Biomedical subjects

R P Sharma

Publications and source records attributed to R P Sharma.

At least 37 records · Page 2Linked to original sources

PubMed2000

Effects of aromatic residues at the ends of transmembrane alpha-helices on helix interactions with lipid bilayers.

We have studied the effects of aromatic residues at the ends of peptides of the type Ac-KKGL(n)()WL(m)()KKA-amide on their interactions with lipid bilayers as a function of lipid fatty acyl chain length, physical phase, and charge. Peptide Ac-KKGFL(6)WL(8)FKKA-amide (F(2)L(14)) incorporated into bilayers of phosphatidylcholines containing monounsaturated fatty acyl chains of lengths C14-C24 at a peptide:lipid molar ratio of 1:100 in contrast to Ac-KKGL(7)WL(9)KKA-amide (L(16)) which did not incorporate at all into dierucoylphosphatidylcholine [di(C24:1)PC]; Ac-KKGYL(6)WL(8)YKKA-amide (Y(2)L(14)) incorporated partly into di(C24:1)PC. Lipid-binding constants relative to that for dioleoylphosphatidylcholine (C18:1)PC were obtained using a fluorescence quenching method. For Y(2)L(14) and F(2)L(14), relative lipid-binding constants increased with increasing fatty acyl chain length from C14 to C24; strongest binding did not occur at the point where the hydrophobic length of the peptide equalled the hydrophobic thickness of the bilayer. For Ac-KKGYL(9)WL(11)YKKA-amide (Y(2)L(20)), increasing chain length from C18 to C24 had little effect on relative binding constants. Anionic phospholipids bound more strongly than zwitterionic phospholipids to Y(2)L(14) and Y(2)L(20) but effects of charge were relatively small. In two phase (gel and liquid crystalline) mixtures, all the peptides partitioned more strongly into liquid crystalline than gel phase; effects were independent of the structure of the peptide or of the lipid (dipalmitoylphosphatidylcholine or bovine brain sphingomyelin). Addition of cholesterol had little effect on incorporation of the peptides into lipid bilayers. It is concluded that the presence of aromatic residues at the ends of transmembrane alpha-helices effectively buffers them against changes in bilayer thickness caused either by an increase in the chain length of the phospholipid or by the presence of cholesterol.

Cholesterol↗

PubMed2000

Tolerance to fumonisin toxicity in a mouse strain lacking the P75 tumor necrosis factor receptor.

Fumonisin B1 (FB1), a potent mycotoxin prevalent in corn and cereals, causes a variety of toxic effects in different mammalian species. The biochemical responses of FB1 involve inhibition of ceramide synthase leading to accumulation of free sphingoid bases and a possible involvement of tumor necrosis factor alpha (TNFalpha). To further characterize the role of TNFalpha, toxic response to FB1 was investigated in male C57BL/6J mice (WT) and a corresponding TNFalpha receptor knockout (TRK) strain, genetically modified to lack the TNFalpha1b receptor. The hepatotoxic effects of 5 daily injections of 2.25 mg/kg per day of FB1 were observed in WT but were reduced in TRK, evidenced by circulating alanine aminotransferase and aspartate aminotransferase levels and histopathological evaluation of the tissue. FB1 induced TNFalpha expression in the livers of both WT and TRK mice to a similar extent (3-4 fold over control); however, a corresponding increase of cellular NFkappaB, expected after the downstream cellular signaling of TNFalpha, was noted only in the WT. Accumulation of liver sphingosine after FB1 treatment was similar in both WT and TRK, but the FB1-induced increases in liver sphinganine and kidney sphingosine and sphinganine were lower in TRK than in WT. Results emphasized the role of TNFalpha in FB1-induced hepatotoxicity in mice and the possible relationship of sphingoid base accumulation and TNFalpha induction. Moreover, the presence of TNFalpha receptor 1b appears to be important in mediating the hepatotoxic responses of TNFalpha and FB1 in mice.

Alanine Transaminase↗

PubMed2000

A simple microbiological assay for the stereospecific differentiation of alpha and beta isomers of arteether.

A new rapid bioassay has been developed which can precisely differentiate between stereospecific alpha and beta isomers of the antimalarial drug arteether. This method was developed through the disc diffusion bioactivity tests wherein semisynthetically produced alpha arteether was able to inhibit the growth of E. coli strains which are defective in DNA gyrase enzyme. The wild type E. coli with intact DNA gyrase did not show this sensitivity to alpha arteether. The beta isomer of arteether was, however, ineffective against both the mutant and wild type strains. Direct experimental proof of gyrase involvement was obtained through mobilization of gyr genes by transformation of E. coli gyr- mutant strains with wild type gyrA clone pMK90 (carried on the thermo-inducible lambda Col E1 vector). This resulted in alpha arteether resistant and nalidixic acid sensitive phenotype clearly demonstrating the use of gyrA mutant strains in differentiating alpha and beta isomers of arteether by this simple bioassay.

Antimalarials↗

PubMed2000

Fumonisin hepatotoxicity is reduced in mice carrying the human tumour necrosis factor alpha transgene.

Our previous studies have indicated that tumour necrosis factor alpha (TNFalpha) is involved in fumonisin B1 (FB1)-induced toxic responses. To investigate the role of TNFalpha in FB1 toxicity further we employed male transgenic mice expressing human TNFalpha gene (TG) and their wild-type equivalent C57BL/6 (WT). It was hypothesized that TG animals would have enhanced response to FB1. Repeated subcutaneous treatment of animals with 2.25 mg/kg per day of FB1 for 5 days caused minimal changes in body weight, organ weights, blood cell counts, and TNFalpha levels in plasma 1 day after the last injection. The mRNA for TNFalpha in liver increased in both TG and WT after FB1 treatment, providing evidence that FB1 induces hepatic TNFalpha expression. Liver and kidney lesions were found in TG after FB1 treatment; however, liver lesions seen in FB1-treated TG were considerably less than those observed in WT. The decreased hepatotoxicity in TG after FB1 treatment correlated with plasma concentrations of alanine aminotransferase and aspartate aminotransferase. Free sphinganine levels increased significantly in both the liver and kidney of WT and TG mice treated with FB1. The increase of free sphinganine in the liver from TG mice was 40% less than in WT mice and paralleled the changes in serum liver enzymes. Regional brain neurotransmitters and their metabolites were increased to a similar extent by FB1 in both WT and TG mice. Since the data did not support the original hypothesis, we investigated the levels of NFkappaB in liver. The cytosolic NFkappaB was significantly higher in TG compared with WT. Induction of NFkappaB, caused by increased endogenous production of TNFalpha, is a possible explanation of decreased FB1 hepatotoxicity in TG. The results suggest a protective role for NFkappaB in FB1-induced liver damage.

Alanine Transaminase↗

PubMed2000

Increase in dopamine metabolites in murine striatum after oral exposure to inorganic but not organic form of selenium.

Selenium (Se) is an essential as well as a toxic trace element. Se intoxication has been reported in both livestock and humans. The central nervous system is sensitive to Se poisoning; exposure to Se causes blind staggers in cattle, poliomyelomalacia in pigs, and nervous system disorders in humans. Differences in neurotoxicity between inorganic and organic Se have been demonstrated. In this study, groups of five male BALB/c mice each were administered sodium selenite or selenomethionine in drinking water ad libitum at 0, 1, 3, and 9 ppm as Se for 14 days. At the end of Se exposure, their brains were removed and dissected into different regions. The concentration of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT), and 5-hydroxyindolacetic acid (5-HIAA) were determined in each brain region. Food and water consumption and body weight gain were significantly decreased in the group treated with the highest concentration of sodium selenite. In mice administered sodium selenite at 3 and 9 ppm, DOPAC was significantly higher in the striatum than in the control group. The striatal HVA was also increased in the group treated with 3 ppm Se; the DA showed a similar pattern, but the increase was not statistically significant. No alterations of NE, 5-HT, or 5-HIAA levels were detected in any brain region of mice treated with sodium selenite. No significant differences in any parameter among the groups treated with selenomethionine were observed indicating that inorganic Se was more neurotoxic than organic Se via drinking water. The alterations of DA metabolites by inorganic Se in DA-rich striatum suggested a Se-specific increased neural activity of dopaminergic pathways. Results may be useful in further elucidation of neurotoxicity of Se and in establishing a safe level of intake for this element.

Administration, Oral↗

PubMed2000

Increased production of proinflammatory cytokines by murine macrophages following oral exposure to sodium selenite but not to seleno-L-methionine.

Selenium (Se) is an essential as well as a toxic trace element in animal and human nutrition. The immune system is a known target of Se intoxication. The objectives of the present study were to determine the effects of oral exposure to inorganic and organic forms of Se on the murine immune system and to compare the relative toxicity of the different chemical forms. Male BALB/c mice, 6-7 weeks of age, were exposed continuously to 0, 1, 3 or 9 ppm of Se as sodium selenite or seleno-L-methionine in the drinking water for 14 days. Following the treatment period mice were euthanized; trunk blood, spleen, thymus, liver and kidney were aseptically collected and organs weighed. Single-cell splenocyte cultures were made from the spleens and used to determine the effects of Se treatment on mitogen-induced lymphocyte blastogenesis and cytokine production. There were no changes in the 0 and 1 ppm Se groups as selenite. The thymus/body weight ratio was significantly reduced at 3 ppm Se as sodium selenite, and all other parameters remained unaffected. Exposure to 9 ppm of Se as sodium selenite resulted in marked decrease in body weight gain and relative organ weights. Treatment of mice with 9 ppm Se as sodium selenite increased erythrocyte counts in peripheral blood, reduced splenic cellularity, but increased the basal rate of splenocyte proliferation and induced a dose-dependent increase in phytohemagglutinin-P-induced lymphocyte proliferation. Sodium selenite at this dose increased the production of proinflammatory cytokines, tumor necrosis factor alpha and interleukin-1 beta, in lipopolysaccharide-stimulated splenic macrophages. Mice exposed to Se as seleno-L-methionine in the drinking water did not display any effects on the parameters examined at the dose range in this study. Results indicated that splenic macrophages and lymphocytes are sensitive to Se intoxication and there is a disparity in the immune system toxicity of inorganic and organic forms of Se administered via the drinking water, inorganic Se being more toxic.

Administration, Oral↗

PubMed2000

Effect of all-trans-retinoic acid on cytokine production in a murine macrophage cell line.

All-trans-retinoic acid (RA) is a cancer chemopreventive agent and a pluripotent morphogen. It belongs to the class of retinoids that, besides being inducers of differentiation and growth-inhibitos, exert immunomodulatory and anti-inflammatory functions by mechanisms that are not clearly understood. Macrophages play different roles in diverse physiological processes, including ones in orchestrating immune and inflammatory responses. Products of activated macrophages such as interleukin-1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha), interleukin-6, interleukin-8, and nitric oxide (NO) are important regulators of inflammatory reactions. In this study J774A. 1 cells, a murine macrophage cell line, was used to study the effects of RA on the production of NO, TNFalpha and IL-1beta. Cells were stimulated with lipopolysaccharide (LPS) with or without RA. RA depressed the levels of NO in a dose-dependent manner. NO production and subsequent nitrite accumulation in the media peaked at 24 h, plateaued at 48 h, and remained at the same level through 72 h. The presence of RA decreased TNFalpha levels, measured by both bioassay and enzyme-linked immunosorbent assay (ELISA), but these did not correlate with increased mRNA expression measured by reverse-transcriptase polymerase chain reaction at 6 h after LPS stimulation. IL-1beta protein production measured by both ELISA and bioassay decreased with RA treatment. IL-1beta mRNA expression was not affected by RA except at low doses. This study indicated that RA modulates cytokine production in J774A.1 macrophage cells. Inhibition of inflammatory cytokine production may play a role in the anti-inflammatory activity of RA. The results suggested that effects of RA are complex and are time and concentration dependent.

Animals↗

PubMed2000

Disruption of sphingolipid metabolism in small intestines, liver and kidney of mice dosed subcutaneously with fumonisin B(1).

Fumonisin B(1) is a fungal inhibitor of ceramide synthase, a key enzyme in the de novo biosynthesis of sphingolipids. The resulting increase in tissue free sphinganine (and sometimes sphingosine) is used as a biomarker for fumonisin exposure. This study determined whether a single subcutaneous injection of fumonisin B(1) could cause an increase in free sphingoid bases in the intestinal epithelial cells of mice over 24 hr. It was hypothesized that fumonisin administered subcutaneously would be excreted into the small intestine via biliary excretion, and this should be detectable by increased sphingoid bases in the intestine. A significant time-dependent increase in sphingoid bases occurred in the intestine and liver peaking at 4-8 hr and declining to control levels by 24 hr. In the kidney the increase in free sphinganine was persistent. The parallel time course of the change in sphinganine in the intestine and liver suggested fumonisin B(1) was rapidly excreted into the small intestine. Rapid cell turnover in the intestine could account for the reversal of the sphinganine increase. The rapid return to the control level in liver was unexpected since ceramide synthase inhibition in cultured cells is persistent suggesting that liver handles fumonisin B(1) or sphingoid bases quite differently than kidney.

Animals↗

PubMed2000

The Src homology-2 domains (SH2 domains) of the protein tyrosine kinase p56lck: structure, mechanism and drug design.

Src homology 2 (SH2) domains are found in many intercellular signal-transduction proteins which bind phosphotyrosine containing polypeptide sequences with high affinity and specificity and are considered potential targets for drug discovery. The protein p56lck is a member of the family of Src tyrosine kinase. The SH2 domain is thought to be responsible for the recruitment and regulation of p56lck kinase activity. There have been enormous efforts in the development of SH2 domain inhibitors for diseases such as cancer, osteoporosis and other diseases. This review focuses on current understanding of SH2 domain structure, mechanism and drug discovery with an emphasis on p56lck SH2 domain. A potential impact of the accumulated crystallographic effort on the development of methods for structure-based drug design is briefly addressed.

Amino Acid Sequence↗

PubMed2000

Effects of mountaineering training at high altitude (4,350 m) on physical work performance of women.

BACKGROUND: Little is known about work performance of women in hypobaric hypoxia. Moreover, whether native women of moderate altitude (2,000-2,100 m) differ from their lowland counterparts in their ability to adjust to hypobaric hypoxia is also not known. Hence, physiological alterations on work performance due to mountaineering training with altitude adaptation was evaluated in two groups of women and compared to the differences in the responses of the native women of moderate altitudes (Highlanders-HL) with those of the plains (Lowlanders-LL). METHODS: Pre-training tests were conducted at 2,100 m, then during sojourn to 4,350 m and re-tested again after return to 2,100 m. Physical work performance was assessed following standard step-test-exercise on a 30 cm stool with 24 cycles x min(-1) for 5 min. Heart rate, BP, ventilation, oxygen consumption and oxygen saturation were monitored at rest and during exercise followed by 5 min recovery in all three situations. RESULTS: During initial assessment, HL showed higher cardiovascular efficiency with faster recovery of exercise heart rate. Both groups showed significant improvement in physical performance due to mountaineering training at high altitude (HA). The difference in performance between two groups narrowed down at 4,350 m and further reduced during re-test with maintenance of initial superiority of the HL. CONCLUSIONS: a) Native women of moderate altitude (HL) are more fit compared with their plains counterparts (LL); b) All women achieved marked improvement in cardiovascular and respiratory efficiency as well as the step-test score due to intense mountaineering training at HA, and the rate of improvement in physical performance was higher in LL; c) Further, induction by trekking under progressive hypoxia coupled with rigorous mountaineering activity at HA merits in understanding better acclimatization and improved physical performance.

Acclimatization↗

PubMed1999

Analysis of taxol and major taxoids in Himalayan yew, Taxus wallichiana.

A reversed-phase column liquid chromatography method for the analysis of taxol, 10-deacetylbaccatin III, baccatin IV, 1-hydroxybaccatin I, 2-acetoxybrevifoliol, brevifoliol, 2'-deacetoxydecinnamoyltaxinine J and 2'-deacetoxytaxinine J in yew needles has been developed using a Nova-Pak Phenyl column and a binary gradient profile. The various aspects of analysis such as extraction efficiency, detection limits, reproducibility and peak purity were validated using UV-Vis as well as photodiode array detection.

Antineoplastic Agents, Phytogenic↗

PubMed1999

Increased proinflammatory cytokines production by ergotamine in male BALB/c mice.

The ergopeptine alkaloid ergotamine (ET) mimics the effects of ergopeptine alkaloids found in endophyte-infected (E+) fescue forage considered causative for fescue toxicosis. Altered immune capacity, compromised intake and thermoregulation, and inflammatory changes are observed in fescue toxicosis. Taken together, these suggest the cytokine pattern may be altered by ergot alkaloids. Thus, the objective of this study was to determine whether major splenocyte-derived cytokines--interleukin 2 (IL-2), interleukin 4 (IL-4), interferon gamma (IFN-gamma)--and macrophage-derived cytokines--interleukin 1beta, (IL-1beta), interleukin 6 (IL-6), and tumor necrosis factor alpha (TNF-alpha)--were affected by ergotamine. Two sets of male BALB/c mice (n = 5/treatment) were treated with ergotamine tartrate (s.c.) for 10 d at doses of 0 (control), 0.4, 2, 10, or 50 mg/kg body weight. Twenty-four hours after the last treatment, splenocytes (S) were isolated from one set of animals and macrophages (Mphi) from the other set for determination of IL-2, IL-4, INF-gamma, and IL-1beta, IL-6, TNF-alpha, respectively. Following activation with 5 microg/ml concanavalin A (Con A) (S) and 10 microg/ml lipopolysaccharide (LPS) (Mphi), cells were incubated for 48 and 24 h, respectively, and supernatants were collected and assayed for respective cytokines by enzyme-linked immunosorbent assay (ELISA). Additionally, differential white blood cell (WBC) counts were performed and the neutrophil (N):lymphocyte (L) ratio calculated. Ergotamine treatment significantly increased IL-6 levels at the 2.0 mg/kg dose and greater and TNF-alpha at the highest dose. There was no treatment effect on IL-1beta, IL-2, IL-4, and IFN-gamma. Also, no effect was observed upon total and differential WBC counts as well as N:L ratio. Ergotamine affected the proinflammatory cytokine IL-6, and this increase may contribute to fescue tosicosis.

Animals↗

PubMed1999

Amino acid substitution in alpha-helix 7 of Cry1Ac delta-endotoxin of Bacillus thuringiensis leads to enhanced toxicity to Helicoverpa armigera Hubner.

Insecticidal proteins or delta-endotoxins of Bacillus thuringiensis are highly toxic to a wide range of agronomically important pests. The toxins are formed of three structural domains. The N-terminal domain is a bundle of eight alpha-helices and is implicated in pore formation in insect midgut epithelial membranes. All the delta-endotoxins share a common hydrophobic motif of eight amino acids in alpha-helix 7. A similar motif is also present in fragment B of diphtheria toxin (DT). Site-directed mutagenesis of Cry1Ac delta-endotoxin of B. thuringiensis was carried out to substitute its hydrophobic motif with that of DT fragment B. The mutant toxin was shown to be more toxic to the larvae of Helicoverpa armigera (cotton bollworm) than the wild-type toxin. Voltage clamp analysis with planar lipid bilayers revealed that the mutant toxin opens larger ion channels and induces higher levels of conductance than the wild-type toxin.

Amino Acid Substitution↗

PubMed1999

The prolactin response to fenfluramine in schizophrenia is associated with negative symptoms.

We examined the serotonergic system in drug-free inpatients [schizophrenia (n=28) and schizoaffective (n=7)] by administering a challenge dose of oral dl-fenfluramine (fenfluramine) in a controlled angiocatheter study. Seventeen of these patients were also randomized to a placebo condition in addition to receiving fenfluramine. Response to fenfluramine as reflected by changes in serum prolactin and cortisol were examined by repeated measures ANOVA, as well as Area Under the Curves (AUCs). The prolactin response, but not the cortisol response, was significantly correlated with measures of negative symptoms.

Administration, Oral↗

PubMed1999

Hallucinations in the acute schizophrenic-type psychosis: effects of gender and age of illness onset.

Our objective was to test the hypothesis that gender, the age of illness onset, or the interaction between these two variables, would distinguish acutely ill schizophrenic and schizoaffective patients who hallucinated from those who did not. Hallucinatory experiences were measured by the hallucination item of the Brief Psychiatric Rating Scale in a sample of 160 drug-free inpatients admitted for the treatment of an acute episode. Patients were categorized as either non-hallucinators or hallucinators. An additional analysis included only those who had 'severe' hallucinations (i.e., score > or = 5). Female gender, but not age of onset, predicted a higher frequency of hallucinations (irrespective of degree of severity) in the total sample, but specifically in the schizophrenic patients. These results indicate that there may be gender differences in the propensity to experience hallucinations during the acute schizophrenic episode.

Acute Disease↗

PubMed1999

Region-specific decrease of dopamine and its metabolites in brains of mice given ergotamine.

Ergot alkaloids (EA) such as the ergopeptine alkaloid ergotamine (ET) are adrenergic, dopaminergic, and serotonergic agents. The objective of this experiment was to investigate regional brain neurotransmitter alterations caused by EA. Male BALB/c mice were treated s.c. daily with ergotamine tartrate for 10 d at 0 (saline), 0.4, 2, 10, or 50 mg/kg body weight. Twenty-four hours after the last treatment, animals were sacrificed and brains dissected. Regional concentrations of norepinephrine (NE), dopamine (DA), serotonin (5-HT), and metabolites 3-methoxy-4-hydroxyphenylethylene glycol (MHPG), dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindole-3-acetic acid (5-HIAA) were measured by high-performance liquid chromatography (HPLC). Moreover, selected organ weights and plasma prolactin (PRL) were determined. Dopamine concentration was significantly reduced by ET at all doses in the striatal and hypothalamic regions. A reduction of the DA metabolite HVA occurred in striatum at only the highest dose, whereas in the hypothalamus both HVA and DOPAC were markedly reduced. Concentrations of NE, MHPG, 5-HT, and 5-HIAA were not affected by treatment in these regions. In the cerebellum, MHPG was significantly elevated at the 50 mg/kg dose. No effect of treatment was observed in the cerebrum, medulla, and midbrain. Further, no treatment-related differences in plasma PRL and organ weights other than a significant liver weight decrease at intermediate doses were found. Therefore, the effects of ET were predominantly upon DA metabolism in the corpus striatum and hypothalamus. The reductions in DA, HVA, and DOPAC indicate decreased DA synthesis.

Adrenergic alpha-Agonists↗

PubMed1999

Effects of endotoxin and tumor necrosis factor alpha on regional brain neurotransmitters in mice.

Alterations in regional brain concentration of dopamine (DA), norepinephrine (NE), serotonin (5-HT) and their metabolites were investigated in male BALB/c mice injected intraperitoneally with bacterial lipopolysaccharide (LPS, 2 mg kg(-1)) or recombinant murine tumor necrosis factor alpha (TNFalpha, 0.1 mg kg(-1)) at 2, 6, 12 and 24 h after the injection. At 2 h post-injection the LPS administration resulted in hypothermia, which was not apparent at later time points. No consistent effects were observed by either LPS or TNFalpha on peripheral leukocyte counts or plasma transaminase levels. Both LPS and TNFalpha slightly elevated NE metabolism in the striatum at 2-12 h. Concentrations of DA and its metabolites were significantly elevated only in the hypothalamus following TNFalpha at 24 h. Tumor necrosis factor alpha exerted pronounced effects on 5-HT metabolism in most brain regions at 2 h. Results suggest that the effect of LPS is more complex compared with TNFalpha because of the endogenous production of other cytokines including the TNFalpha.

Animals↗

PubMed1999

Modulation of tumor necrosis factor alpha expression in mouse brain after exposure to aluminum in drinking water.

Aluminum, a known neurotoxic substance and a ground-water pollutant, is a possible contributing factor in various nervous disorders including Alzheimer's disease. It has been hypothesized that cytokines are involved in aluminum neurotoxicity. We investigated the alterations in mRNA expression of tumor necrosis factor alpha (TNFalpha), interleukin-1beta (IL-1beta), and interferon gamma (IFNgamma), cytokines related to neuronal damage, in cerebrum and peripheral immune cells of mice after exposure to aluminum through drinking water. Groups of male BALB/c mice were administered aluminum ammonium sulfate in drinking water ad libitum at 0, 5, 25, and 125 ppm aluminum for 1 month. An additional group received 250 ppm ammonium as ammonium sulfate. After treatment, the cerebrum, splenic macrophages and lymphocytes were collected. The expression of TNFalpha mRNA in cerebrum was significantly increased among aluminum-treated groups compared with the control, in a dose-dependent manner. Other cytokines did not show any aluminum-related effects. In peripheral cells, there were no significant differences of cytokine mRNA expressions among treatment groups. Increased expression of TNFalpha mRNA by aluminum in cerebrum may reflect activation of microglia, a major source of TNFalpha in this brain region. Because the aluminum-induced alteration in cytokine message occurred at aluminum concentrations similar to those noted in contaminated water, these results may be relevant in considering the risk of aluminum neurotoxicity in drinking water.

Aluminum↗