Enhancement of the Protective Activity of Vanillic Acid against Tetrachloro-Carbon (CCl4) Hepatotoxicity in Male Rats by the Synthesis of Silver Nanoparticles (AgNPs)

In the current study, the hepatoprotective activity of vanillic acid, silymarin, and vanillic acid-loaded silver nanoparticles (AgNPs) against CCl₄-induced hepatotoxicity was tested in male rats for four weeks. Thirty male rats were divided into five groups (n = 6). The 1st group was a negative control, the 2nd group was a positive control, the 3rd group was treated with 100 mg/kg b.w. of vanillic acid, the 4th group was treated with 100 mg/kg b.w. of vanillic acid–AgNPs, and the 5th group was treated with 50 mg/kg b.w. of silymarin. The CCl₄-induced hepatic toxicity in the 2nd group was revealed by the liver function and all other biochemical tests. Liver enzymes, bilirubin, lipid peroxidation, lactate dehydrogenase, and interleukin-6 were elevated, whereas, total protein, antioxidant enzymes, and irisin were decreased compared to the negative control. The hepatic tissues were also injured as a result of the CCl₄-induced hepatotoxicity. Treating the hepatotoxic rats with vanillic acid moderately protected the rats of the 3rd group, whereas treatment with vanillic AgNPs and silymarin in G4 and G5, respectively, greatly protected the rats against the CCl₄ hepatotoxicity, approaching the normal biochemical levels and liver tissue appearance. The biochemical tests were confirmed by the histological investigations of liver tissue.     

Synthesis,Molecular Docking,and Preclinical Evaluation of a New Succinimide Derivative for Cardioprotective,Hepatoprotective and Lipid-Lowering Effects

Cardiac and hepatotoxicities are major concerns in the development of new drugs. Better alternatives to other treatments are being sought to protect these vital organs from the toxicities of these pharmaceuticals. In this regard, a preclinical study is designed to investigate the histopathological effects of a new succinimide derivative (Comp-1) on myocardial and liver tissues, and the biochemical effects on selected cardiac biomarkers, hepatic enzymes, and lipid profiles. For this, an initially lethal/toxic dose was determined, followed by a grouping of selected albino rats into five groups (each group had n = 6). The control group received daily oral saline for 8 days. The 5-FU (5-Fluorouracil) group received oral saline daily for 8 days, added with the administration of a single dose of 5-FU (150 mg/kg I.P.) on day 5 of the study. The atenolol group received oral atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5 of the protocol. Similarly, two groups of rats treated with test compound (Comp-1) were administered with 5 mg/kg I.P. and 10 mg/kg I.P. for 8 days, followed by 5-FU (150 mg/kg I.P.) on day 5. Toxicity induced by 5-FU was manifested by increases in the serum creatinine kinase myocardial band (CK-MB), troponin I (cTnI) and lactate dehydrogenase (LDH), lipid profile, and selected liver enzymes, including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total), and BD (direct bilirubin). These biomarkers were highly significantly decreased after the administration of the mentioned doses of the test compound (5 mg/kg and 10 mg/kg). Similarly, histological examination revealed cardiac and hepatic tissue toxicity by 5-FU. However, those toxic effects were also significantly recovered/improved after the administration of Comp-1 at the said doses. This derivative showed dose-dependent effects and was most effective at a dose of 10 mg/kg body weight. Binding energy data computed via docking simulations revealed that our compound interacts toward the human beta2-adrenergic G protein-coupled receptor (S = −7.89 kcal/mol) with a slight stronger affinity than the calcium channel T-type (S = −7.07 kcal/mol). In conclusion, the histological and biochemical results showed that the test compound (Comp-1) had prominent cardioprotective, hepatoprotective, and lipolytic effects against 5-FU-induced toxicity in the subjected animal model.     

Design,synthesis and preclinical evaluations of (s)-2-((s)-1-benzyl-2,5-dioxopyrrolidin-3-yl)-3-(4-isopropylphenyl)-2-methylpropanal (succ-5) as cardioprotective,hepatoprotective and lipid lowering molecule. in-vivo and in-silico approaches

In this study, the newly synthesized compound (Succ-5) was analyzed through spectral methods, seen for potential receptor targets via molecular docking, and pre-clinically evaluated for therapeutic effects and safety profile using biochemical and histopathological techniques. The biochemical analysis included assessment of cardiac biomarkers, hepatic enzymes, and lipid profiles, while histopathology included evaluation of cardiac and liver tissues. The toxic dose was determined pre-clinically, followed by dividing albino rats into five treatment groups (each having n = 6). The control group received oral saline for eight days. The 5-FU (5-Fluorouracil) group received oral saline for 8 days and 5-FU (150 mg/kg I.P.) on day 5. The atenolol group was administered with atenolol (20 mg/kg) for 8 days and 5-FU (150 mg/kg I.P.) on day 5. Two groups of rats were administered with the test compound (Succ-5) at doses of 5 mg/kg I.P and 10 mg/kg I.P (for 8-days), followed by 5-FU (150 mg/kg I.P.) on day 5. Elevated serum levels of CK-MB (creatinine kinase myocardial band), cTnI (troponin I), LDH (lactate dehydrogenase), lipid profile, and selected liver enzymes including ALP (alkaline phosphatase), ALT (alanine transaminase), AST (aspartate aminotransferase), BT (bilirubin total) and BD (direct bilirubin) were associated with 5-FU toxicity. After administration of the test compound at the mentioned doses, these biomarkers significantly decreased. Likewise, histological examination revealed 5-FU damaged the heart and hepatic tissues, which were also considerably recovered following administration of the test compound. Immunohistochemistry of heart tissue also revealed the low expression of COX-2 and TNF-α in Succ-5 treated groups compared to toxic group. Dose-response evaluation showed that a dose of 10 mg/kg provided better results than 5 mg/kg. The analysis of binding energy values computed via docking simulations showed that Succ-5 interacts with the human beta2-adrenergic G protein-coupled receptor with a slightly stronger affinity than calcium channel T-type. In conclusion, the histological and biochemical findings revealed that the test compound had significant cardioprotective, hepatoprotective, and lipolytic effects in the 5-FU-induced toxicity.     

Enhancement of bioavailability and hepatoprotection by silibinin through conversion to nanoparticles prepared by liquid antisolvent method

The current research was intended to establish the impact of Silibinin nanoparticles (SB-APSP) produced by the antisolvent precipitation with a syringe pump (APSP). The in-vivo bioavailability and hepatoprotective activity of SB-APSP were evaluated in experimental animals. To determine the pharmacokinetic parameters, silibinin and its nanoparticles were given orally to rabbits at a dose of 50 mg/Kg body weight. Blood samples were drawn at different time intervals and were analyzed using HPLC. The bioavailability of un processed silibinin was lower as compared to silibinin nanoparticles (3.45 ± 0.07 and 23.76 ± 0.07 µg/mL respectively). The AUC and C_max of SB-APSP were found to be 15.56 and 6.88 folds greater for nanoparticles when compared to silibinin. Hepatoprotective study in Male Sprague Dawley rats revealed that SB-APSP provide better recovery of the damaged liver cell induced by CCl₄. Histopathology of the liver revealed that SB-APSP provide better protection to the liver cells from the damage induced by CCl₄ and maintained the hepatic lobule histopathology more efficiently. It was concluded that the SB-APSP can more effectively protect the liver in experimental animals in a far better way compared to the un-processed Silibinin and could be used as an efficient hepatoprotective agent.     

Chemical characterisation and hepatoprotective potential of Cosmos sulphureus Cav. and Cosmos bipinnatus Cav.

This study was conducted to validate the hepatoprotective activity of Cosmos sulphureus and Cosmos bipinnatus. Aqua-methanolic extracts of both plants were evaluated for the presence of various phyto-constituents through HPLC. Different doses of both plant extracts were administered to rats for nine days. Standard control was silymarin 100 mg/kg. Paracetamol 1 gm/kg was administered 3 h post treatment on 9th day for induction of hepatotoxicity. Blood was collected for the evaluation of liver biochemical markers and livers were removed for histopathological evaluation 24 h post-paracetamol treatment. HPLC analysis revealed the presence of quercetin, gallic acid, caffeic acid and chlorogenic acid in both plant extracts. The extracts of both plants decreased the level of alanine aminotransaminase and total bilirubin significantly (p < 0.05), dose dependently and protected hepatocytes from paracetamol-induced hepatotoxicity. It can be concluded that both plants may possess hepatoprotective activity possibly due to the presence of quercetin and phenolic compounds.     

Toxicology Assessment of a Dual-Function Peptide 5rolGLP-HV in Mice

5rolGLP-HV had an ideal therapeutic potential in the prevention of hyperglycemia in type 2 diabetes and delay of the thrombosis. The objective of the study was to investigate the toxicology effects of 5rolGLP-HV and guarantee its safety. In acute toxicity test, the mice were orally receiving 5rolGLP-HV at a single dose of 300 mg/kg or 2000 mg/kg. For sub-chronic toxicity study, the mice received 5rolGLP-HV at doses of 800 mg/kg or 1600 mg/kg for 9 weeks. No significant adverse effects were evident in acute and sub-chronic toxicity tests, indicating that the LD50 value is greater than 2000 mg/kg. Although the liver and kidney exhibited a little abnormal in sub-chronic toxicity study, they could recovery to normal after withdrawal 5rolGLP-HV for 2 weeks. In micronucleus assay, the mice received 5rolGLP-HV at doses of 250, 500, or 1000 mg/kg for two consecutive days. The micronucleus numbers and the polychromatic erythrocytes to normochromatic erythrocytes (PCE/NCE) ratios among 5rolGLP-HV groups were within the normal range. Similarly, sperm aberration test demonstrated that 5rolGLP-HV had no teratogenic effect on the mice sperm. In conclusion, the combined results clearly demonstrated the safety of 5rolGLP-HV and support its use as a drug to treat diabetes and thrombosis.     

Intraperitoneal photodynamic therapy in the Fischer 344 rat using 5-aminolevulinic acid and violet laser light: a toxicity study

OBJECTIVE: Our study was designed to investigate 5-aminolevulinic acid (ALA) as a candidate for intraperitoneal photodynamic therapy (IP-PDT). The toxicity of IP-PDT and the effects of IP-PDT on abdominal and pelvic organs, particularly the small intestine, were investigated after ALA administration and illumination with violet laser light. STUDY DESIGN AND RESULTS: The toxicity of IP-PDT was evaluated in Fischer 344 rats in two ways. In the first part of the study local PDT effects on the intestine were analyzed histologically. Violet laser light (lambda: 406-415 nm) was applied as a 2 cm diameter spot on the intestine 3 h after intraperitoneal (i.p.) administration of 50 mg/kg ALA. (A) Histological tissue samples were taken 0 min, 6 h and 1, 2 and 3 days after treatment (optical dose 3.2 J/cm(2)). Immediately after local PDT (3.2 J/cm(2), 50 mg/kg ALA) showed no effect on the intestine. However, 6 h post PDT there was complete destruction of the mesothelial lining and the outer (longitudinal) smooth muscle. Ganglion cells of the myenteric (Auerbach) plexus were also destroyed. The inner circular smooth muscle, the muscularis mucosa and the lamina propria were unharmed. Marked lymphectasia was present at this time. (B) To determine the threshold light dose of tissue destruction caused by PDT, different optical doses (1.6, 3.2, 6.4 J/cm(2)) were administered and histologic analysis of tissue samples were obtained 1 day post treatment. Destruction of the entire external musculature, submucosal structures and muscularis mucosa of the intestine at the illumination site could be observed above 1.6 J/cm(2) (50 mg/kg ALA). In the second part of the study whole peritoneal cavity PDT (WPC-PDT) was performed by illumination of the whole peritoneal cavity with 1.6 J/cm(2) violet light 3 h after ALA administration using different drug doses (200, 100 and 50 mg/kg). WPC-PDT showed lethal toxicity with a drug dose above 50 mg/kg ALA at 1.6 J/cm(2). The probable cause of death in the first 3 days after IP-PDT was rhabdomyolysis, whereas when death occurred at longer time intervals, megaintestine associated with significant damage could be observed; however, without perforation of the intestinal wall. CONCLUSION: In rats WPC-PDT with 50 mg/kg ALA, 1.6 J/cm2 at lambda=415 nm was the maximum tolerable light dose. This dose is likely to be above the threshold of destruction of ovarian cancer micrometastasis.     

PEG-m-THPC-mediated photodynamic effects on normal rat tissues

Photodynamic therapy (PDT) of malignancies uses light to activate a photosensitizer preferentially accumulated in cancer cells. The first pegylated photosensitizer, tetrakis-(m-methoxypolyethylene glycol) derivative of 7,8-dihydro-5,10,15,20-tetrakis(3-hydroxyphenyl)-21-23-[H]-porphyrin (PEG-m-THPC), was evaluated in non-tumor-bearing rats. The aim of this study was to assess the photodynamic threshold for damage and its sequelae in normal rat tissue. Thirty-five Fischer rats were sensitized with 3, 9 or 30 mg/kg body weight PEG-m-THPC. Colon, vagina and perineum were irradiated with laser light of 652 nm wavelength and an optical dose of 50, 150 or 450 J/cm fiber length. Temperature in the pelvis was measured during PDT. Three days following PDT the effect on skin, vagina, colon, striated muscle, connective tissue, nerves and blood vessels was assessed by histology. The healing of the above-mentioned tissues was assessed on two rats 3 and 8 weeks after PDT using 9 mg/kg PEG-m-THPC activated with 450 J/cm laser light. No dark toxicity was observed. PDT using 30 mg/kg PEG-m-THPC induced severe necrosis irrespective of the optical dose. Body weight of 9 or 3 mg/kg activated with less than 450 J/cm induced moderate or no damage. No substantial increase in body temperature was seen during PDT. Tissues with severe PDT-induced damage seem to have a good tendency to regenerate. We conclude that within the dose required for tumor treatment PEG-m-THPC is a safe photosensitizer with promising properties. PDT of the colon mucosa below 9 mg/kg PEG-m-THPC and 150 J/cm seems to be safe. All other tissues can be exposed to 9 mg/kg PEG-m-THPC activated with less than 450 J/cm laser light with little side effects.     

Hypoglycemic and hypolipidemic effects of polyphenols from burs of Castanea mollissima Blume

Substantial evidence suggests that phenolic extracts of Castanea mollissima spiny burs (CMPE) increase pancreatic cell viability after STZ (streptozotocin) treatment as a result of their antioxidant properties. In the present study, the hypoglycemic and hypolipidemic activities of CMPE were studied in normal and STZ-induced diabetic rats CMPE were orally administrated at doses of 150 and 300 mg/kg twice a day for 12 consecutive days. Serum glucose, triglyceride, total cholesterol, HDL- and LDL-cholesterol levels, malondialdehyde (MDA) level and SOD activity in liver, kidney, spleen and heart tissues were measured spectrophotometrically. In normal rats, no significant changes were observed in serum glucose, lipid profiles and tissue MDA and GSH levels after orally administration of CMPE. In diabetic rats, oral administration of CMPE at a dose of 300 mg/kg caused significant decreases in serum glucose, triglyceride, total cholesterol, LDL-cholesterol levels, as well as MDA and GSH levels in spleen and liver tissues. However, the 300 mg/kg dosage caused a significant body weight loss in both normal and diabetic rats. The observed effects indicated that CMPE could be further developed as a drug to prevent abnormal changes in blood glucose and lipid profile and to attenuate lipid peroxidation in liver and spleen tissues.     

Antioxidant Extract from Cleistocalyx nervosum var. paniala Pulp Ameliorates Acetaminophen-Induced Acute Hepatotoxicity in Rats

The indigenous purplish red fruit, Cleistocalyx nervosum var. paniala (CN), is grown in northern Thailand. The aqueous extract of CN pulp is known to exhibit antioxidant and anticarcinogenic properties. To search for an antioxidant fraction separated from CN, various hydroalcoholic extractions were performed. The acidified ethanolic extract of CN obtained from 0.5% (v/v) citric acid in 80% (v/v) ethanol yielded greater polyphenol content and DPPH radical scavenging activity when compared with other hydroethanolic extracts. Cyanidin-3-glucoside is a major anthocyanin present in the acidified ethanolic extract of CN (AECN). At a dose of 5000 mg/kg bw, an anthocyanin-rich extract was found to be safe when given to rats without any acute toxicity. To examine the hepatoprotective properties of AECN, an overdose of acetaminophen (APAP) was induced in a rat model, while silymarin was used as a standard reference. The administration of AECN at a dose of 300 mg/kg bw for 28 days improved hepatocyte architecture and modulated serum alanine aminotransferase levels in APAP-induced rats. Furthermore, it significantly decreased serum and hepatic malondialdehyde levels but increased hepatic glutathione content, as well as glutathione peroxidase and UDP-glucuronosyltransferase activities. In conclusion, AECN may effectively reduce oxidative stress induced acute hepatotoxicity in overdose APAP-treated rats through the suppression of oxidative stress and the enhancement of the antioxidant system in rat livers.     

Tissue-protective effects of fullerenol C60(OH)24 and amifostine in irradiated rats

Polyhydroxylated fullerenes, named fullerenols (C(60)(OH)(n); n=12-26) are excellent antioxidants. Harmful effects of ionizing radiation on living organism are mainly mediated by free radical species and fullerenols attract an attention as a potential radioprotectors. Our preliminary investigations on mice and rats subjected to radiation injury show that fullerenol C(60)(OH)(24) provides high survival rate of irradiated small rodents. Radioprotective effect was comparable to that of the standard radioprotector amifostine. The aim of this study was to compare the efficacy of fullerenol C(60)(OH)(24) (10 and 100mg/kg i.p.) and amifostine (300 mg/kg i.p.) in protection of rats against harmful effects of ionizing radiation. The animals were whole-body irradiated by X-rays (8 MV). Both compounds were given 30 min before irradiation. In order to evaluate the general radioprotective efficacy of fullerenol and amifostine rats were irradiated with an absolutely lethal dose of X-rays (8 Gy) and their survival and body mass gain were monitored during the period of 30 days after irradiation. The aim of the second part of the study is to investigate the tissue-protective effects of tested compounds (100 mg/kg i.p. of fullerenol and 300 mg/kg i.p. of amifostine, 30 min before irradiation). It was carried out on rats irradiated with a sublethal dose of X-rays (7 Gy). Influence of ionizing radiation on hematopoesis as well as the radioprotective efficiency of the compounds given were evaluated by determining blood cell count during 28 days after irradiation. For this purpose the blood was taken from tail vein before irradiation and on the 3rd, 7th, 14th, 21st and 28th day after irradiation. In order to estimate the radioprotective effects of fullerenol and amifostine on other rat tissue, the animals were sacrificed on the 7th and 28th day after irradiation and their main organs (lung, heart, liver, kidney, small intestine and spleen) were taken for histopathological analysis. In the experiment in which the general radioprotective efficacy of fullerenol and amifostine was examined, fullerenol given in a dose of 100mg/kg produced better protection than given in a dose of 10mg/kg. This effect was comparable to that of amifostine. The results of hematological investigations showed that fullerenol better than amifostine prevented radiation-induced reduction in the white cell count (granulocytes and lymphocytes), particularly in the first 7 days after irradiation. Pathohistology examinations revealed better radioprotective effects of fullerenol compared to those of amifostine on the spleen, small intestine and lung, while amifostine had better radioprotective effects than fullerenol in protection of the heart, liver and kidney. These results confirm satisfactory radioprotective efficacy of fullerenol and encourage further investigations as a potential radioprotector.     

Musa sp. Leaves Extract Ameliorates the Hepato-Renal Toxicities Induced by Cadmium in Mice

Heavy metals intoxication causes several health problems that necessitate finding new protective and therapeutic approaches. This study aimed to evaluate the impact of Musa sp. leaves extract (MLE) on hepato-renal toxicities induced by cadmium (Cd) in male mice. The phytochemical screening, metal chelating activity (MCA), and the median lethal dose (LD₅₀) of MLE were determined. Fifty CD-1 male mice were used and intraperitoneally (i.p.) injected with MLE (1000 to 5000 mg/kg b.wt) for MLE LD₅₀ determination. Another 50 mice were used for evaluating the effect of MLE on Cd toxicity. Blood samples were collected for hematological, liver, and kidney functions assessments. Liver tissue homogenates were used for determination of oxidant/antioxidant parameters. Liver and kidney tissues were harvested for histopathological and molecular investigations. MLE showed potent in vitro antioxidant activities. The MCA and LD₅₀ of the MLE were 75 µg/mL and 3000 mg/kg b.wt, respectively. MLE showed beneficial therapeutic activity against hepato-renal toxicities in Cd-intoxicated mice, evidenced by improving the hematological, biochemical, histopathological, and molecular alterations.     

Acute and sub-acute toxicity study of hydroalcoholic fruit extract of Pithecellobium dulce

This study was carried out to evaluate the acute and sub-acute toxicity profile of the hydroalcoholic fruit extract (HAEPD) of Pithecellobium dulce (Leguminosae). Albino rats were treated orally with 100, 200 and 500?mg?kg(-1) bodyweight (BW) of HAEPD for 90 days to assess its sub-acute toxicity. HAEPD at single doses of 100, 500, 1000, 2000 and 4000?mg?kg(-1) BW was also administered to rats to assess its acute toxicity. The rats were observed for physical discomfort, BW change and feeding habits. Pithecellobium dulce did not cause any abnormal changes in haematological or biochemical parameters. Pathologically, no gross abnormality in the tissue architecture was observed. The LD(50) was found to be 3916?mg?kg(-1) BW and potential effective doses for efficacy studies are 100 and 300?mg?kg(-1) BW as the minimum and maximum doses, respectively. It is concluded that HAEPD can be used safely for experimental and clinical trials.     

Bio-safety assessment of carbon quantum dots,N-doped and folic acid modified carbon quantum dots: A systemic comparison

The carbon quantum dots(CQDs) and their functionalized materials are promising in biomedical field because of their unique properties;meanwhile,a growing concern has been raised about the potential toxicity of these modified materials in biosystem.In this study,we synthesized original CQDs and two common functionalized CQDs including N-doped CQDs(NCQDs) and folic acid-modified CQDs(FACQDs),and compared the toxicity and biocompatibility with each other in vitro and in vivo.L929,C6 and normal cell MDCK were selected to detect the adverse reaction of these materials in vitro.No acute toxicity or obvious changes were noted from in vitro cytotoxicity studies with the dose of these CQD materials increasing to a high concentration at 1 mg/mL.Among these materials,the FA-CQDs show a much lower toxicity.Moreover,in vivo toxicity studies were performed on the nude mice for 15 days.The experimental animals in 10 or 15 mg/kg groups were similar with animals treated by phosphate buffer solution(PBS) after 15 days.The results of the multifa rious biochemical parameters also suggest that the functionalized products of CQDs do not influence the biological indicators at feasible concentration.Our findings in vitro and in vivo through toxicity tests demonstrate that CQDs and their modified materials are safe for future biological applications.     

Inhibitory effect of silibinin on tumour necrosis factor-alpha and hydrogen peroxide production by human monocytes

Silibinin is a chemically defined flavonoid and the main active component of silymarin, a polyphenolic complex from Silybum marianum, which has anti-inflammatory, hepatoprotective and anticarcinogenic properties. Monocytes obtained from healthy individuals were incubated with silibinin to evaluate cell viability, hydrogen peroxide (H(2)O(2)) release and tumour necrosis factor-alpha (TNF-α) production by these cells. The duration of treatment and different silibinin concentrations had no significant effect on cell viability. Monocytes showed a dose-dependent inhibitory effect on H(2)O(2) release by phorbol myristate acetate-stimulated monocytes in silibinin concentrations ranging from 6.25 to 50 μg mL(-1). Significant inhibition of TNF-α production by lipopolysaccharide-stimulated monocytes was observed at concentrations of 12.5, 50 and 100 μg mL(-1) of silibinin. These results suggest that silibinin exerts antioxidant and anti-inflammatory properties on human monocytes through an inhibitory effect on H(2)O(2) release and on TNF-α production, respectively.     

Effects of Centella asiatica extract on antioxidant status and liver metabolome of rotenone‐treated rats using GC–MS

Centella asiatica has been used as a culinary vegetable or medicinal herb. In this study, the hepatoprotective effect of the standardized extract of C. asiatica (ECa233) in rotenone‐treated rats was examined using a GC–MS‐based metabolomic approach. ECa233 contains >80% triterpenoids with a ratio of madecassoside to asiaticoside of 1.5(±0.5):1. Rats were randomly divided into three groups (with six rats/group): sham negative control, rotenone positive control and the ECa233 test group. Rats in the ECa233 group received 10 mg/kg ECa233 orally for 20 days, followed by 2.5 mg/kg intraperitoneal rotenone injection to induce toxicity before being sacrificed. Metabolomic analysis showed that supplementation of ECa233 protected rat liver against rotenone toxicity. Pipecolinic acid was one of the most important metabolites; its level was decreased in the rotenone group as compared with the control. Supplementation with ECa233 before administration of rotenone raised pipecolinic acid to levels intermediate between controls and rotenone alone. The metabolomics approach also helped discover a possible new genuine epimetabolite in the present work. Antioxidant tests revealed that ECa233 inhibited lipid peroxidation and increased catalase activities in liver tissue.     

THE EFFECT OF PORPHYRIN PHOTOSENSITIZERS ON THE TOXICITY OF l,3-BIS(2-CHLOROETHYL)-1- NITROSOUREA IN C57BL/6J MICE

Abstract The most widely used agents for photodynamic therapy are the porphyrin photosensitizers. It has been shown that hematoporphyrin derivative (HpD) can cause murine marrow hypercellularity and splenic hypertrophy. We have examined the effect on survival and marrow cellularity of high dose l,3-bis(2-chloroethyl)-l-nitrosourea (BCNU) after HpD or dihematoporphyrin ether (DHE) pretreatment in C57BL/6J mice.
The lethal toxicity of the LD_S0+ 10% dose of BCNU (60 mg kg⁻¹) was significantly reduced by pretreatment with HpD when the HpD was administered at least 3 days prior to the BCNU. HpD administered 1 or 2 days prior to BCNU or after BCNU had no effect. The percent death rate was reduced from 80 to 0% when HpD was administered 7 and 5 days prior to BCNU.
No alteration of the lethal toxicity rate of BCNU at doses of 80 mg kg⁻¹ were identified with DHE pretreatment although some increase in median survival was noted in two groups. Some reduction in lethal toxicity was noted when 60 mg kg⁻¹ BCNU was used and the pretreatment dose of DHE was 10 or 25 mg kg⁻¹ given twice 3 days apart. Furthermore, a significant reduction of BCNU induced marrow cell depletion was found when low doses of DHE were used as pretreatment. High doses of DHE resulted in marrow depletion. Both HpD and DHE altered the toxicity of BCNU.
Should porphyrin photosensitizers, which alone have little toxicity, prove to protect against nitrosourea toxicity then an important dose limiting factor (myelotoxicity) could be altered if not reduction in the tumouricidal activity occurs.     

Evaluation of hepatoprotective activity of aqueous extracts of leaves of Basella alba in albino rats

This study was done to evaluate possible hepatoprotective effects of aqueous leaf extracts of Basella alba in comparison with silymarin in paracetamol-induced hepatotoxicity in albino rats. Six groups of six albino rats each received orally for 6 weeks, vehicle, paracetamol (2 g/kg/day), paracetamol (2 g/kg/day) plus silymarin (50 mg/kg/day), paracetamol (2 g/kg/day) plus B. alba extract (60 mg/kg/day), paracetamol (2 g/kg/day) plus B. alba extract (80 mg/kg/day) and paracetamol (2 g/kg/day) plus B. alba extract (100 mg/kg/day). Hepatoprotective effect was evaluated by comparing serum bilirubin, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, proteins, alkaline phosphatase and liver histopathology. Results were represented as mean ± SEM. One-way ANOVA was done followed by post hoc Tukey's test with a highly significance level of P < 0.001. Aqueous leaf extracts of B. alba 100 mg/kg/day orally had significant hepatoprotective effect in paracetamol-induced hepatotoxicity in albino rats. The results were well comparable and even in some respects superior to standard drug silymarin.     

Proteomics to display lovastatin-induced protein and pathway regulation in rat liver

Lovastatin is a lipid lowering agent that acts by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, a key regulatory enzyme in cholesterol biosynthesis. In this study the pattern of gene network regulation induced in hepatic proteins as a response to lovastatin treatment was analyzed by proteomics. In livers of male F344 rats treated with 1.6 mg/kg/day lovastatin or 150 mg/kg/day lovastatin for seven days, 36 proteins were found to be significantly altered (p<0.001) in relation to treatment. The changed proteins were classified according to their cellular function and participation in biochemical pathways. The following observations were made: (i) inhibition of HMG-CoA reductase provoked a regulatory response in the cholesterol synthesis pathway including the induction of cytosolic HMG-CoA synthase and of isopentenyl-diphosphate delta-isomerase, (ii) manipulation of the lipid metabolism triggered alterations in key enzymes of the carbohydrate metabolism, and (iii) lovastatin treatment was associated with signs of toxicity as reflected by changes in a heterogeneous set of cellular stress proteins involved in functions such as cytoskeletal structure, calcium homeostasis, protease inhibition, cell signaling or apoptosis. These results present new insights into liver gene network regulations induced by lovastatin and illustrate a yet unexplored application of proteomics to discover new targets by analysis of existing drugs and the pathways that they regulate.     

核磁共振技术及模式识别对硝酸镥急性毒性的研究

通过分析Wistar大鼠灌胃0.2,2,10和100mg/kg体重硝酸镥[Lu(NO₃)3]48h内尿液的¹HNMR谱,研究了重稀土化合物Lu(NO₃)3在大鼠体内的急性生物效应.以氯化汞、铬酸钠、四氯化碳、盐酸肼和异硫氰酸-α-萘酯为模型药物,利用模式识别技术解析大鼠尿液的¹HNMR谱,对不同剂量Lu(NO₃)3的生物效应进行了分类.结果表明,应用核磁共振和模式识别相结合的方法,可清楚地认识稀土化合物生物效应,低剂量Lu(NO₃)3(0.2,2mg/kg体重)的毒性与肾毒化合物铬酸钠类似,而高剂量Lu(NO₃)3(10,100mg/kg体重)归入肝毒化合物四氯化碳组.该方法也可用于其它金属化合物及中药等药物的毒理学研究.