Lack of therapeutic improvement of liver fibrosis in rats by dexamethasone in spite of ascites amelioration

Pathophysiology of liver fibrosis (LF) includes hepatic parenchymal cell destruction and connective tissue formation. Although dexamethasone has been used in the liver diseases, there is controversy over the beneficial effects of dexamethasone on LF. Previous studies showed that CCAAT/enhancer binding protein-beta (C/EBPbeta) activation contributes to hepatocyte regeneration and dissolution of fibrosis and that dexamethasone activates C/EBPbeta whereas C/EBPbeta-mediated gene induction by dexamethasone is antagonized by a corepressor. The present study investigated the possible therapeutic effect of dexamethasone for the treatment of LF in rats. We injected rats with multiple doses of dimethylnitrosamine (DMN) for 4 weeks and then used the LF rats to determine whether dexamethasone treatment therapeutically improved liver functions and resolved fibers accumulated in the liver. Dexamethasone (100 microg/kg, po, three times per week for 4 weeks) failed to restore the body weight gain and liver weight decreased by LF. The body weight gain reduced during LF was further decreased by dexamethasone treatment. Animals were subjected to blood biochemical, liver histopathological and immunochemical analyses. Although dexamethasone treatment significantly reduced ascites in LF rats, the plasma albumin and total protein levels decreased in fibrotic rats were not restored. Impaired liver functions during LF including elevated plasma aminotransferases and bilirubin levels along with GSTA2 repression were not recovered by dexamethasone. Dexamethasone failed to decrease the fibrosis score and to eliminate the extracellular matrix and alpha-smooth muscle actin accumulated in the fibrotic liver. The results of the present study showed that dexamethasone ameliorated ascites in LF rats but failed to improve the liver functions and fiber accumulation, and that the possible beneficial effect of dexamethasone might result from anti-inflammatory effect but not from liver improvement.     

Analogs of penfluridol as chemotherapeutic agents with reduced central nervous system activity

Several recent reports have highlighted the feasibility of the use of penfluridol, a well-known antipsychotic agent, as a chemotherapeutic agent. In vivo experiments have confirmed the cytotoxic activity of penfluridol in triple-negative breast cancer model, lung cancer model, and further studies have been proposed to assess its anticancer activity and viability for the treatment of glioblastomas. However, penfluridol anticancer activity was observed at a dosage significantly higher than that administered in antipsychotic therapy, thus raising the concern for the potential onset of CNS side effects in patients undergoing intensive pharmacological treatment. In this study, we evaluate the potential CNS toxicity of penfluridol side by side with a set of analogs.     

Site-specific effects of apolipoprotein E expression on diet-induced obesity and white adipose tissue metabolic activation

Apolipoprotein E (APOE) has been strongly implicated in the development of diet induced obesity. In the present study, we investigated the contribution of brain and peripherally expressed human apolipoprotein E3 (APOE3), the most common human isoform, to diet induced obesity.In our studies APOE3 knock-in (Apoe3^knock-in), Apoe-deficient (apoe^?/?) and brain-specific expressing APOE3 (Apoe3^brain) mice were fed western-type diet for 12 week and biochemical analyses were performed. Moreover, AAV-mediated gene transfer of APOE3 to apoe^?/? mice was employed, as a means to achieve APOE3 expression selectively in periphery, since peripherally expressed APOE does not cross blood brain barrier (BBB) or blood-cerebrospinal fluid barrier (BCSFB).Our data suggest a bimodal role of APOE3 in visceral white adipose tissue (WAT) mitochondrial metabolic activation that is highly dependent on its site of expression and independent of postprandial dietary lipid deposition.Our findings indicate that brain APOE3 expression is associated with a potent inhibition of visceral WAT mitochondrial oxidative phosphorylation, leading to significantly reduced substrate oxidation, increased fat accumulation and obesity. In contrast, peripherally expressed APOE3 is associated with a notable shift of substrate oxidation towards non-shivering thermogenesis in visceral WAT mitochondria, leading to resistance to obesity.     

Aspartate modulates the circadian patterns of a few biochemical variables in Wistar rats

D-aspartate was used to demonstrate possible sources of excitatory input to the suprachiasmatic nucleus (SCN) in rats. Aspartate (50 mg/kg bodyweight) was orally administrated chronically for 60 days to Wistar rats and 24 h rhythmic patterns of glucose, cholesterol, total protein and aspartate transaminase (AST) were studied under light - dark (LD 12:12 h) cycle. Our results showed acrophase advances in glucose and delays in cholesterol and AST rhythms. Increased mesor and altered amplitude values were found in all rhythms; aspartate levels in the brain were found to be significantly increased in aspartate treated animals. We hypothesised that the altered biochemical rhythms in aspartate treated rats could be due to (1) modulation of neurotransmission in SCN, (2) behavioural rhythms and (3) feeding rhythms.     

Combined metadoxine and garlic oil treatment efficaciously abrogates alcoholic steatosis and CYP2E1 induction in rat liver with restoration of AMPK activity

Alcoholic steatosis is the earliest and most common response to heavy alcohol intake, and may precede more severe forms of liver injury. Accumulation of fat, largely triglyceride, in hepatocytes results from the inhibition of fatty acid oxidation and excessive oxidative stress involving CYP2E1. This study evaluated the therapeutic effects of metadoxine, garlic oil or their combination on alcoholic steatosis. Feeding rats an alcohol-containing diet for 4 weeks elicited an increase in hepatic triglyceride content and induced CYP2E1. The concurrent administration of metadoxine and garlic oil (MG) to rats during the last week of the diet feeding efficaciously abrogated both fat accumulation and CYP2E1 induction as compared to the individual treatment at higher doses. Histopathology confirmed the ability of MG combination to inhibit lipid accumulation. Blood biochemistry verified improvement of liver function in rats treated with MG. Alcohol administration resulted in a decrease in AMP-activated protein kinase-alpha (AMPKalpha) phosphorylation, which was restored by MG treatments. Recovery of AMPK activity by MG was supported by an increase in acetyl-CoA carboxylase phosphorylation. Hepatic fatty acid synthase (FAS) expression was markedly decreased after alcohol consumption, which correlated with a decrease in AMPK activity and a commensurate increase in lipid content. Combined MG treatments caused restoration of the FAS level. These results demonstrate that the combination of MG effectively treats alcoholic steatosis with CYP2E1 inhibition, which may be associated with the recovery of AMPK activity, promising that the combination therapy may constitute an advance in the development of clinical candidates for alcoholic steatosis.     

Effects of subacute treatment of ethylene glycol on serum marker enzymes and erythrocyte and tissue antioxidant defense systems and lipid peroxidation in rats

The present study was aimed to investigate the effects of ethylene glycol (EG) on serum marker enzymes, antioxidant defense systems and lipid peroxidation concentration (malondialdehyde=MDA) in various tissues of rats exposed to ethylene glycol. EG (1.25% or 2.5%) in drinking water was administered orally to rats (Sprague-Dawley albino) ad libitum for 21 days continuously. EG treatments caused different effects on the serum marker enzymes, antioxidant defense system and MDA content in various tissues of the treatment groups as compared with the controls. EG also caused a significant increase in the serum marker enzyme activities with 2.5% dosage whereas, no changes were not observed with 1.25% dosage of EG treatment. Lipid peroxidation significantly increased in all the tissues except for in the heart and stomach of rats treated with both dosages of EG. Also, the antioxidative systems were also seriously affected by EG. For example, SOD significantly decreased in the liver treated with both dosages whereas, SOD activity in the erythrocytes, kidney, heart and stomach were significantly increased and not changed in the brain with two dosages of EG. Also, while CAT activity significantly decreased in the erythrocytes, liver and kidney, the activity in the stomach significantly increased, but did not change in the brain and heart with two doses of EG. GR activity significantly decreased in the erythrocytes treated with both dosages of EG whereas GR was not affected in other tissues by EG treatment. GST activity significantly elevated in the heart and brain but did not change in the other tissues of rats treated with both dosages of EG. Meanwhile, GSH depletion in the erythrocytes of rats treated with 2.5% dosage of EG was found to be significant whereas, the level of GSH in the brain was significantly increased treated with both the dosages of EG. The observations presented led us to conclude that the administration of subacute EG promotes lipid peroxidatin content, elevates tissue damage serum marker enzymes and changes in the antioxidative systems in rats. These data, along with the determined changes suggest that EG produced substantial systemic organ toxicity in the erythrocyte, liver, brain, heart kidney and stomach during the period of a 21-day subacute exposure.     

Evaluation of blood-brain barrier penetration and examination of binding to human serum albumin of 7-O-arylpiperazinylcoumarins as potential antipsychotic agents

The delivery of drugs to the brain is complicated by the multiple factors including low blood–brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT_1A and 5-HT_2A with particular analysis of the requirements for the CNS chemotherapeutics. The binding constants to human serum albumin (HSA) were determined at physiological pH using fluorescence spectroscopy, and then their mode of action was explained by analysis of theoretical HSA complexes. Dynamic simulation of systems allowed for reliable evaluation of the interaction strength. The analyzed coumarins were able to pass BBB, and they present good drug likeness properties. They showed high affinities to HSA (log K_Q = 5.3–6.0 which corresponds to −8.12 to −7.15 kcalmol⁻¹ of Gibbs free energy). The changes of the emission intensity upon binding to HSA were scrutinized showing the different mode of action for 4-phenylpiperazinylcoumarins. The values of computed Gibbs free energy and determined on the basis of experimentally obtained binding constants log K_Q coincide suggesting a good quality of the theoretical model. Overall the 8-acetyl-7-O-arylpiperazinyl-4-methylcoumarin derivatives represent valuable lead compounds to be further tested in various preclinical assays as a possible chemotherapeutics against CNS diseases. Studied coumarins can be metabolized by cytochrome P450 to aldehydes and hydroxy derivatives. The existence of other binding sites inside HSA than Sudlow’s site 1 was postulated. The longer aliphatic linker between coumarin and piperazine moieties favored binding to HSA in other than Sudlow site 1 pocket.     

AT2R − 1332 G:A polymorphism and its interaction with AT1R 1166 A:C,ACE I/D and MMP-9 − 1562 C:T polymorphisms: Risk factors for susceptibility to preeclampsia

The possible association of angiotensin type 2 receptor (AT2R) − 1332 G:A polymorphism with susceptibility to preeclampsia was studied in 252 women consisted of 155 women with preeclampsia and 97 healthy pregnant women. Also, the interaction of this polymorphism with angiotensin type 1 receptor (AT1R) 1166 A:C, angiotensin converting enzyme insertion/deletion (ACE I/D) and also with matrix metalloproteinase-9 (MMP-9) − 1562 C:T polymorphism was investigated. The AT2R − 1332 G:A polymorphism was detected using PCR–RFLP method. Significantly higher frequencies of GG+GA genotype and G allele of AT2R were observed in mild (80.2%, p = 0.003 and 47.5%, p = 0.012, respectively) and severe (77.8%, p = 0.034 and 48.1%, p = 0.026, respectively) preeclampsia compared to controls (60.8% and 35.1%, respectively). The presence of G allele was associated with 1.69-fold increased risk of preeclampsia (p = 0.005). In severe preeclamptic women, systolic and diastolic blood pressures in the presence of GG+GA genotype were significantly higher compared to those in the presence of AA genotype. The concomitant presence of both alleles of AT2R G and AT1R C was associated with 1.3 times increased risk of mild preeclampsia (p = 0.03). There was an interaction between AT2R G and ACE D alleles that significantly increased the risk of mild and severe preeclampsia by 1.38- and 1.3-fold, respectively. Also, interaction between MMP-9 T and AT2R G alleles increased the risk of severe preeclampsia 1.39-fold (p = 0.028). Our study demonstrated that the G allele of AT2R − 1332 G:A polymorphism is associated with an increased risk of preeclampsia. Also, epistatic interaction of G allele and each allele of the AT1R C, ACE D and MMP-9 T was associated with the risk of preeclampsia. Our findings suggest that the renin–angiotensin system (RAS) variants and gene–gene interactions affect the risk of preeclampsia.     

皂荚皂苷对麻醉犬心肌缺血的影响

为了研究皂荚皂苷对犬急性心肌缺血的防治作用,本文采用麻醉开胸犬,结扎冠状动脉左前降支(LAD),产生急性心肌缺血模型,测定犬冠状动脉血流量(CABF)和心外膜电图(EECG),心肌梗死面积及血清中天冬氨酸氨基转移酶(AST)、肌酸激酶(CK)、乳酸脱氢酶(LDH)、超氧化物歧化酶(SOD)和丙二醛(MDA)的变化。结果显示皂荚皂苷24 mg/kg1、2 mg/kg6、mg/kg三个给药剂量组经十二指肠给药后,都有不同程度增加冠状动脉血流量,减轻心肌缺血程度,缩小心肌梗死面积,降低血清中AST、CK、LDH活性,并可增加血清中SOD活性及降低血清中MDA含量。表明皂荚皂苷对结扎犬冠脉造成的急性心肌缺血有明显的防治作用。     

Identifying frankincense impact by biochemical analysis and histological examination on rats

Frankincense (Gum Olibanum), made from resins of Burseraceae family, grows in Somalia, India and Yemen. Many years ago the oldest doctors used this plant for treatment of many diseases. This study identifies frankincense impact by biochemical analysis and histological examination on rats. In this study, forty male Wister Albino rats weighing 70–100 g were maintained in clean cages. The rats were divided into 2 groups, each group contained 20 rats. Frankincense extract was prepared by heating distilled water (400 ml) to 80 °C and soaking 20 g of herbs for about 60 min. After cooking at room temperature the dose was given orally through special drinking bottles daily. The first group acted as control drinking water. The second group served as treated group and was given frankincense in the drinking water during the whole duration of the experiment. After 15 and 30 days of treatment, the rats were anesthetized with ether, and blood was collected from the livers and kidneys; some biochemical analyses were performed including aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP) and non-bilirubin, urea, uric acid, and creatinine. Rats were killed by cervical decapitation of livers and kidneys. Each group was divided into 2 parts. The first part was used for the determination of glutathione (GSH), glucose 6 phosphate dehydrogenase (G6PDH), xanthine oxidase (XO), malonyldealdehyde (MDA), nitric oxide (NO), and xanthine oxidase (XO). The second part of livers and kidneys was kept in formalin solution (10%) and stained by Hematoxylin and Eosin (H & E), to be used for histological examination. I demonstrated in the biochemical analysis in the serum, tissue and histological examination, different impact between group (B) and group (A), and that frankincense is not absolutely safe and that precautions must be taken during it’s us as a traditional medicine and that increase the awareness with safety and health hazards of many other traditional medicine is critically needed.