3) and benzo[a]pyrene (B[a]P). At nontoxic concentrations, all bichalcophenes alone or in combination with NaN3 (1 μg/plate) or B[a]P (20 μM) with S9 mix were not mutagenic. The bichalcophenes significantly reduced NaN3- and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions in a concentration-independent manner. However, the antimutagenic activity of bichalcophenes against B[a]P varied depending on the exposure regimen, being more effective under pre-exposure conditions. The antimutagenic activity was correlated with a high antioxidant activity that could promote the DNA repair system. Bichalcophenes are least likely to interfere with the microsomal bioactivation of B[a]P. Monocationic bichalcophenes were superior to the corresponding mononitriles as antimutagenic agents against both mutagens investigated, possibly due to the higher nucleophilic centers they have which could bind and protect the bacterial DNA. Three monocationic compounds were shown to have a strong anticancer activity against the 58 cell line. Based on the results of the present investigation, monocationic compounds (1, 4, and 5B) will be selected for further time consuming and costly chemoprevention studies in animal models.

The position of imidazopyridine and metabolic activation are pivotal factors in the antimutagenic activity of novel imidazo[1,2-a]pyridine derivatives.

The antimutagenic activity of eight novel imidazo[1,2-a]pyridine derivatives (I-VIII) against sodium azide (NaN3) and benzo[a]pyrene (B[a]P) was evaluated using the Salmonella reverse mutation assay. At non-toxic concentrations (12.5-50 µM), imidazopyridines I, II, III, and V with a terminal imidazopyridine group were mutagenic, while derivatives VII and VIII with a central imidazopyridine group were not mutagenic. Compounds IV, VII, and VIII exerted a moderate antimutagenic activity against NaN3 under pre-exposure conditions, and a strong activity (>40%) against B[a]P in the presence of S9 under both pre- and co-exposure conditions and mostly independent on the dose. Imidazopyridines possibly inhibited the microsomal-dependent activation of B[a]P. The demethylated derivative VII was the most active antimutagen. All imidazopyridines had a low to moderate antioxidant activity. The antibacterial activity of imidazopyridines was sporadic and moderate probably due to the failure of bacteria to convert imidazopyridines into active metabolites. The position of imidazopyridine was a pivotal factor in the mutagenic/antimutagenic activity. The strong antimutagenic compounds were dicationic planar compounds with a centered imidazo[1,2-a]pyridine spacer. With LD50 of 60 mg/kg in mice for both derivatives VII and VIII, it is safe to investigate the anticancer activity of these derivatives in animal models.

Upregulation of Chemoprotective Enzymes and Glutathione by Nigella sativa (Black Seed) and Thymoquinone in CCl4-Intoxicated Rats

To examine the hepatoprotective activities of Nigella sativa (Ns) and thymoquinone (TQ) against carbon tetrachloride (CCl4)-induced hepatotoxicity, the effects of water extract of Ns seeds (50 mg/kg) or TQ (5 mg/kg in corn oil) by gavage for 5 days on detoxifying enzymes and glutathione were compared in healthy and CCl4-challenged (1 mL/kg in corn oil, intraperitoneally [ip], a single dose) rats. Both Ns and TQ countered the elevations in serum alanine aminotransferase activity, oxidized glutathione level, and stress ratio caused by CCl4. Both Ns and TQ ameliorated the reductions in the activities and messenger RNA (mRNA) levels of glutathione S-transferase, NAD(P)H-quinone oxidoreductase, and microsomal epoxide hydrolase, as well as the reductions in reduced glutathione and cysteine levels produced by CCl4. In many instances, Ns was much superior to TQ in providing protection against the damaging effects caused by CCl4. This protection could be attributed to the induction of chemoprotective enzymes probably through increasing transcription.

The influence of taurine pretreatment on aluminum chloride induced nephrotoxicity in Swiss albino mice

The present study was carried out to investigate (1) the alterations in biochemical parameters, free radicals and enzyme activities induced by aluminum chloride (AlCl₃) in kidney of male Swiss albino mice, and (2) the role of taurine in alleviating the nephrotoxic effects of AlCl₃. Taurine plays an important role as an antioxidant and is consequently expected to protect tissues from damage caused by reactive oxygen metabolites.The animals were randomized into four groups (n=6/group). Group I was the control group. Group II received a single dose of AlCl₃ (25 mg Al³⁺/kg b.w, ip). Group III received taurine (100 mg/kg b.w., ip) for 5 consecutive days before administration of AlCl₃ (25 mg Al³⁺/kg b.w, ip). Group IV received taurine (100 mg/kg b.w., ip) for 5 consecutive days. 24 h following the administration of compounds, all the mice were assessed using serum and tissue homogenate biomarkers as well as the pathological evaluation. Exposure to AlCl₃ led to an increased level of renal lipid peroxidation as measured by malondialdehyde (MDA), while reduced glutathione (GSH), glutathione peroxidase (GPx) and catalase (CAT) decreased. Marked elevation of blood urea and serum creatinine concentrations were also observed in AlCl₃ treated mice, thereby indicating renal damage. All these factors were significantly improved by taurine pretreatment. The histological and ultrastructural observations on the kidney tissues also confirmed the renoprotective nature of taurine. Thus these results may indicate that taurine treatment protects against functional, biochemical and morphological damage in AlCl₃-induced acute renal failure in mice.

Anticancer, antioxidant activities, and DNA affinity of novel monocationic bithiophenes and analogues.

A series of 15 monocationic bithiophenes and isosteres were prepared and subjected to in vitro antiproliferative screening using the full National Cancer Institute (NCI)-60 cell line panel, representing nine types of cancer. Among the nine types of cancer involved in a five-dose screen, non-small cell lung and breast cancer cell lines were the most responsive to the antiproliferative effect of the tested compounds, especially cell lines A549/ATCC, NCI-H322M, and NCI-H460, whereas compounds 1a, 1c, 1d, and 7 exhibited potent activity, with GI50 values (drug concentration that causes 50% inhibition of cell growth) from less than 10 nM to 102 nM. In addition, compounds 1c and 1d gave GI50 values of 73 nM and 79 nM, respectively, against the MDA-MB-468 breast cancer cell line. Structure–activity relationship findings indicated that the mononitriles were far less active than their corresponding monoamidines and, within the amidines series, the bioisosteric replacement of a thiophene ring by a furan led to a reduction in antiproliferative activity. Also, molecular manipulations, involving substitution on the phenyl ring, or its replacement by a pyridyl, or alteration of the position of the amidine group, led to significant alteration in antiproliferative activity. On the other hand, DNA studies demonstrated that these monoamidine bichalcophenes have promising ability to cleave the genomic DNA. These monoamidines show a wide range of DNA affinities, as judged from their DNA cleavage effect, which are remarkably sensitive to all kinds of structural modifications. Finally, the novel bichalcophenes were tested for their antioxidant property by the ABTS (2,2′-azino- bis(3-ethylbenzthiazoline-6-sulfonic acid) diammonium salt) assay, as well as lipid and nitric oxide scavenging techniques, and were found to exhibit good-to-potent antioxidant abilities.

Novel 4-substituted phenyl-2,2'-bichalcophenes and aza-analogs as antibacterial agents: a structural activity relationship

Antibiotic resistance is a major health problem; therefore, new antibacterial agents will need to be continuously developed. A series of novel bichalcophenes has been tested and found to have antimicrobial activity against selected bacteria. Due to the promising antimicrobial effects of these 4-substituted phenyl bichalcophene derivatives, the study reported here was launched to examine the interaction between novel bichalcophenes and tetracycline. The minimum inhibitory concentration values for all bichalcophenes were between 8 and 64 μM. Many of the bichalcophenes had synergistic activity that increased the inhibitory effect of tetracycline against bacterial growth, as indicated by the fractional inhibitory concentration index. The post-antibiotic effects of the novel bichalcophenes were determined. Many bichalcophenes were able to elongate the period required for bacteria to recover and grow after a brief exposure to tetracycline. Escherichia coli did not develop resistance to many bichalcophenes over a period of 7 days. A structural activity relationship could be characterized, as monocationic derivatives were more active than the corresponding mononitriles. The presence of a pyridyl group and/or furan ring reduced the activity, while the presence of a phenyl or thiophene ring enhanced the antibacterial activity. Our results suggest that bichalcophenes could be useful to elevate the shelf life of many antibiotics.

Efficacy of two novel 2,2′-bifurans to inhibit methicillin-resistant Staphylococcus aureus infection in male mice in comparison to vancomycin

The therapeutic efficacy of two novel bifurans and vancomycin in an animal model of a methicillin-resistant Staphylococcus aureus (MRSA) infection was compared. Adult male CF-1 mice (25–35 g) were intraperitoneally injected with 200 μL/mouse containing 107 cell-forming units of MRSA. After 16 hours, animals were treated with 110 mg/kg of vancomycin, or 5 mg/kg of mononitrile bifuran (1A) or monocationic bifuran (1B) and killed after 8 hours. Treatment with bifurans did not cause any toxicity. Treatment of MRSA-infected animals with bifurans resulted in significant reductions in the viable bacterial count in blood, liver, kidney, and spleen. Colonies recovered from livers and kidneys of mice injected with 1A or 1B lost the initial resistance pattern and became susceptible to methicillin and ciprofloxacin. MRSA elevated the serum urea level and activities of alanine aminotransferase and γ-glutamyl transpeptidase. MRSA also elevated the hepatic level of malondialdehyde, and serum levels of tumor necrosis factor and interleukin-6. MRSA also reduced the glutathione content and activities of catalase and glutathione S-transferase in liver. Similar to vancomycin, bifurans ameliorated most of the previous effects. Compound 1B was superior to 1A, and sometimes both provided better antistaphylococcal agents than vancomycin against MRSA pathogenesis. The present findings along with our previous studies support further evaluation of the efficacy of these bifurans in clinical studies.

Gram Stain Index (GSI) of Bacterial and Archaeal Cells in the Natural Microbial Communities of Slightly and Extremely Saline Environments

The use of GSI (Gram Stain Index) was studied for natural microbial cells in slightly and extremely saline environments. The GSI spectra of archaeal cells in an extremely saline environment showed unique profiles, different from those of Bacteria. These profiles can be applied for structural analysis of the microbial communities in aquatic environments.

Evaluation of the biological activity of novel monocationic fluoroaryl-2,2′-bichalcophenes and their analogues

A series of bichalcophene fluorobenzamidines 5a–e was synthesized from the corresponding mononitriles 4a–e via a direct reaction with lithium bis(trimethylsilyl)amide LiN(TMS)2 followed by de-protection with ethanolic HCl (gas). Bichalcophene fluorobenzonitriles 4a–e were prepared adopting a Stille coupling reaction between the bromo compounds 3a–c and 2-(tri-n-butylstannyl)furan or analogues. As an approach to drug discovery, the structure–antimutagenicity relationship of novel fluoroarylbichalcophenes was examined using the Ames Salmonella/microsomal assay. At nontoxic concentrations (10 and 20 μM), all derivatives alone or in combination with sodium azide (NaN3; 2 μg/plate) or benzo[a]pyrene (B[a]P; 20 μM) in the presence of S9 mix were not mutagenic. The fluoroaryl derivatives significantly reduced the NaN3-induced and B[a]P-induced mutagenicity under pre-exposure and co-exposure conditions. The recorded antimutagenic activity of fluoroaryl derivatives varied depending on the kind of mutagen and the exposure regimen. Monocationic fluoroarylbichalcophenes were superior to the corresponding mononitriles in reducing B[a]P-induced mutagenicity. Nevertheless, mononitriles were more active against NaN3, especially at low concentrations and under pre-exposure treatments. The antimutagenic activity was congruent with a high antioxidant activity that could promote the DNA repair system. The fluorine substitution changed the antimutagenic signature of bichalcophenes. Some of these compounds could be selected for further anticancer studies.