PRIMA-1 synergizes olaparib-induced cell death in p53 mutant triple negative human breast cancer cell line via restoring p53 function, arresting cell cycle, and inducing apoptosis.

This study concerned with assessing the effect of restoring p53 using PRIMA-1 on the anti-cancer activity of olaparib against TP53-mutant triple negative breast cancer (TNBC) cells and exploring the optimum synergistic concentrations and the underlying mechanism. Human BC cell lines, MDA-MB-231 with mutated TP53 gene, and MCF-7 with wild-type TP53 gene were treated with olaparib and/or PRIMA-1. The IC50 value for olaparib was significantly decreased by PRIMA-1 in MDA-MB-231 cells compared to MCF-7 cells. Contrary to MCF-7 cells, co-treatment with olaparib and PRIMA-1 had a synergistic anti-proliferative effect in MDA-MB-231 at all tested concentrations with the best synergistic combination at 45 and 8.5 µM, respectively, and furthermore PRIMA-1 enhanced olaparib-induced apoptosis. This synergistic apoptotic effect was associated with a significant boost in mRNA expression of TP53 gene, cell cycle arrest at G2/M phase, modulation of BRCA-1, BAX and Bcl2 proteins expressions, and induction of active caspase-3. These results present a clue for the utility of combined olaparib and PRIMA-1 in treatment of TP53-mutant TNBC invitro. PRIMA-1 triggers olaparib-induced MDA-MB-231 cell death in a synergistic manner via restoring TP53, decreasing BRCA-1 expression, cell cycle arrest, and enhancement of apoptosis via p53/BAX/Bcl2/caspase 3 pathway.

Estrogen Attenuates Diethylnitrosamine-Induced Hepatocellular Carcinoma in Female Rats via Modulation of Estrogen Receptor/FASN/CD36/IL-6 Axis.

This study was designed to evaluate the potential protective impact of estrogen and estrogen receptor against diethylnitrosamine (DEN)-induced hepatocellular carcinoma (HCC) in rats. The levels of liver injury serum biomarkers, liver content of interleukin-6 (IL-6), relative liver weight and distortion of liver histological pictures were significantly increased in ovariectomized (OVX) rats and SHAM rats that received DEN alone and were further exaggerated when DEN was combined with fulvestrant (F) compared to non-DEN treated rats. The OVX rats showed higher insults than SHAM rats. The tapering impact on these parameters was clear in OVX rats that received estradiol benzoate (EB), silymarin (S) or orlistat (ORS). The immunohistochemistry and/or Western blot analysis of liver tissues showed a prominent increase in fatty acid synthase (FASN) and cluster of differentiation 36 (CD36) expressions in OVX and SHAM rats who received DEN and/ or F compared to SHAM rats. In contrast to S, treatment of OVX rats with EB mitigated DEN-induced expression of FASN and CD36 in liver tissue, while ORS improved DEN-induced expression of FASN. In conclusion, the protective effect against HCC was mediated via estrogen receptor alpha (ER-α) which abrogates its downstream genes involved in lipid metabolism namely FASN and CD36 depriving the tumor from survival vital energy source. In addition, ORS induced similar mitigating effect against DEN-induced HCC which could be attributed to FASN inhibition and anti-inflammatory effect. Furthermore, S alleviated DEN-induced HCC, independent of its estrogenic effect.

In vivo- and in silico-driven identification of novel synthetic quinoxalines as anticonvulsants and AMPA inhibitors.

The lack of effective therapies for epileptic patients and the potentially harmful consequences of untreated seizure incidents have made epileptic disorders in humans a major health concern. Therefore, new and more potent anticonvulsant drugs are continually sought after, to combat epilepsy. On the basis of the pharmacophoric structural specifications of effective α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) antagonists with an efficient anticonvulsant activity, the present work reports the design and synthesis of two novel sets of quinoxaline derivatives. The anticonvulsant activity of the synthesized compounds was evaluated in vivo according to the pentylenetetrazol-induced seizure protocol, and the results were compared with those of perampanel as a reference drug. Among the synthesized compounds, 24, 28, 32, and 33 showed promising activities with ED50 values of 37.50, 23.02, 29.16, and 23.86 mg/kg, respectively. Docking studies of these compounds suggested that AMPA binding could be the mechanism of action of these derivatives. Overall, the pharmacophore-based structural optimization, in vivo and in silico docking, and druglikeness studies indicated that the designed compounds could serve as promising candidates for the development of effective anticonvulsant agents with good pharmacokinetic profiles.

Modulatory effects of perindopril on cisplatin-induced nephrotoxicity in mice: Implication of inflammatory cytokines and caspase-3 mediated apoptosis.

Cisplatin-induced nephrotoxicity limits its anticancer effectiveness, thus this study's aim was to assess the potential modulatory effect of perindopril on cisplatin-induced nephrotoxicity and to elucidate the possible underlying mechanisms. Renal dysfunction was induced in mice by a single injection of cisplatin (10 mg kg-1, i.p.) and perindopril was administered orally (2 mg kg-1, once daily) for 5 days. Perindopril remarkably ameliorated cisplatin-induced perturbations in renal histology, renal levels of tumor necrosis factor-alpha, interleukin-6 and interleukin-10, apoptosis-regulating protein expressions (Bax and Bcl2), and partially normalized Bax to Bcl2 ratio and active caspase 3 protein expression. Conversely, perindopril had no significant effect on cisplatin-induced elevations in serum creatinine and urea, microalbuminuria, kidney to body weight ratio, lipid peroxidation marker, superoxide dismutase and catalase activities and reduced glutathione content. In conclusion, perindopril may be safely used with cisplatin in mice since it ameliorated cisplatin-induced histopathological changes, inflammation and apoptosis without affecting renal biomarkers or oxidative stress.

Pantoprazole abrogated cisplatin-induced nephrotoxicity in mice via suppression of inflammation, apoptosis, and oxidative stress.

The current study was designed to evaluate the potential abatement effect of pantoprazole against cisplatin-induced nephrotoxicity and establishing the possible protective mechanisms. Thirty-two male mice were allocated for treatment with saline, single dose of cisplatin (10 mg/kg/i.p), pantoprazole (30 mg/kg/once daily) for 5 days or combination of pantoprazole and cisplatin for 5 days. Urine, blood, and both kidneys were collected for further evaluations. Pantoprazole significantly countermand cisplatin-induced disfigurement of renal histology, kidney weight to body weight ratio, serum levels of creatinine and urea, and microalbuminuria. Furthermore, pantoprazole mostly normalized cisplatin-induced distortion of renal levels of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-6, interleukin-10) and renal content of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase 3). In addition, pantoprazole significantly subsided cisplatin-induced distortion of renal lipid peroxidation marker (MDA), renal superoxide dismutase, and catalase activities and renal reduced glutathione content. This study provides an evidence for the protective utility of short-term pantoprazole against cisplatin-induced nephrotoxicity in mice. The protective mechanism of pantoprazole could be through diminution of cisplatin-induced inflammation, oxidative stress, and their subsequent apoptotic renal cell death via abatement of apoptosis regulating protein expressions (Bax, Bcl2, and active caspase3).

Cadmium-induced hepatocellular injury: Modulatory effects of γ-glutamyl cysteine on the biomarkers of inflammation, DNA damage, and apoptotic cell death.

Cadmium is an extremely toxic pollutant that reaches human body through intake of the industrially polluted food and water as well as through cigarette smoking and exposure to polluted air. Cadmium accumulates in different body organs especially the liver. It induces tissue injury largely through inflammation and oxidative stress-based mechanisms. The aim of the current study was to investigate the ability of γ glutamyl cysteine (γGC) to protect against cadmium-induced hepatocellular injury employing Wistar rats as a mammalian model. The results of the current work indicated that γGC upregulated the level of the anti-inflammatory cytokine IL-10 and downregulated the levels of the pro-inflammatory cytokines (TNF-α, IL-6, and IL-1ß) in the cadmium-exposed rats. In addition, γGC reduced the liver tissues cadmium content in the cadmium-treated rats, suppressed the cadmium-induced hepatocellular apoptosis and oxidative modifications of cellular DNA, lipids, and proteins. Additionally, γGC enhanced the antioxidant potential of the liver tissues in the cadmium-treated rats as evidenced by a remarkable increase in the activity of the antioxidant enzymes superoxide dismutase and glutathione peroxidase and significant increase in the levels of the total antioxidant capacity and reduced glutathione as well as a significant reduction in oxidized to reduced glutathione (GSSG/GSH) ratio. Moreover, it effectively improved liver cell integrity in the cadmium-treated rats as demonstrated by a significant reduction in the serum activity of the liver enzymes (ALT and AST) and amelioration of the cadmium-evoked histopathological alterations. Together, these findings underscore, for the first time, the alleviating effects of γGC against cadmium-induced hepatocellular injury that is potentially mediated through reduction of liver tissue cadmium content along with modulation of both hepatocellular redox status and inflammatory cytokines.

Design, Synthesis, Antimicrobial and Anti-biofilm Evaluation, and Molecular Docking of Newly Substituted Fluoroquinazolinones.

BACKGROUND: Quinazolines and quinazolinones derivatives are well known for their important range of therapeutic activities. OBJECTIVE: The study aims to carry out the synthesis of some derivatives of substituted fluoroquinazolinones based on structure-based design and evaluation of their antibacterial, antifungal, and anti-biofilm activities. METHODS: Compounds were chemically synthesized by conventional methods. Structures were established on the basis of spectral and elemental analyses. The antimicrobial potential was tested against various microorganisms using the agar disc-diffusion method. MIC and MBC as well as anti-biofilm activity for the highly active compounds were assessed. Moreover, the computational studies were performed using Auto dock free software package (version 4.0) to explain the predicted mode of binding. RESULTS: All derivatives (5-8), (10a-g), and (A-H) were biologically tested and showed significant antimicrobial activity comparable to the reference compounds. Compounds 10b, 10c, and 10d had a good MIC and MBC against Gram-positive bacteria, whereas 10b and 10d showed significant MIC and MBC against Gram-negative bacteria. However, compounds E and F exhibited good MIC and MBC against fungi. Compound 10c and 8 exhibited significant anti-biofilm activity towards S. aureus and M. luteus. Molecular docking study revealed a strong binding of these derivatives with their receptor-site and detected their predicted mode of binding. CONCLUSION: The synthesized derivatives showed promising antibacterial, antifungal, and antibiofilm activities. Modeling study explained their binding mode and showed strong binding affinity with their receptor-site. The highly active compounds 5 and 10c could be subjected to future optimization and investigation to be effective antimicrobial agents.

Potential testicular toxicity of gentamicin in adult rats.

Gentamycin is an aminoglycoside antibiotic commonly used against Gram-negative bacteria. This study was designed to investigate the testicular toxicity of gentamicin in adult rats. Gentamicin was given to rats at 0, 60, 80 or 100 mg/kg/day for 10 consecutive days. The absolute weight of testes reduced significantly in relation to the dose, while gentamicin at a dose of 60 mg/kg did not show any significant change in the relative testes weight. Sperm count and motility and daily sperm production decreased in a dose-related manner. Serum testosterone level was significantly decreased after gentamicin treatment in a dose-dependent manner. The activities of LDH-X was decreased while that of caspases-3 &-9 were significantly increased in a dose-related manner. H2O2 production and lipid peroxidation were significantly increased while the activities of SOD, CAT, GPX and GR, in addition to, the non-enzymatic GSH level were significantly decreased suggesting that gentamicin-induced oxidative stress. The biochemical findings were confirmed by histopathological examination of the testis. Atrophy, degeneration and loss of spermatogenesis were observed after gentamicin treatment. The findings of this study indicate that gentamicin induces oxidative stress associated with impairment of spermatogenesis, in addition to apoptosis. These data provide insight into the mode of action of gentamicin-induced impairment of spermatogenesis in the rat testis.

Antifibrotic effect of meloxicam in rat liver: role of nuclear factor kappa B, proinflammatory cytokines, and oxidative stress.

This study was aimed at investigating the antifibrotic effect of meloxicam in CCl4-induced liver fibrosis and elucidating its underlying mechanism. Forty male rats were equally randomized for 8-week treatment with corn oil (negative control), CCl4 (to induce liver fibrosis), and/or meloxicam. Meloxicam effectively ameliorated the CCl4-induced alterations in liver histology, liver weight to body weight ratio, liver functions, and serum markers for liver fibrosis (hyaluronic acid, laminin, and PCIII). Meloxicam significantly abrogated CCl4-induced elevation of messenger RNA (mRNA) expressions for collagen I and alpha smooth muscle actin (α-SMA) and hepatic contents of hydroxyproline, transforming growth factor beta (TGF-ß), and tissue inhibitor of matrix metalloproteases (TIMP-1). Meloxicam mitigated CCl4-induced elevation in hepatic levels of nuclear factor kappa B (NF-κB), tumor necrosis factor alpha (TNF-α), total nitric oxide (NO), interleukin-l beta (IL 1ß), and prostaglandin E2 (PGE2). Meloxicam modulated CCl4-induced disturbance of liver cytochrome P450 subfamily 2E1 (CYP2E1) and glutathione-S-transferase (GST). The attenuation of meloxicam to liver fibrosis was associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of reduced glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. This study provides an evidence for antifibrotic effect of meloxicam against CCl4-induced liver fibrosis in rat. The antifibrotic mechanism of meloxicam could be through decreasing NF-κB level and subsequent proinflammatory cytokine production (TNF-α, NO, IL-1 beta, and PGE2) and, hence, collagen deposition through inhibition of TIMP-1 and TGF-ß. Abrogation of oxidative stress and modulation of liver-metabolizing enzymes (CYP2E1 and GST) were also involved.

Gamma-Glutamyl Cysteine Attenuates Tissue Damage and Enhances Tissue Regeneration in a rat Model of Lead-Induced Nephrotoxicity.

Lead is a biohazardous metal that is commonly involved in human illness including renal injury. Although it is a non-redox reactive metal, lead-induced renal injury is largely based on oxidative stress. The current work aimed at exploring the possible protective effect of γ-glutamyl cysteine (γGC) against lead-induced renal injury. Rats were allocated to normal and γGC control groups, lead-treated group, and lead and γGC-treated group. γGC alleviated lead-induced renal injury as evidenced by attenuation of histopathological aberration, amelioration of oxidative injury as demonstrated by significant reduction in lipid and protein oxidation, elevation of total antioxidant capacity, and glutathione level. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) was significantly elevated. γGC significantly decreased levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1ß and the activity of the apoptotic marker caspase-3. In addition, γGC reduced kidney lead content, enhanced weight gain, and improved renal function as demonstrated by reduced serum levels of urea and creatinine. Importantly, γGC upregulated proliferating cell nuclear antigen (PCNA) expression, denoting enhanced renal regenerative capacity. Together, our findings highlight evidence for alleviating effects of γGC against lead-induced renal injury that is potentially mediated through diminution of oxidative tissue injury, reduction of inflammatory response, attenuation of apoptosis, and enhancement of renal regenerative capacity.

Lipoic acid attenuates Aroclor 1260-induced hepatotoxicity in adult rats.

The present study was aimed to investigate the mechanistic aspect of Aroclor 1260-induced hepatotoxicity and its protection by lipoic acid. The adult male Albino rats were divided into six groups. Group I served as control. Group II received lipoic acid (35 mg/kg/day). Aroclor 1260 was given to rats by oral gavage at doses 20, 40, or 60 mg/kg/day (Groups III, IV, and V, respectively). Group VI was pretreated with lipoic acid (35 mg/kg/day) 24 h before Aroclor 1260 (40 mg/kg/day). Treatment in all groups was continued for further 15 consecutive days. Serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, and lactate dehydrogenase activities and total bilirubin, total cholesterol, and triglycerides were significantly increased while total protein, total albumin, and high-density lipoprotein were significantly decreased. Hydrogen peroxide production and lipid peroxidation were significantly increased while superoxide dismutase and catalase activities and reduced glutathione (GSH) content was significantly decreased in liver. Caspase-3 & -9 activities were significantly increased in liver. Lipoic acid pretreatment significantly reverted all these abnormalities toward their normal levels. In conclusion, Aroclor 1260 induced liver dysfunction, at least in part, by induction of oxidative stress. Apoptotic effect of hepatic cells is involved in Aroclor 1260-induced liver injury. Lipoic acid could protect rats against Aroclor 1260-induced hepatotoxicity. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 913-922, 2016.

Dibutyl phthalate induces oxidative stress and impairs spermatogenesis in adult rats.

Phthalates are abundantly produced plasticizers, and dibutyl phthalate (DBP) is the most widely used derivative in various consumer products and medical devices. This study was conducted to further explore the potential testicular toxicity of DBP in adult rats and to elucidate the underlying mechanisms. Adult male albino rats were treated orally with DBP at doses of 0, 200, 400, or 600 mg/kg/day for 15 consecutive days. Testicular weight, sperm count, and motility were significantly decreased. Treatment with DBP decreased serum follicle-stimulating hormone and testosterone levels and testicular lactate dehydrogenase activity. DBP treatment also decreased serum total antioxidant capacity and the activities of the testicular antioxidant enzymes, such as superoxide dismutase, catalase, and glutathione reductase. Further, DBP treatment provoked degeneration with absence of spermatogenesis and sperms and necrosis in some of seminiferous tubules. These results indicated that oxidative stress and subsequent decrease in testosterone secretion were the potential underlying mechanism of DBP-induced testicular toxicity.

Crocin Abrogates Carbon Tetrachloride-Induced Renal Toxicity in Rats via Modulation of Metabolizing Enzymes and Diminution of Oxidative Stress, Apoptosis, and Inflammatory Cytokines.

This work aimed at investigating the potential modulatory effects and mechanisms of crocin against CCl4 -induced nephrotoxicity. Forty male rats were allocated for three weeks treatment with corn oil, CCl4 , crocin, or crocin plus CCl4 . Crocin effectively mitigated CCl4 -induced kidney injury as evidenced by amelioration of alterations in kidney histopathology, renal weight/100 g body weight ratio and kidney functions. Crocin modulated CCl4 -induced disturbance of kidney cytochrom-P450 subfamily 2E1 and glutathione-S-transferase. The attenuation of crocin to kidney injury was also associated with suppression of oxidative stress via reduction of lipid peroxides along with induction of renal glutathione content and enhancement of superoxide dismutase, glutathione peroxidase, and catalase activities. Crocin mitigated CCl4 -induced elevation of the renal levels of tumor necrosis factor-alpha, interleukin-6, prostaglandin E2, and active caspases-3. Collectively, crocin alleviated CCl4 -induced renal damage via modulation of kidney metabolizing enzymes, suppression of oxidative stress, inhibition of inflammatory cytokines, PGE2, and active caspase3 in kidney.

Modulatory effects of meloxicam on cardiotoxicity and antitumor activity of doxorubicin in mice.

PURPOSE: This study was undertaken to assess the possible modulatory effects and mechanisms of meloxicam, a cyclooxygenase-2 inhibitor, on the antitumor activity and cardiotoxicity of doxorubicin in a mice model of mammary carcinoma. METHODS: Solid tumor mass was developed in female albino mice using Ehrlich carcinoma cells. Forty mice-bearing tumor were divided randomly into four groups for treatment: with saline, meloxicam 10 mg/kg, doxorubicin 5 mg/kg and meloxicam 1 h ahead of doxorubicin, twice weekly for 2 weeks. Tumor volume was followed up and cardiac protective utility was estimated via measuring heart and serum parameters. RESULTS: Meloxicam expressed a non-significant increase in doxorubicin antitumor activity. Conversely, meloxicam significantly (p < 0.01) mitigated doxorubicin-induced elevation of serum cardiac enzymes [creatine kinase, lactate dehydrogenase and troponin-I]; cardiac lipid peroxidations marker; cardiac active caspase-3 content; and cardiac prostaglandin E2 content. Meloxicam significantly abrogated doxorubicin-induced disturbance in heart histology and relative heart weight to body weight. Meloxicam normalized doxorubicin-induced suppression in heart antioxidant enzymes activities and gene expressions [superoxide dismutase, glutathione peroxidase (GSH-Px) and catalase], and heart GSH content. In addition, meloxicam ameliorated doxorubicin-induced disturbance in phase II metabolizing enzyme, cardiac quinone reductase (QR), at activity level and mRNA expression. CONCLUSION: Meloxicam protects heart against doxorubicin toxicity without affecting its antitumor activity against solid mammary cancer model in mice. This protective effect is attributed to antioxidant effect, antiradical effect, antiinflammatory action, antiapoptotic effect and induction of QR enzyme.

Modulator effects of meloxicam against doxorubicin-induced nephrotoxicity in mice.

Doxorubicin-induced renal toxicity overshadows its anticancer effectiveness. This study is aimed at assessing the possible modulator effects of meloxicam, a cyclooxigenase-2 inhibitor, on doxorubicin-induced nephrotoxicity in mice and exploring some of the modulator mechanisms. Forty male mice were divided for treatment, for 2 weeks, with saline, meloxicam (daily), doxorubicin (twice/week), or both meloxicam and doxorubicin. Doxorubicin induced a significant increase in relative kidney weight to body weight, kidney lipid perooxidation, plasma levels of interleukin-6 and tumor necrosis factor-α, kidney caspase-3 activity, and kidney prostaglandin E2 (PGE2) content. Doxorubicin disturbed kidney histology, abrogated renal function tests (serum creatinine, uric acid, and blood urea nitrogen), induced a significant decrease in antioxidant enzyme activities (superoxide dismutase, glutathione peroxidase, and catalase) and reduced glutathione (GSH) content. The administration of meloxicam with doxorubicin mitigated all doxorubicin-disturbed parameters. Meloxicam ameliorated doxorubicin-induced renal injury via inhibition of inflammatory PGE2, inflammatory cytokines, caspase-3 activity, antioxidant effect, and free radical scavenging activity.

Beryllium chloride-induced oxidative DNA damage and alteration in the expression patterns of DNA repair-related genes.

Beryllium metal has physical properties that make its use essential for very specific applications, such as medical diagnostics, nuclear/fusion reactors and aerospace applications. Because of the widespread human exposure to beryllium metals and the discrepancy of the genotoxic results in the reported literature, detail assessments of the genetic damage of beryllium are warranted. Mice exposed to beryllium chloride at an oral dose of 23mg/kg for seven consecutive days exhibited a significant increase in the level of DNA-strand breaking and micronuclei formation as detected by a bone marrow standard comet assay and micronucleus test. Whereas slight beryllium chloride-induced oxidative DNA damage was detected following formamidopyrimidine DNA glycosylase digestion, digestion with endonuclease III resulted in considerable increases in oxidative DNA damage after the 11.5 and 23mg/kg/day treatment as detected by enzyme-modified comet assays. Increased 8-hydroxydeoxyguanosine was also directly correlated with increased bone marrow micronuclei formation and DNA strand breaks, which further confirm the involvement of oxidative stress in the induction of bone marrow genetic damage after exposure to beryllium chloride. Gene expression analysis on the bone marrow cells from beryllium chloride-exposed mice showed significant alterations in genes associated with DNA damage repair. Therefore, beryllium chloride may cause genetic damage to bone marrow cells due to the oxidative stress and the induced unrepaired DNA damage is probably due to the down-regulation in the expression of DNA repair genes, which may lead to genotoxicity and eventually cause carcinogenicity.

Ameliorative effects of resveratrol on liver injury in streptozotocin-induced diabetic rats.

The objective of this study was to investigate the ameliorative property and potential mechanism of resveratrol (RVT) in a dose of 10 mg/kg for 15 consecutive days against liver injury in streptozotocin-induced diabetic rats. Diabetic rats significantly (P < 0.05) exhibited liver injury manifested by increased aspartylaminotransferase, alanine aminotransferase, and bilirubin; disturbed liver weight to body weight; and confirmed by hematoxylin and eosin staining. Liver from diabetic rats exhibited significant increase in malondialdehyde level and significant decrease in reduced glutathione, glutathione-S-transferase, quinone reductase, catalase, and superoxide dismutase. Diabetic rats showed significant disturbance in serum lipid profile. Treatment with RVT significantly (P < 0.05) abrogated diabetes-induced perturbation in these parameters and liver histology. These data suggest that RVT treatment is associated with promising hepatoprotective effect against diabetes-induced liver damage via reduction of serum glucose level and oxidative damage and improving serum lipid profile.

Crocin "saffron" protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes.

Beryllium chloride (BeCl(2)) is a highly toxic substance that accumulates in different tissues after absorption. The purpose of this study was to investigate protective role of crocin against BeCl(2)-intoxication in rats. Male Wistar rats were used in this study and categorised into four groups (n=8). Group I served as normal control rats. Group II treated orally with BeCl(2) 86 mg/kg b.w. for five consecutive days. This dose was equivalent to experimental LD(50). Group III treated intraperitoneally with crocin 200 mg/kg b.w. for seven consecutive days. Group IV received crocin for seven consecutive days before BeCl(2) administration. Blood samples and liver and brain homogenates were obtained for haematological, biochemical and RT-PCR examinations. The haematocrit value, RBCs count and haemoglobin concentration were significantly decreased in BeCl(2)-treated rats. A significant increase was observed in rat liver and brain malondialdehyde level and protein carbonyls content in BeCl(2) exposed group compared to the control group, and these values were significantly declined upon administration of crocin. Lactate dehydrogenase levels in rat liver and brain significantly increased compared to the control group and was associated with significant decrease in catalase and superoxide dismutase activities. Reduced glutathione hepatic contents of BeCl(2)-treated rats were significantly decreased. There was significant decline in mRNA expression of catalase and superoxide dismutase genes in BeCl(2)-intoxicated rats compared to the normal rats. Crocin treatment prior to BeCl(2) intake resulted in significant increase in mRNA expressions of catalase and superoxide dismutase genes near to normalcy. The haematological and biochemical parameters were restored near to normal levels. Our results suggested that, BeCl(2) induced oxidation of cellular lipids and proteins and that administration of crocin reduced BeCl(2)-induced oxidative stress combined with initiation of mRNA expression of antioxidant genes.

Meloxicam modulates oxidative stress status, inhibits prostaglandin E2, and abrogates apoptosis in carbon tetrachloride-induced rat hepatic injury.

The current study aimed at investigating the potential hepatoprotective property and mechanism of meloxicam (MEL) against carbon tetrachloride (CCl(4))-induced hepatocellular damage in rats. Subcutaneous administration of CCl(4) (2 mL/kg, twice/week for 8 weeks) induced hepatocellular damage substantiated by hematoxylin and eosin staining and significant elevation in serum aspartate transaminase, alanine transaminase, and total bilirubin. In addition, CCL(4) treatment led to elevation in liver contents of lipid peroxidation marker (malondialdehyde), prostaglandin E2, active caspase 3, and Terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells and reduction in the activities of superoxide dismutase, catalase, glutathione-S-transferase, and reduced glutathione in the liver tissue. Prior oral treatment with MEL (5 mg/kg, twice/week) retained the normal liver histology and significantly restored all of these parameters close to normal values. These results demonstrated the hepatoprotective utility of MEL against the CCl(4)-induced liver injury which might ascribe to its antioxidant, free radical scavenging, antiapoptotic and anti-inflammatory effects.

Antioxidant and antiapoptotic effects of capsaicin against carbon tetrachloride-induced hepatotoxicity in rats.

The aim of the study was to evaluate the potential hepatoprotective utility of capsaicin against carbon tetrachloride (CCl4)-induced liver injury and to explore the possible mechanisms whereby this agent mediated its beneficial effects. We randomized 40 rats into four groups for treatment with corn oil, CCl4, capsaicin and both CCl4 and capsaicin, respectively, for 8 weeks. At the end of the experiment, blood samples were collected and used for determination of aspartylaminotransferase (AST), alanine aminotransferase (ALT), and total bilirubin, while the liver tissues were subjected to hematoxylin and eosin examination; evaluation of malondialdehyde (MDA), reduced glutathione (GSH) and active caspase-3 contents; and evaluation of superoxide dismutase (SOD), catalase (CAT) and glutathione-S-transferase (GST) activities. Animals treated with CCl4 exhibited significant elevation in AST, ALT, total bilirubin and caspase-3 and exhibited significant decrease in activities of SOD, CAT, GST and GSH contents. The combination (both capsaicin and CCl4) group has preserved the liver histology, liver enzymes and bilirubin close to normal, exhibited significant induction in the activities of CAT, SOD and GST, increased the liver content of GSH and active caspase-3 and conversely showed significant decrease in liver MDA content compared to CCl4 challenged rats. Capsaicin confers an appealing hepatoprotective effect which might be explained partially via diminishing the generation of MDA, induction of antioxidant systems and inhibition of active caspase-3.