Geometry and evolution of Hasimoto surface in Minkowski 3-space.

The main goal of this paper is to introduce the evolution equations for a timelike Hasimoto surface from its fundamental form coefficients in Minkowski 3-space [Formula: see text]. By utilizing the evolved quasi-curve (q-curve), we present and analyze three types of Hasimoto surfaces, attributed to the quasi-tangent, quasi-normal, and quasi-binormal vectors of the curve. Finally, we provide an illustrated example to strengthen our main results.

Effect of mesenchymal stem cells versus aloe vera on healing of deep second-degree burn.

BACKGROUND: Burn injuries constitute a major health problem which cause more severe physiological stress than other traumas. Aloe vera has been used in traditional medicine for a long time for burn treatment. Mesenchymal stem cells (MSCs) have delivered new approaches to the management of deep burns. The present study assessed the effect of aloe vera versus MSCs on experimentally induced deep second-degree burn. METHODS: Sixty adult female albino rats randomized into 6 groups: group I served as negative control, group II received topical aloe vera only, group III were injected intradermally with MSCs, group IV subjected to burn injury, group V received topical aloe vera post burn and group VI were injected intradermally with MSCs post burn. Healing of burn injury was evaluated grossly. Skin specimens were obtained after 14 & 21-days post-burn induction and prepared for histological techniques (H&E and Masson's trichrome stain). Polymerase chain reaction (PCR) analysis of Sry gene for group VI was done. RESULTS: After 14 days, groups V&VI showed fully regenerated epidermis with a significant increase in the epidermal thickness and a significant decrease in the optical density of collagen fibers compared to control groups. After 21 days, group V showed less epidermal thickness compared to that of day 14 and nearly normal collagen fibers arrangement. However, group VI showed a significant increase in the epidermal thickness compared to groups V&I and an interwoven collagen fibers arrangement with a significant decrease in the optical density of collagen fibers in comparison to control groups. PCR results of the tested samples revealed that 100% of the recipient rats contain Sry positive gene. CONCLUSIONS: Topical aloe vera promoted burn wound healing faster and better than intradermal injection of MSCs.

Dual opposing actions of STW 5 on TRP receptors mediate neuronal desensitisation in vitro.

AIMS: STW 5 is an herbal drug combination used for the treatment of functional gastrointestinal disorders (FGIDs) with visceral hypersensitivity as the therapy-resistant hallmark. STW 5 has been clinically proven to alleviate visceral hypersensitivity-related symptoms, including abdominal pain, bloating, nausea, and early satiety. However, the molecular and cellular mechanisms underlying the antinociceptive action of STW 5 remain unknown. Here, we investigate the role of STW 5 in the calcium mobilisation of dorsal root ganglion (DRG) sensory neurons. MAIN METHODS: Calcium imaging experiments were performed with freshly dissociated cultured murine DRG neurons isolated from mice by microfluorometry. TRPA1-deficient DRGs, TRPV1-deficient DRGs, TRPA1/V1 double-deficient DRGs, and wild-type DRGs have been used to investigate the role of TRPs ion channels in mediating STW 5 action. KEY FINDINGS: STW 5 (1.74 and 5.8 mg/ml) induced calcium ion influx into DRG neurons in a concentration-dependent manner. Calcium transients were desensitised during repeated exposure to STW 5, an effect that was facilitated in TRPA1-deficient DRGs and less pronounced in TRPV1-deficient DRGs compared to wild-type (WT) DRGs. SIGNIFICANCE: Repeated exposure to STW 5 induced desensitisation of sensory neurons and may ultimately contribute to its proven clinical efficacy against sensory-related symptoms in patients with FGID, including abdominal pain, bloating, nausea, and early satiety. This effect is modulated by the two prominent irritant sensors in nociceptors, TRPA1 and TRPV1.

Correction to: "Enoxaparin prevents fibrin accumulation in liver tissues and attenuates methotrexate-induced liver injury in rats".

The authors found a mistake in Figure 2 and would like to correct the manuscript.

Pirfenidone alleviates concanavalin A-induced liver fibrosis in mice.

AIMS: Liver fibrosis (LF) is a life-threatening complication of most chronic liver diseases resulting from a variety of injurious agents and hepatotoxic insults. To date, there are no specific therapies for LF, and all the currently available drugs have been developed for other indications. Thus, there is a pressing need to develop new drugs for treatment of LF. Therefore, the current study aimed to elucidate the potential antifibrotic effect of Pirfenidone (PFD) against concanavalin A (ConA)-induced immunological model of liver fibrosis in mice. MAIN METHODS: Hepatic fibrosis was induced in mice by injecting ConA (10 mg/kg/wk./i.v) for 4 weeks. Then, the mice were treated with or without PFD (125 mg/kg/ip/day) for 2 weeks. Hepatic fibrosis was determined by Masson Trichrome staining; Haematoxylin & eosin (H&E) staining, immunohistochemistry staining of type II and IV collagens, and colorimetric assessment of hydroxyprolline (HP) content in the liver tissues. In addition, the expression of α-SMA mRNA was determined by real time RT-PCR. The serum levels of TGF-ß, TNF-α, TIMP-1 and MMP-2 were measured by ELISA. KEY FINDINGS: Treatment with PFD significantly reduced ConA-induced expression of type II and IV collagens, α-SMA mRNA expression, and HP content and decreased inflammatory cells infiltration in hepatic tissues. Furthermore, serum levels of TGF-ß, TNF-α, and TIMP-1 were significantly reduced with concomitant increase in MMP-2 expression. SIGNIFICANCE: Treatment with PFD ameliorates concanavalin A-induced hepatic inflammation and fibrosis in mice. Thus, PFD may represent a promising therapeutic option for hepatic fibrosis and its related complications.

Enoxaparin prevents fibrin accumulation in liver tissues and attenuates methotrexate-induced liver injury in rats.

Methotrexate (MTX) is a widely used drug for treatment of many malignant, rheumatic, and autoimmune diseases. However, hepatotoxicity remains one of the most serious side effects of MTX. The extrinsic coagulation pathway is activated after tissue injury through the release of tissue factor (TF) which activates a cascade of clotting factors including prothrombin and fibrinogen. Liver sinusoidal endothelial cells express endothelial nitric oxide synthase (eNOS) as a source for nitric oxide (NO) that serves as vasodilator and antithrombotic factor. In the current study, we tested the possible role of coagulation system activation in MTX-induced hepatotoxicity. Our results showed that single-dose administration of MTX significantly altered rat liver functions with concurrent turbulence in redox status. Immunofluorescence staining showed accumulation of fibrin in the periportal hepatocytes and downregulation of eNOS expression in hepatic endothelial and sinusoidal cells following MTX treatment. Moreover, MTX administration increased the expression of inducible nitric oxide synthase (iNOS) and NOSTRIN (eNOS traffic inducer) in the hepatic sinusoids. On the other hand, pre-treatment with enoxaparin rescued against MTX-induced liver injury with subsequent amelioration of liver redox status. Furthermore, it significantly prevented the effect of MTX on the expression of fibrin, iNOS, eNOS, and NOSTRIN. We concluded that liver tissue aggregation of the coagulation product, fibrin, may play a crucial role in the pathogenesis of MTX-induced liver injury.

The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers.

KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3' UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.

The role of HERC2 and RNF8 ubiquitin E3 ligases in the promotion of translesion DNA synthesis in the chicken DT40 cell line.

The replicative DNA polymerases are generally blocked by template DNA damage. The resulting replication arrest can be released by one of two post-replication repair (PRR) pathways, translesion DNA synthesis (TLS) and template switching by homologous recombination (HR). The HERC2 ubiquitin ligase plays a role in homologous recombination by facilitating the assembly of the Ubc13 ubiquitin-conjugating enzyme with the RNF8 ubiquitin ligase. To explore the role of HERC2 and RNF8 in PRR, we examined immunoglobulin diversification in chicken DT40 cells deficient in HERC2 and RNF8. Unexpectedly, the HERC2(-/-) and RNF8(-/-) cells and HERC2(-/-)/RNF8(-/-) double mutant cells exhibit a significant reduction in the rate of immunoglobulin (Ig) hypermutation, compared to wild-type cells. Further, the HERC2(-/-) and RNF8(-/-) mutants exhibit defective maintenance of replication fork progression immediately after exposure to UV while retaining proficient post-replicative gap filling. These mutants are both proficient in mono-ubiquitination of PCNA. Taken together, these results suggest that HERC2 and RNF8 promote TLS past abasic sites and UV-lesions at or very close to stalled replication forks.

Pioglitazone.

Pioglitazone is a thiazolidinedione antidiabetic with actions similar to those of rosiglitazone. It is used in the management of type 2 diabetes mellitus and is prepared by reducing 5-[4-[2-(5-ethyl-2-pyridyl)ethoxy]benzilidene]-2,4-thiazolidinedione with sodium borohydride in the presence of a cobalt ion and dimethyl glyoxime. Ultraviolet spectroscopy shows maximum absorption at 270nm. Infrared spectroscopy shows principal peaks at wave numbers 3082, 2964, 1736, 1690, 1472, 1331, 1254, 1040, 841, 728cm(-1) (KBr disk). The determination method by high-performance liquid chromatography was linear over the range of 25-1500ng/mL of pioglitazone in plasma (r(2)>0.999). The within- and between-day precision values were in the range of 2.4-6.8%. The limit of quantitation of the method was 25ng/mL. It is well absorbed with a mean absolute bioavailability of 83% and reaching maximum concentrations in around 1.5h. It is metabolized by the hepatic cytochrome P450 enzyme system. Following oral administration, approximately 15-30% of the pioglitazone dose is recovered in the urine. Renal elimination of pioglitazone is negligible, and the drug is excreted primarily as metabolites and their conjugates. It is presumed that most of the oral dose is excreted into the bile either unchanged or as metabolites and eliminated in the feces.

Bioavailability of paracetamol with/without caffeine in Egyptian patients with hepatitis C virus.

PURPOSE: This study investigates the involvement of liver dysfunction in the modulation of paracetamol pharmacokinetic profile in genotype-4 HCV patients treated with either paracetamol alone (Para) or in combination with caffeine (Para-Caf). METHODS: Twenty healthy volunteers and 20 Child-Pugh B HCV patients, each divided into two equal subgroups, were examined, whose liver/kidney functions were correlated with their main clinical manifestation. After an overnight fasting, healthy and hepatic subjects received either a single dose of Para (1000 mg paracetamol) or Para-Caf (1000 mg paracetamol/130 mg caffeine). Two milliliters of saliva samples were collected prior to and at different time-intervals after drug administration and analyzed using HPLC. RESULTS: There was a noticeable increase in the mean concentration time profile of salivary paracetamol concentrations in hepatic patients, with concomitant decrease in paracetamol clearance (CLT), along with induction in the primary pharmacokinetic (PK) parameters, C max, AUC(0-8 h) and AUC(0-∞) (by about 95, 82, and 64 %, respectively, after treatment with Para, and 98, 96, and 101 %, respectively, after treatment with Para-Caf), when compared with the corresponding parameters in healthy subjects. Additionally, the healthy subjects treated with Para-Caf exhibited bioinequivalent increase in C max, K a, and t 1/2 with decrease in T max when compared with the healthy individuals treated with Para alone. A similar pattern was recorded in hepatic patients after addition of caffeine to paracetamol, with even augmented significant increase in K a and t 1/2 (by 100 and 32 %, respectively). CONCLUSIONS: Liver dysfunction modified the PK of paracetamol expressed as earlier effective paracetamol concentration, with obvious decrease in its clearance. Caffeine induced faster absorption (evidenced by shorter T max and higher K a) and prolonged t 1/2 of paracetamol, the effects that were more profound in hepatic patients. Further studies are needed to evaluate the influence of liver damage on paracetamol pharmacokinetics whenever repeated dosing is applied, to avoid possible drug accumulation.

All-trans retinoic acid potentiates cisplatin-induced kidney injury in rats: impact of retinoic acid signaling pathway.

Cisplatin (cis-diammine dichloroplatinum (II), CDDP) is a widely used drug for treatment of various types of cancers. However, CDDP-induced nephrotoxicity remains the main dose-limiting side effect. Retinoids are a group of vitamin A-related compounds that exert their effects through retinoid receptors activation. In this study, we investigated the effect of CDDP treatment on retinoic acid receptor-α (RAR-α) and retinoid X receptor-α (RXR-α) expression. In addition, we investigated the possible modulatory effects of RAR agonist, all-trans retinoic acid (ATRA), on CDDP-induced nephrotoxicity. Rats were treated with saline, DMSO, CDDP, ATRA, or CDDP/ATRA. Twenty-four hours after the last ATRA injection, rats were killed; blood samples were collected; kidneys were dissected; and biochemical, immunohistochemical, and histological examinations were performed. Our results revealed that CDDP treatment significantly increased serum levels of creatinine and urea, with concomitant decrease in serum albumin. Moreover, reduced glutathione (GSH) content as well as superoxide dismutase (SOD) and catalase (CAT) activities were significantly reduced with concurrent increase in kidney malondialdehyde (MDA) content following CDDP treatment. Furthermore, CDDP markedly upregulated tubular RAR-α, RXR-α, fibrin, and inducible nitric oxide synthase (iNOS) protein expression. Although administration of ATRA to control rats did not produce marked alterations in kidney function parameters, administration of ATRA to CDDP-treated rats significantly exacerbated CDDP-induced nephrotoxicity. In addition, CDDP/ATRA co-treatment significantly increased RAR-α, RXR-α, fibrin, and iNOS protein expression compared to CDDP alone. In conclusion, we report, for the first time, the crucial role of retinoid receptors in CDDP-induced nephrotoxicity. Moreover, our findings indicate that co-administration of ATRA with CDDP, although beneficial on the therapeutic effects, their deleterious effects on the kidney may limit their clinical use.

All-trans retinoic acid mitigates methotrexate-induced liver injury in rats; relevance of retinoic acid signaling pathway.

Methotrexate (MTX) is a widely used drug for treatment of rheumatic and autoimmune diseases as well as different types of cancer. One of the major side effects of MTX is hepatotoxicity. Retinoid receptors, including retinoid X receptor (RXR), and retinoic acid receptor (RAR) are vitamin A receptors that are highly expressed in the liver and regulate important physiological processes through regulation of different genes. In this study, we investigated the effect of MTX on RXR-α and RAR-α expression in the liver and the potential protective effects of all-trans retinoic acid (ATRA) in MTX-induced hepatotoxicity. Rats were randomly divided into five groups: The rates were treated with saline, DMSO, MTX (20 mg/kg/IP; single dose), ATRA (7.5 mg/kg/day, I.P), or MTX and ATRA. Rats were killed 24 h after the last ATRA injection. The liver tissues were dissected out, weighed, and subjected to histological, immunohistochemical, and biochemical examinations. Our results demonstrated that treatment with MTX resulted in significant decrease in reduced glutathione (GSH) content and superoxide dismutase (SOD) activity, with concomitant increase in ALT, AST, and MDA levels. In addition, MTX markedly downregulated the expression of both RXR-α and RAR-α, and changed the appearance of RXR-α to be very small speckled droplets. Treatment with ATRA significantly ameliorated MTX-induced effects on GSH, ALT, and MDA. Moreover, ATRA administration increased the expression and nuclear translocation of RXR-α in rat hepatocytes. In conclusion, our study revealed, for the first time, that retinoid receptors may play an important role in the MTX-induced hepatotoxicity.

Melissa officinalis extract induces apoptosis and inhibits proliferation in colon cancer cells through formation of reactive oxygen species.

PURPOSE: Efficient strategies for the prevention of colon cancer are extensively being explored, including dietary intervention and the development of novel phytopharmaceuticals. Safe extracts of edible plants contain structurally diverse molecules that can effectively interfere with multi-factorial diseases such as colon cancer. In this study, we describe the antiproliferative and proapoptotic effects of ethanolic lemon balm (Melissa officinalis) leaves extract in human colon carcinoma cells. We further investigated the role of extra- and intracellular reactive oxygen species (ROS). METHODS: Antitumor effects of lemon balm extract (LBE) were investigated in HT-29 and T84 human colon carcinoma cells. Inhibition of proliferation was analyzed by DNA quantification. The causal cell cycle arrest was determined by flow cytometry of propidium iodide-stained cells and by immunoblotting of cell cycle regulator proteins. To investigate apoptosis, cleavage of caspases 3 and 7 was detected by immunoblotting and fluorescence microscopy. Phosphatidylserine externalization was measured by Annexin V assays. Mechanistic insights were gained by measurement of ROS using the indicator dyes CM-H2DCFDA and Cell ROX Green. RESULTS: After 3 and 4 days of treatment, LBE inhibited the proliferation of HT-29 and T84 colon carcinoma cells with an inhibitory concentration (IC50) of 346 and 120 µg/ml, respectively. Antiproliferative effects were associated with a G2/M cell cycle arrest and reduced protein expression of cyclin dependent kinases (CDK) 2, 4, 6, cyclin D3, and induced expression of cyclin-dependent kinase inhibitor 2C (p18) and 1A (p21). LBE (600 µg/ml) induced cleavage of caspases 3 and 7 and phosphatidylserine externalization. LBE-induced apoptosis was further associated with formation of ROS, whereas quenching of ROS by antioxidants completely rescued the colon carcinoma cells from LBE-induced apoptosis. CONCLUSIONS: Lemon balm (Melissa officinalis) extract inhibits the proliferation of colon carcinoma cells and induces apoptosis through formation of ROS. Taken together, LBE or subfractions thereof could be used for the prevention of colon cancer.

Elongation factor-2 kinase regulates TG2/ß1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion.

Pancreatic ductal adenocarcinoma is one of the lethal cancers with extensive local tumour invasion, metastasis, early systemic dissemination and poorest prognosis. Thus, understanding the mechanisms regulating invasion/metastasis and epithelial-mesenchymal transition (EMT), is the key for developing effective therapeutic strategies for pancreatic cancer (PaCa). Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical kinase that we found to be highly up-regulated in PaCa cells. However, its role in PaCa invasion/progression remains unknown. Here, we investigated the role of eEF-2K in cellular invasion, and we found that down-regulation of eEF-2K, by siRNA or rottlerin, displays impairment of PaCa cells invasion/migration, with significant decreases in the expression of tissue transglutaminase (TG2), the multifunctional enzyme implicated in regulation of cell attachment, motility and survival. These events were associated with reductions in ß1 integrin/uPAR/MMP-2 expressions as well as decrease in Src activity. Furthermore, inhibition of eEF-2K/TG2 axis suppresses the EMT, as demonstrated by the modulation of the zinc finger transcription factors, ZEB1/Snail, and the tight junction proteins, claudins. Importantly, while eEF-2K silencing recapitulates the rottlerin-induced inhibition of invasion and correlated events, eEF-2K overexpression, by lentivirus-based expression system, suppresses such rottlerin effects and potentiates PaCa cells invasion/migration capability. Collectively, our results show, for the first time, that eEF-2K is involved in regulation of the invasive phenotype of PaCa cells through promoting a new signalling pathway, which is mediated by TG2/ß1 integrin/Src/uPAR/MMP-2, and the induction of EMT biomarkers which enhance cancer cell motility and metastatic potential. Thus, eEF-2K could represent a novel potential therapeutic target in pancreatic cancer.

Targeting elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells.

Pancreatic cancer (PaCa) is one of the most aggressive, apoptosis-resistant and currently incurable cancers with a poor survival rate. Eukaryotic elongation factor-2 kinase (eEF-2K) is an atypical kinase, whose role in PaCa survival is not yet known. Here, we show that eEF-2K is overexpressed in PaCa cells and its down-regulation induces apoptotic cell death. Rottlerin (ROT), a polyphenolic compound initially identified as a PKC-δ inhibitor, induces apoptosis and autophagy in a variety of cancer cells including PaCa cells. We demonstrated that ROT induces intrinsic apoptosis, with dissipation of mitochondrial membrane potential (ΔΨm), and stimulates extrinsic apoptosis with concomitant induction of TNF-related apoptosis inducing ligand (TRAIL) receptors, DR4 and DR5, with caspase-8 activation, in PANC-1 and MIAPaCa-2 cells. Notably, while none of these effects were dependent on PKC-δ inhibition, ROT down-regulates eEF-2K at mRNA level, and induce eEF-2K protein degradation through ubiquitin-proteasome pathway. Down-regulation of eEF-2K recapitulates the events observed after ROT treatment, while its over-expression suppressed the ROT-induced apoptosis. Furthermore, eEF-2K regulates the expression of tissue transglutaminase (TG2), an enzyme previously implicated in proliferation, drug resistance and survival of cancer cells. Inhibition of eEF-2K/TG2 axis leads to caspase-independent apoptosis which is associated with induction of apoptosis-inducing factor (AIF). Collectively, these results indicate, for the first time, that the down-regulation of eEF-2K leads to induction of intrinsic, extrinsic as well as AIF-dependent apoptosis in PaCa cells, suggesting that eEF-2K may represent an attractive therapeutic target for the future anticancer agents in PaCa.

Effect of RAS inhibition on TGF-ß, renal function and structure in experimentally induced diabetic hypertensive nephropathy rats.

OBJECTIVE: Transforming growth factor-ß (TGF-ß) implicated in the pathogenesis of diabetic nephropathy. Hence, developing agents that antagonize fibrogenic signals is a critical issue facing researchers. MATERIAL AND METHODS: Fifty rats were allocated to five groups: 1=control rats, 2=diabetic hypertensive rats 3=diabetic hypertensive rats treated with spironolactone, 4=diabetic hypertensive rats treated with moexpril, 5=diabetic hypertensive rats treated with both spironolactone and moexpril. Measurement of TGF-ß, aldosterone, creatinine and ACE. Degree of fibrosis was calculated. RESULTS: Serum creatinine, mean arterial blood pressure (MAP), aldosterone, ACE, TGF-ß and renal fibrosis increased significantly in untreated diabetic hypertensive rats compared with control rats. Administration of spironolactone, moexpril, or both decreased these changes. CONCLUSIONS: Addition of the spironolactone to moexpril was more effective in reducing fibrosis and improvement of renal function than monotherapy with either drug, possibly due to a dual inhibitory effect on the RAS, and thus suppression of TGF-ß.

Anti-EGFR (cetuximab) combined with irinotecan for treatment of elderly patients with metastatic colorectal cancer (mCRC).

PURPOSE: This study was conducted to test the efficacy and toxicity of cetuximab and irinotecan as a biweekly regimen in treatment of elderly patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Forty-nine elderly patients (≥65 years) with mCRC who progressed after at least one previous line of treatment were enrolled into this study from May 2008 to January 2011. All recruited patients received cetuximab 500 mg/m(2) and irinotecan 180 mg/m(2) every 2 weeks. RESULTS: Thirty-seven patients (76 %) were men, and 76 % of patients had colonic cancer in origin. Median age was 69 years. Median overall survival time was 7 months, and median progression-free survival was 4 months. Grade 3-4 skin rash occurred in 20 % of patients, grade 3-4 diarrhea in 18 % of patients, and neutropenia in 28 % of patients. CONCLUSION: Cetuximab combined with irinotecan when administered biweekly is safe and effective for treatment of pretreated elderly patients with mCRC.

The chemopreventive effect of dimethylthiourea against carmustine-induced myelotoxicity in rats.

The possible chemopreventive role of dimethylthiourea (DMTU) against carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-induced myelotoxicity was assessed through evaluation of apoptosis, lipid peroxidation, glutathione (GSH) content and some antioxidant enzymes activities in bone marrow cells of rats. Thirty-six rats were randomly classified into four groups. The first group was injected i.p. with ethanol and served as a control. The second group was treated with BCNU. The third group was given DMTU, while the fourth group was co-administered with DMTU prior to BCNU administration. BCNU treatment in a single dose of 30 mg/kg significantly decreased the normal counts of RBCs, WBCs and platelets as well as hemoglobin level. In addition, BCNU exhibited marked apoptotic effect associated with significant alterations in the oxidative cascade parameters. Treatment of animals with DMTU in a single dose of 500 mg/kg 1h before BCNU injection, followed by 125 mg/kg twice daily for 5 consecutive days significantly mitigated the induced changes in the hematological parameters. The induced alterations in the oxidant and antioxidant parameters as well as apoptosis were also improved. Conclusively, DMTU treatment exhibited marked chemopreventive effect against BCNU-induced myelotoxicity; an effect which may be partially attributed to its inherently antioxidant potential.

Effect of food restriction on ghrelin in adult male rats and its relation to male reproductive hormones.

Ghrelin is an endogenous ligand for growth hormone secretagogue (GHS) receptor (GHS-R). It has recently emerged as an orexigenic food intake controlling signal acting upon hypothalamic centres. To study the effect of food restriction on ghrelin level and its relation to male reproductive hormones, 32 adult male albino rats divided into two groups: Group I (8 rats as a control group) fed ad libitum for 21 days and 24 rats as Group II (food-restricted group) fed 30% of ad libitum intake of food consumed by the control group. Rats were weighed every 3 days. Group II rats were further subdivided into three subgroups: IIa, IIb and IIc that were killed at days 8, 16 and 21 from the start of food restriction respectively. Ghrelin level was assayed by ELISA technique in serum samples and tissue homogenates prepared from the stomach and hypothalamus. In addition, male reproductive hormones: testosterone, follicle-stimulating hormone (FSH) and luteinizing hormone (LH) were assayed in serum by chemiluminescence. Mean body weight of food restricted rats was observed to decrease during the period of the experiment. Food restriction produced a significant increase of serum ghrelin and a significant decrease of both gastric and hypothalamic ghrelin in group II when compared with group I. The changes in ghrelin level varied with the duration of food restriction. Significant inverse correlation was found between serum ghrelin and each of gastric and hypothalamic ghrelin in group II. A significant decrease of testosterone, FSH and LH were found in food restricted rats compared with controls. The decrease was significantly related to the duration of food restriction. Significant inverse correlation was detected between serum ghrelin and each of the male reproductive hormones in food restricted group II rats. Thus ghrelin could be one of the hormones responsible for the suppression of male reproductive axis in case of negative energy balance.

Protective effect of N-acetylcysteine against carmustine-induced myelotoxicity in rats.

Carmustine (BCNU) is used to treat a variety of tumors, in particular gliomas. However, the success of such treatment is limited by severe myelosuppression. The role of N-acetylcysteine (NAC) in protection against BCNU-induced myelotoxicity is still needed to be explored. The aim of this work is to study the possible protective role of NAC against BCNU-induced myelotoxicity through evaluation of apoptosis, lipid peroxidation, antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase(CAT)) as well as glutathione (GSH) content in bone marrow cells of rats. Administration of BCNU in a single dose (30 mg/kg, i.p.) significantly decreased RBCs, WBCs and platelets counts as well as hemoglobin level. In addition, BCNU produced a significant apoptotic effect as well as a significant lipid peroxidation in bone marrow cells. Pretreatment of animals with NAC (150 mg/kg, i.p.) daily for 5 days significantly ameliorated the changes in oxidant and antioxidant parameters as well as apoptosis induced by BCNU. In addition the pattern of blood parameters was shifted markedly to normal values in animals pretreated with NAC when compared to BCNU-treated group. Conclusively, NAC could have a potential protective effect against BCNU-induced myelotoxicity; an effect that is mainly attributed to the antioxidant property.