Kegg Pathway: Alanine and aspartate metabolism

metabolism. 2009 Nov 13;
Xie Z, Li H, Wang K, Lin J, Wang Q, Zhao G, Jia W, Zhang Q

Excessive energy intake greatly contributes to the development of nonalcoholic fatty liver disease (NAFLD) in modern society. To better understand the comprehensive mechanisms of NAFLD development, we investigated the metabolic alterations of rats with NAFLD induced by high-fat diet (HFD). Male Wistar rats were fed a HFD or standard chow for control. After 16 weeks, rat serum was collected for biochemical measurement. The rats' livers were resected and subjected to histology inspection and gene expression analysis with complementary DNA microarray and metabolic analysis with gas chromatography-mass spectroscopy. In HFD rats, the serum cholesterol, triglycerides, glucose, and insulin contents were increased; and the total cholesterol and triglycerides in the livers were also significantly increased. Complementary DNA microarray analysis revealed that 130 genes were regulated by HFD. Together with real-time reverse transcriptase polymerase chain reaction, lipid metabolism regulatory members like sterol regulatory element binding factor 1 and stearoyl-coenzyme A desaturase 1 had up-regulation, whereas others like peroxisome proliferator-activated receptor, carnitine palmitoyltransferase 1, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase had repressed expression, in HFD rat livers. Metabolomic analysis showed that tetradecanoic acid, hexadecanoic acid, and oleic acid had elevation and arachidonic acid and eicosapentaenoic acid had decreased content in HFD rat livers. Amino acids including glycine, Alanine, aspartic acid, glutamic acid, and proline contents were decreased. The integrative results from transcriptomic and metabolomic studies revealed that, in HFD rat livers, fatty acid utilization through beta-oxidation was inhibited and lipogenesis was enhanced. These observations facilitated our understanding of the pathways involved in the development of NAFLD induced by HFD.

Biotechnol Prog. 2009 Nov 6;
Shaikh AS, Tang YJ, Mukhopadhyay A, Martín HG, Gin J, Benke PI, Keasling JD

Microbial production of many commercially important secondary metabolites occurs during stationary phase, and methods to measure metabolic flux during this growth phase would be valuable. Metabolic flux analysis is often based on isotopomer information from proteinogenic amino acids. As such, flux analysis primarily reflects the metabolism pertinent to the growth phase during which most proteins are synthesized. To investigate central metabolism and amino acids synthesis activity during stationary phase, addition of fully (13)C-labeled glucose followed by induction of green fluorescent protein (GFP) expression during stationary phase was used. Our results indicate that Escherichia coli was able to produce new proteins (i.e., GFP) in the stationary phase, and the amino acids in GFP were mostly from degraded proteins synthesized during the exponential growth phase. Among amino acid biosynthetic pathways, only those for serine, Alanine, glutamate/glutamine, and aspartate/asparagine had significant activity during the stationary phase. (c) 2009 American Institute of Chemical Engineers Biotechnol. Prog., 2010.

Food Chem Toxicol. 2009 Nov 1;
Nunes ES, Desai SN, Desai PV

Iron in the form of ferrous sulphate coming from sources such as mines, writing inks, blue pigments, dyeing industries, photography, medicine, deodorizers, disinfectants, fungicides and molluscides, etc. contributes in elevating ferrous sulphate of water bodies. The present study investigated the action of ferrous sulphate on the local fish Tilapia mossambica. Tilapia exposed to 0.001g/L ferrous sulphate for 30 days showed reduction of cytosolic AST and ALT activities of cerebral cortex by 35.4% and 29.1%, respectively, while exposure to 0.01% ferrous sulphate promoted 49.2% and 38.4% reduction of AST and ALT activities. Similarly mitochondrial AST and ALT activities reduced by 50% and 34.8%, respectively, on exposure to 0.001g/L ferrous sulphate while 0.01g/L ferrous sulphate promoted 51% and 47.8% reductions of AST and ALT activities at the end of 30days, suggesting interference in the glutamate and protein metabolism of Tilapia brain.

Amino Acids. 2009 Oct 30;
Sorrequieta A, Ferraro G, Boggio SB, Valle EM

In tomato, free amino acids increase dramatically during fruit ripening and their abundance changed differentially. More evident is L: -glutamate which gives the characteristic "umami" flavor. Glutamate is the principal free amino acid of ripe fruits of cultivated varieties. In this paper, we examined the capacity of tomato fruits to process endogenous as well as exogenous polypeptides during the ripening transition, in order to analyze their contribution to the free amino acid pool. In addition, the activity of some enzymes involved in glutamate metabolism such as gamma-glutamyl transpeptidase (gamma-GTase), glutamate dehydrogenase (GDH), alpha-ketoglutarate-dependent gamma-aminobutyrate transaminase (GABA-T), Alanine and aspartate aminotransferases was evaluated. Results showed that peptidases were very active in ripening fruits, and they were able to release free amino acids from endogenous proteins and glutamate from exogenously added glutamate-containing peptides. In addition, red fruit contained enough gamma-GTase activity to sustain glutamate liberation from endogenous substrates such as glutathione. From all the glutamate metabolizing enzymes, GDH and GABA-T showed the higher increase in activities when the ripening process starts. In summary, tomato fruits increase free amino acid content during ripening, most probably due to the raise of different peptidase activities. However, glutamate level of ripe fruit seems to be mostly related to GDH and GABA-T activities that could contribute to increase L: -glutamate level during the ripening transition.

J Am Coll Surg. 2009 Nov; 209(5): 638-44
Nadler EP, Reddy S, Isenalumhe A, Youn HA, Peck V, Ren CJ, Fielding GA

BACKGROUND: The distribution of weight loss and its impact on metabolic health has not been documented for laparoscopic adjustable gastric banding (LAGB) in the adolescent population. We hypothesized that LAGB in obese adolescents would result in loss of android fat mass, resolution of comorbidities, and improvement in metabolic status. STUDY DESIGN: Adolescents ages 14 to 17 who met criteria for bariatric surgery were enrolled in our FDA-approved LAGB trial. Demographic data, body mass index, body composition and bone density, laboratory evaluations, and comorbid conditions were assessed pre- and postoperatively. RESULTS: Forty-five patients had complete 1-year followup and 41 patients had complete 2-year followup. Mean preoperative weight was 299 + or - 57 lb and body mass index was 48 + or - 6.4 kg/m(2). The percent excess weight losses at 6 months, 1 year, and 2 years were 31 + or - 16, 46 + or - 21, and 47 + or - 22, respectively. At 1-year followup, patients after LAGB had a significant decrease in their total and android fat mass. In addition, 47 of 85 identified comorbidities (55%) were completely resolved and 25 (29%) were improved in comparison with baseline. Improvements in alkaline phosphatase, aspartate aminotransferase, Alanine aminotransferase, hemoglobin A1c, fasting insulin, triglycerides, and high density lipoprotein, were also seen. CONCLUSIONS: The percent excess weight loss after LAGB in morbidly obese adolescents is approximately 45% at 1- and 2-year followup, with the majority of weight loss consisting of android fat mass. Resolution or improvement of comorbidities is seen, and improved metabolic status, as demonstrated by liver function tests, lipid levels, and measures of glucose homeostasis, may be expected. These data support LAGB as an appropriate surgical option for morbidly obese adolescents.

Hum Gene Ther. 2008 Nov; 19(11): 1325-31
Crowther C, Ely A, Hornby J, Mufamadi S, Salazar F, Marion P, Arbuthnot P

Achieving safe delivery of anti-hepatitis B virus (HBV) RNA interference (RNAi) effectors is an important objective of this gene-silencing technology. Adenoviruses (Ads) have a natural tropism for the liver after systemic administration, and are useful for delivery of expressed anti-HBV RNAi sequences. However, a drawback of Ad vectors is diminished efficacy and toxicity that results from stimulation of innate and adaptive immunity. To attenuate these effects we used monomethoxy polyethylene glycol-succinimidyl propionate (mPEG-SPA) to modify first-generation vectors that express an anti-HBV RNAi effector. Efficient hepatocyte transduction and knockdown of HBV replication were achieved after intravenous administration of 5 x 10(9) PEGylated or native recombinant Ads to HBV transgenic mice. After the first injection, circulating HBV viral particle equivalents (VPEs) remained low for 3 weeks and began to increase after 5 weeks. A second dose of PEGylated anti-HBV Ad caused a less sustained decrease in circulating VPEs, but no silencing after a second dose was observed in animals treated with unmodified vector. Release of inflammatory cytokines, including monocyte chemoattractant protein-1 (MCP-1), interferon-gamma, interleukin-6, and tumor necrosis factor-alpha, was elevated in animals receiving unmodified vectors. However, only a modest increase in MCP-1 was observed in mice that received a second dose of PEG Ads. Also, polymer-conjugated vectors induced a weaker adaptive immune response and were less hepatotoxic than their unmodified counterparts. Collectively, these observations show that PEG modification of Ads expressing RNAi effectors improves their potential for therapeutic application against HBV infection.

Int J Obes (Lond). 2009 Oct 20;
Romeo S, Sentinelli F, Dash S, Yeo GS, Savage DB, Leonetti F, Capoccia D, Incani M, Maglio C, Iacovino M, O'Rahilly S, Baroni MG

Context:The PNPLA3 I148M variant (rs738409) is robustly associated with hepatic steatosis. Intriguingly, initial findings in cohorts with a mean body mass index (BMI) of 30 kg m(-2) also suggested that it is associated with elevated liver enzymes but not with insulin resistance and dyslipidaemia.Objective:To determine whether the PNPLA3 variant alters the susceptibility of morbidly obese subjects to develop liver injury and metabolic sequelae.Participants and methods:The study was carried out in 678 obese Italians (mean BMI=41 kg m(-2)) who were genotyped for the I148M variant. All participants provided fasting blood samples and then underwent oral glucose tolerance tests.Main outcome measures:Indices of liver injury (Alanine transaminase (ALT), aspartate transaminase (AST)), glucose tolerance and insulin resistance were measured.Results:Markers of hepatic injury such as ALT and AST were significantly higher in carriers of the 148M allele (P=2.2 x 10(-5) and 0.001, respectively). In all, 50% of 148M risk allele homozygotes had pathological levels of ALT (>40 U l(-1)) compared with 25% of 148I allele homozygotes (P=0.005). Glucose tolerance and insulin sensitivity were similar in all three genotypes.Conclusion:Obese Southern Europeans carrying the 148M allele have increased indices of liver damage uncoupled from proxy measures of insulin resistance.International Journal of Obesity advance online publication, 20 October 2009; doi:10.1038/ijo.2009.216.

J Pharmacol Sci. 2009 Oct; 111(2): 175-81
Kim SJ, Lee MY, Kwon do Y, Kim SY, Kim YC

Our previous studies showed that administration of a subtoxic dose of acetaminophen (APAP) to female rats increased generation of carbon monoxide from dichloromethane, a metabolic reaction catalyzed mainly by cytochrome P450 (CYP) 2E1. In this study we examined the changes in metabolism and toxicity of APAP upon repeated administration. An intraperitoneal dose of APAP (500 mg/kg) alone did not increase aspartate aminotransferase, Alanine aminotransferase, or sorbitol dehydrogenase activity in serum, but was significantly hepatotoxic when the rats had been pretreated with an identical dose of APAP 18 h earlier. The concentrations and disappearance of APAP and its metabolites in plasma were monitored for 8 h after the treatment. APAP pretreatment reduced the elevation of APAP-sulfate, but increased APAP-cysteine concentrations in plasma. APAP or APAP-glucuronide concentrations were not altered. Administration of a single dose of APAP 18 h before sacrifice increased microsomal CYP activities measured with p-nitrophenol, p-nitroanisole, and aminopyrine as probes. Expression of CYP2E1, CYP3A, and CYP1A proteins in the liver was also elevated significantly. The results suggest that administration of APAP at a subtoxic dose may result in an induction of hepatic CYP enzymes, thereby altering metabolism and toxicological consequences of various chemical substances that are substrates for the same enzyme system.

Jpn J Vet Res. 2009 Aug; 57(2): 109-18
El BK, Hashimoto Y, Muzandu K, Ikenaka Y, Ibrahim ZS, Kazusaka A, Fujita S, Ishizuka M

Pleurotus cornucopiae (PC) mushrooms are found in the field and commonly known in Japan as Tamogidake mushrooms. The present study investigated the protective effects of an aqueous extract of PC on carbon tetrachloride (CCl4)-induced hepatotoxicity and the possible mechanism involved in this protection including cytochrome P450 (CYP) 2E1. Wistar rats were pretreated with aqueous extracts of PC (0, 100, 200, and 400 mg/kg) orally for 8 days prior to the intraperitoneal administration of a single dose of CCl4 (0.5 ml/kg) or corn oil. Pretreatment with PC mushroom extract significantly prevented the increased serum enzyme activities of Alanine and aspartate aminotransferases in a dose-dependent manner, and suppressed the expression of CYP2E1. PC mushroom extract also protected hepatocytes from the damage effects of CCl4 as remarked by histological and electromicroscopical findings. It was concluded that repeated daily doses of aqueous extracts of PC mushroom reduced the toxic effects exerted by CCl4 on the liver.

MMW Fortschr Med. 2009 Sep 10; 151(37): 48-50
Tiesmeier J, Dienes HP, Schuppert F

Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi. 2009 Feb; 23(1): 53-5
Wang H, Song CZ, Meng QH, Ren Y, Zhang FY, Zhao JJ

OBJECTIVE: To explore the role of glutamine in LPS and D-Gal induced acute hepatic injury. METHODS: A total of 61 Wistar rats were randomly divided into three groups: control group, model group and GLN pretreated group. The animal model was established by LPS and D-Gal intraperitoneal injection. GLN at dose of 1 g/kg was intragastrically administrated for 7 d before intraperitoneal injection. To evaluate the hepatic injury, the serum Alanine aminotransferase (ALT), aspartate aminotransferase (AST) and total bilirubin (TBiL) were detected by automatic biochemistry analysator. The liver and bowel tissue was observed by lightmicroscope and transmission electron microscope (TEM). The apoptosis of hepatocyte was detected by TUNEL. HPLC-PED was used in the study of intestinal permeability. RESULTS: No significant differences were noted between ALT, AST, TBIL level, death rate and intestinal permeability (L/M) between model group and GLN pretreated group; In microscope, the confused structure of hepatic injury and inflammatory infiltration were similar between model group and GLN pretreated group. The injury of bowel was not obviously. Compared with the model group, there was better trend in liver and bowel in GLN pretreated group by transmission electron microscope (TEM). The apoptosis index in GLN pretreated group were lower than those in model group. CONCLUSION: LPS can induce acute liver injury in D-Gal-sensitized rats.Glutamine has't the trend of protecting liver function and intestinal barrier function,decreasing death rates.

J Egypt Soc Parasitol. 2009 Aug; 39(2): 641-51
Yousif MA, Khafagy HF, El-Shanawani FM, El-Sabae HH, Omar SH, Allam MN, Kamel HH

The effect of sevoflurane anesthesia with or without induced hypotension on hepatocellular integrity was studied. Forty adult consented patients scheduled for various urological procedures were allocated randomly to either NTG group (nitroglycerin-induced hypotension) or a control group of twenty patients each. Anesthesia was induced and maintained by fentanyl, sevoflurane & vecuronium in both groups. In NTG group, nitro-glycerin infusion was adjusted to maintain mean arterial pressure (MAP) of 50-65 mm Hg. Specific and sensitive hepatic biomarkers; alpha (alpha) and pi (pi) glutathione S-transferases (GST) and hyaluronic acid (HA), also traditional liver enzymes; aspartate (AST) and Alanine (ALT) aminotransferases were measured at: TO (pre-induction), T1, T2, T3 (15, 30 & 60 minutes after MAP stabilization respectively) and T4 (24 hours after anesthesia end). Plasma alpha-GST significantly increased at T3 in control group (p < 0.05) and in NTG group (p < 0.01) compared to TO in same group. In NTG group, hyaluronic acid con-centrations was significantly increased at T1, T2 (p < 0.05) and T3 (p < 0.01) from T0. Compared to control group, alpha- GST & HA concentrations showed significant increases in NTG group at T3 with p < 0.05 then returned back to normal range at T4. But, pi-GST, AST and ALT showed no significant changes throughout the study in both groups.

World J Gastroenterol. 2009 Oct 7; 15(37): 4720-5
Peng XD, Dai LL, Huang CQ, He CM, Chen LJ

AIM: To investigate the correlation between the antifibrotic effect of baicalin and serum cytokine production in rat hepatic fibrosis. METHODS: Forty male Sprague-Dawley rats were divided randomly into four groups: normal control group, model group, baicalin-treated group, and colchicine-treated group. Except for the normal control group, all rats in the other groups were administered with carbon tetrachloride to induce hepatic fibrosis. At the same time, the last two groups were also treated with baicalin or colchicine. At the end of the 8 wk, all animals were sacrificed. Serum Alanine aminotransferase (ALT), aspartate aminotransferase (AST), transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10 were measured. Liver index, hepatic hydroxyproline content and the degree of liver fibrosis were also evaluated. RESULTS: The levels of ALT, AST and liver index in the baicalin-treated group were markedly lower than those in the model group (ALT: 143.88 +/- 14.55 U/L vs 193.58 +/- 24.35 U/L; AST: 263.66 +/- 44.23 U/L vs 404.37 +/- 68.29 U/L; liver index: 0.033 +/- 0.005 vs 0.049 +/- 0.009, P < 0.01). Baicalin therapy also significantly attenuated the degree of hepatic fibrosis, collagen area and collagen area percentage in liver tissue (P < 0.01). Furthermore, the levels of serum TGFbeta1, TNF-alpha and IL-6 were strikingly reduced in the baicalin-treated group compared with the model group, while the production of IL-10 was up-regulated: (TGF-beta1: 260.21 +/- 31.01 pg/mL vs 375.49 +/- 57.47 pg/mL; TNF-alpha: 193.40 +/- 15.18 pg/mL vs 260.04 +/- 37.70 pg/mL; IL-6: 339.87 +/- 72.95 pg/mL vs 606.47 +/- 130.73 pg/mL; IL-10: 506.22 +/- 112.07 pg/mL vs 316.95 +/- 62.74 pg/mL, P < 0.01). CONCLUSION: Baicalin shows certain therapeutic effects on hepatic fibrosis, probably by immunoregulating the imbalance between profibrotic and antifibrotic cytokines.

Cell Biol Toxicol. 2009 Sep 27;
Mazzio EA, Smith B, Soliman KF

Tumor cells have a high tolerance for acidic and hypoxic microenvironments, also producing abundant lactic acid through accelerated glycolysis in the presence or absence of O(2). While the accumulation of lactate is thought to be a major contributor to the reduction of pH-circumscribing aggressive tumors, it is not known if other endogenous metabolic products contribute this acidity. Furthermore, anaerobic metabolism in cancer cells bears similarity to homo-fermentative lactic acid bacteria, however very little is known about an alternative pathway that may drive adenosine triphosphate (ATP) production independent of glycolysis. In this study, we quantify over 40 end-products (amines, acids, alcohols, aldehydes, or ketones) produced by malignant neuroblastoma under accelerated glycolysis (+glucose (GLU) supply 1-10 mM) +/- mitochondrial toxin; 1-methyl-4-phenylpyridinium (MPP(+)) to abate aerobic respiration to delineate differences between anaerobic vs. aerobic cell required metabolic pathways. The data show that an acceleration of anaerobic glycolysis prompts an expected reduction in extracellular pH (pH(ex)) from neutral to 6.7 +/- 0.006. Diverse metabolic acids associated with this drop in acidity were quantified by ionic exchange liquid chromatography (LC), showing concomitant rise in lactate (Ctrls 7.5 +/- 0.5 mM; +GLU 12.35 +/- 1.3 mM; +GLU + MPP 18.1 +/- 1.8 mM), acetate (Ctrl 0.84 +/- 0.13 mM: +GLU 1.3 +/- 0.15 mM; +GLU + MPP 2.7 +/- 0.4 mM), fumarate, and a-ketoglutarate (<10 microM) while a range of other metabolic organic acids remained undetected. Amino acids quantified by o-phthalaldehyde precolumn derivatization/electrochemical detection-LC show accumulation of L: -Alanine (1.6 +/- .052 mM), L: -glutamate (285 +/- 9.7 microM), L: -asparagine (202 +/- 2.1 microM), and L: -aspartate (84.2 +/- 4.9 microM) produced during routine metabolism, while other amino acids remain undetected. In contrast, the data show no evidence for accumulation of acetaldehyde, aldehydes, or ketones (Purpald/2,4-dinitrophenylhydrazine-Brady's reagent), acetoin (Voges-Proskauer test), or alcohols (NAD(+)-linked alcohol dehydrogenase). In conclusion, these results provide preliminary evidence to suggest the existence of an active pyruvate-Alanine transaminase or phosphotransacetylase/acetyl-CoA synthetase pathway to be involved with anaerobic energy metabolism of cancer cells.

Magn Reson Med. 2009 Nov; 62(5): 1091-8
Levin YS, Albers MJ, Butler TN, Spielman D, Peehl DM, Kurhanewicz J

Prostate cancer has been shown to undergo unique metabolic changes associated with neoplastic transformation, with associated changes in citrate, Alanine, and lactate concentrations. (13)C high resolution-magic angle spinning (HR-MAS) spectroscopy provides an opportunity to simultaneously investigate the metabolic pathways implicated in these changes by using (13)C-labeled substrates as metabolic probes. In this work, a method to reproducibly interrogate metabolism in prostate cancer cells in primary culture was developed using HR-MAS spectroscopy. Optimization of cell culture protocols, labeling parameters, harvesting, storage, and transfer was performed. Using [3-(13)C] pyruvate as a metabolic probe, (1)H and (13)C HR-MAS spectroscopy was used to quantify the net amount and fractional enrichment of several labeled metabolites that evolved in multiple cell samples from each of five different prostate cancers. Average enrichment across all cancers was 32.4 +/- 5.4% for [3-(13)C] Alanine, 24.5 +/- 5.4% for [4-(13)C] glutamate, 9.1 +/- 2.5% for [3-(13)C] glutamate, 25.2 +/- 5.7% for [3-(13)C] aspartate, and 4.2 +/- 1.0% for [3-(13)C] lactate. Cell samples from the same parent population demonstrated reproducible fractional enrichments of Alanine, glutamate, and aspartate to within 12%, 10%, and 10%, respectively. Furthermore, the cells produced a significant amount of [4-(13)C] glutamate, which supports the bioenergetic theory for prostate cancer. These methods will allow further characterization of metabolic properties of prostate cancer cells in the future. Magn Reson Med, 2009. (c) 2009 Wiley-Liss, Inc.

In Vivo. 2009 Sep-Oct; 23(5): 747-54
Peng HY, Chu YC, Chen SJ, Chou ST

The effects of 80% ethanolic chlorella extracts (GPE) on carbon tetrachloride (CCl(4))-induced hepatic damage were investigated in Sprague-Dawley rats. The rats were orally treated with GPE (0.5 g/kg body weight) or silymarin (0.2 g/kg body weight) over four consecutive weeks with administration of CCl(4) (20% CCl(4), 0.5 ml/rat twice a week). The GPE had a significant protective effect against liver injuries, as well as oxidative stress induced by CCl(4), resulting in reduced lipid peroxidation and improved serum biochemical parameters such as aspartate aminotransferase and Alanine aminotransferase. The reduced levels of glutathione, vitamin C, superoxide dismutase, and catalase in the CCl(4)-treated rats were significantly increased by treatment with GPE. Furthermore, the activity of GPE was comparable to the standard drug silymarin. In conclusion, chlorella may be useful as a hepatoprotective agent against chemical-induced liver damage in vivo.

J Neurosci. 2009 Sep 23; 29(38): 11965-72
Li B, Devidze N, Barengolts D, Prostak N, Sphicas E, Apicella AJ, Malinow R, Emamian ES

Phosphorylation of the NR1 subunit of NMDA receptors (NMDARs) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions, we generated mice in which the NR1 S897 is replaced with Alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long-term potentiation. Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders.

Indian J Exp Biol. 2009 Aug; 47(8): 668-71
Sharififar F, Pournourmohammadi S, Arabnejad M

Immunomodulatory activity of aqueous extract of Achillea wilhelmsii (25, 50 and 100 mg/kg body weight for 5 days) was evaluated on body weight, relative organ weight, delayed type of hypersensitivity (DTH) response and haemagglutination titre (HT) in female Swiss albino mice. No significant body weight gain differences were recorded in various groups of animals. Significant increase in relative organ weight of spleen at 100 mg/kg was observed. No elevation in the levels of liver function test (LFT) enzymes and kidney relative weight was observed in tested doses of the plant. The extract of A. wilhelmsii elicited a significant increase in the DTH response at the dose of 100 mg/kg. In the HT test, plant extract showed stimulatory effect in all doses, however this changes were significant at 50 mg/kg. No mortality was occurred in tested doses. Overall, A. wilhelmsii showed a stimulatory effect on both humoral and cellular immune functions in mice.

Indian J Exp Biol. 2009 Aug; 47(8): 660-7
Hegde K, Joshi AB

Oral pre-treatment with ethanolic extract of the roots of C. carandas (ERCC; 100, 200 and 400 mg/kg, po) showed significant hepatoprotective activity against CCl4 and paracetamol induced hepatotoxicity by decreasing the activities of serum marker enzymes, bilirubin and lipid peroxidation, and significant increase in the levels of uric acid, glutathione, super oxide dismutase, catalase and protein in a dose dependent manner, which was confirmed by the decrease in the total weight of the liver and histopathological examination. Data also showed that ERCC possessed strong antioxidant activity, which may probably lead to the promising hepatoprotective activities of C. carandas root extract. These findings therefore supported the traditional belief on hepatoprotective effect of the roots of C. carandas.

Toxicol Sci. 2009 Dec; 112(2): 507-20
Anderson N, Meier T, Borlak J

Butterbur extracts (Petasites hybridus) are recommended for the prevention of migraine, but pharmacovigilance reports may be suggestive of rare hepatobiliary toxicity. To evaluate its hepatotoxic potential, a series of in vivo and in vitro studies were carried out. Essentially, there were no signs of hepatocellular toxicity at estimated therapeutic C(max) levels of 60 ng/ml. Nonetheless, in a 28-day toxicity study at approximately 200-fold of therapeutic doses, induced liver transaminases and bilirubin elevations were observed. In a subsequent 6-month chronic toxicity study, the initial hepatobiliary effects were reproduced, but at the end of the study, liver function recovered and returned to normal as evidenced by clinical chemistry measurements. To identify possible mechanisms of hepatotoxicity, we investigated liver function in vitro at > 170-fold of therapeutic C(max) levels, including cytotoxicity (lactate dehydrogenase, MTT, and ATP), transaminase activities (Alanine aminotransferase and aspartate aminotransferase), albumin synthesis, urea and testosterone metabolism to assay for cytochrome P450 monooxygenase activity. Only with extracts rich in petasin (37% petasin) and at high and well above therapeutic doses, liver toxicity was observed. A toxicogenomic approach applied to hepatocyte cultures enabled hypothesis generation and was highly suggestive for extracts high in petasin content to impair bile acid transport and lipid and protein metabolism. Importantly, neither chronic rat in vivo nor rat in vitro studies predicted reliably hepatotoxicity, therefore reemphasizing the utility of human-based in vitro investigations for the development of safe medicinal products. Finally, toxicogenomics enabled the characterization of a novel butterbur extract with no signals for hepatotoxicity.