Band 26, Heft 1

To understand HIV pathogenesis or development is no simple undertaking and neither is the cell cycle which is highly complex that requires the coordination of multiple events and machinery. It is interesting that these two processes are interrelated, intersect and interact as HIV-1 infection results in cell cycle arrest at the G2 phase which is accompanied by massive CD4 + T cell death. For its own benefit, in an impressive manner and with the overabundance of tactics, HIV maneuvers DNA damage responses and cell cycle check points for viral replication at different stages from infection, to latency and to pathogenesis. Although the cell cycle is the most critical aspect involved in both viral and cellular replication, in this review, our main focus is on recent developments, including our own observations in the field of cell cycle proteins, checkpoints and strategies utilized by the viruses to manipulate these pathways to promote their own replication and survival. We will also discuss the emerging concept of targeting the replication initiation machinery for HIV therapy.

Background: Growing evidences indicate that endogenous oxidants and antioxidant defense interact in a vicious cycle, which plays a critical role in the pathogenesis of cognitive dysfunction. In this study, we examined the effect of N -acetyl cysteine (NAC) against the intracerebroventricular infusion of streptozotocin (ICV STZ)-induced cognitive impairment and mitochondrial oxidative damage in rats. Methods: Male adult Wistar rats were injected with STZ (3 mg/kg) bilaterally through ICV. NAC (50 and 100 mg/kg) was administered for 3 weeks post-surgery. The rats were sacrificed on the 21st day following the last behavioral test, and cytoplasmic fractions of the hippocampus and cortex were prepared for the quantification of acetylcholinesterase, oxidative stress parameter, mitochondrial enzymes, inflammatory mediators and caspase-3 activity. Results: ICV STZ resulted in poor retention of memory in Morris water maze. It also increased the mito-oxidative damage and tumor necrosis factor-α, interleukin 6 and caspase-3 levels in the hippocampus and cortex compared to sham animals. NAC significantly improved memory retention and attenuated oxidative damage parameters, inflammatory markers in STZ-treated rats. Conclusions: The results of the present study strongly indicate the effectiveness of NAC in preventing cognitive impairment as well as mito-oxidative stress and may be considered as a potential agent in the management of cognitive-related disorders.

Background: The inconsistent therapeutic outcome necessitates designing and identifying novel therapeutic interventions for depression. Hence, the present study deals with the investigation of antidepressant-like effects of a novel 5-HT 3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) on chronic unpredictable mild stress (CUMS) induced behavioral and biochemical alterations. Methods: Animals were subjected to different stressors for a period of 28 days. On day 15 after the subsequent stress procedure, mice were administered with (4a) (2 and 4 mg/kg p.o.), escitalopram (10 mg/kg p.o.), or vehicle (10 mL/kg p.o.) until day 28 along with the CUMS. Thereafter, behavioral battery tests like locomotor score, sucrose preference test, forced swim test (FST), tail suspension test (TST), and elevated plus maze (EPM) were performed. Biochemical assays like lipid peroxidation, nitrite levels, reduced glutathione (GSH), catalase, and superoxide dismutase (SOD) were estimated in the mice brain homogenate. Results: (4a) Dose dependently attenuated the behavioral alterations by increasing the sucrose consumption, reducing the immobility time in FST and TST, increasing the open arm number of entries and time in EPM. Furthermore, biochemical alterations were reversed by (4a) as examined by reduced lipid peroxidation and nitrite levels and elevated antioxidant enzyme levels like GSH, catalase and SOD. Conclusions: (4a) exhibits antidepressant potential by reversing the CUMS induced behavioral and biochemical changes in mice.

Background: Cissus quadrangularis L. (Vitaceae) is used as a bonesetter and as an analgesic. However, the bioactive fractions and the pharmacological mechanism of analgesic activity are not clearly known. Hence, this study aimed to characterize the analgesic activity profile of successively extracted fractions of C. quadrangularis and the pharmacological mechanism of analgesic activity in mice. Methods: Dried C. quadrangularis stem was extracted successively with chloroform and methanol. The dried extracts were separately administered to mice intraperitoneally at the doses of 75, 150 and 300 mg/kg. The mice were tested separately in hot plate and tail flick tests. The mechanism of analgesic activity of chloroform extract was explored in the hot plate test at the dose of 300 mg/kg after pretreatment with naloxone, p -chlorophenylalanine methyl ester ( p CPA) and phentolamine. The data were analyzed by one-way analysis of variance followed by Dunnett’s test. Results: Chloroform extract showed significant (p<0.05) analgesic effect at the doses of 75, 150 and 300 mg/kg in hot plate and tail flick tests. Methanol extract showed significant (p<0.05) analgesic effect at the dose of 300 mg/kg in hot plate and tail flick tests. Analgesic activity was not blocked (p<0.05) in the group pretreated with phentolamine but blocked in the groups pretreated with naloxone and p CPA. Conclusions: The chloroform extract was found to be more potent than methanol extract in inducing analgesic effect in mice, and the analgesic activity may be mediated through opioidergic and serotonergic pathways.

Background: Despite of the wide spectrum of alcoholism experimental models, the majority of them are very specialized on the short list of investigated parameters and could not provide reproduction of complex metabolic changes in the rats. The aim of the present study was to estimate whether rats selected by high alcohol preference, allowed free access to 15% alcohol for 150 days, develop simultaneous multilevel disturbances of cell macromolecules structure, metabolism and oxidative/nitrosative stress. Methods: Wistar albino male rats were divided into groups: I – rats selected by preferences to alcohol were used for chronic alcoholism modeling by replacing water with 15% ethanol (150 days), II – control. Contents of amino acids in serum, liver mRNA CYP2E1 and CYP3A2 expression, DNA fragmentation and lipid peroxidation levels, the reduced glutathione content, superoxide dismutase, catalase, iNOS and cNOS activities were evaluated. Results: In serum of ethanol-treated rats contents of aspartic acid, serine, glycine, alanine and valine were decreased whereas contents of histidine, methionine and phenylalanine were increased. Liver CYP2E1, CYP3A2 mRNA expression, DNA fragmentation levels significantly elevated. Level of cNOS in ethanol-treated rat’s hepatocytes was within the normal limits, whereas iNOS activity was raised 1.6 times. Liver pro- and anti-oxidant system alterations were shown. Conclusions: Rats’ chronic 15% alcohol consumption (150 days) led solely to complex metabolomic changes at different levels, which simultaneously characterized cell macromolecules structure, metabolism, and oxidative/nitrosative stress. Rodent model of chronic alcoholism in the proposed modification could be an adequate and reasonably priced tool for further preclinical development and testing of pharmacotherapeutic agents.

Background: The use of traditional medicinal plants to treat various diseases is common in Sub-Saharan African countries, including Cameroon. Millettia macrophylla , one of such plants, was previously found to exhibit estrogenic properties in female Wistar rats. However, its effects on the male reproductive system are unknown. Based on literature evidence that phytoestrogens impair male sexual behavior, we aimed at assessing the effect of the extracts of M. macrophylla stem bark on the male reproductive system of Wistar rats. Materials and methods: We evaluated the effects of the dichloromethane (DCM) and methanol (MeOH) soluble fractions of M. macrophylla stem bark on male rat sexual behavior, as well as androgen-dependent parameters for 60 days. Results: Data showed a significant decrease (p<0.05) in the wiring-touch frequency, mount frequency, intromission frequency, ejaculatory frequency, penile-licking frequency, and computed indices of sexual behavior, throughout the experimental period, as well as a significant increase (p<0.001) in mount, intromission, and ejaculatory latencies as well as post-ejaculatory interval. Moreover, we observed a significant decrease (p<0.05) in the androgen-dependent sexual parameters evaluated. The DCM extract did not induce significant effects on the assessed parameters. Conclusions: These results suggest that long-term exposure to the estrogenic MeOH fraction of M. macrophylla stem bark negatively alters sexual behavior and spermatogenesis.

Background: The aim of this study was to evaluate the cardioprotective effects of kolaviron (KV), a biflavonoid from Garcinia kola seeds, in rats intoxicated with isoproterenol chloride (ISO) while quercetin (QUE) served as standard. Methods: Forty-two male Wistar rats (180–200 g) were randomly divided into seven groups of six rats each. Group 1 served as control; group 2 received ISO (85 mg/kg subcutaneously); groups 3, 4 and 5 received ISO and KV1 [100 mg/kg orally (p.o.)], KV2 (200 mg/kg, p.o.) and QUE (25 mg/kg, p.o.), respectively; and groups 6 and 7 received QUE and KV2, respectively. Results: Administration of ISO caused significant (p<0.05) elevation of serum creatine phosphokinase, lactate dehydrogenase, alkaline phosphatase, alanine aminotransferase and aspartate aminotransferase by 2.2-, 1.9-, 2.1-, 1.9- and 1.7-fold, respectively, relative to controls, with a concomitant decrease in cardiac activities of these enzymes. Administration of ISO led to significant decrease (p<0.05) in the levels of cardiac superoxide dismutase, catalase, glutathione S -transferase, reduced glutathione and increase in malondialdehyde (MDA). Also, ISO-treated rats had significantly higher values of serum total cholesterol, triglycerides and low-density lipoprotein cholesterol relative to controls. Supplementation with KV2 and QUE caused significant elevation of cardiac antioxidant enzymes, normalized the marker enzymes and reduced MDA levels. Conclusions: KV protects against ISO-induced cardiotoxicity in vivo, suggesting its usefulness as a possible chemoprophylactic agent against cardiotoxic drugs.

Background: During the past 2 years, a great deal of evaluation has been accomplished on the cardiovascular (CV) effects of nonsteroidal anti-inflammatory drugs (NSAIDs), nonselective and selective cyclooxygenase-2 inhibitors (COX-2-Is). Clinical trial databases for nonselective and selective COX-2-Is have shown variable effects on CV risk. There is much controversy regarding the CV safety of these selective and nonselective COX inhibitors (COX-Is). This study was therefore conducted to assess and compare the CV risk of COX-Is in arthritic patients over a period of time. Methods: In this prospective comparative study, adult arthritics of either sex who were freshly diagnosed or taking COX-Is for <3 months were included. Patients were grouped into nonselective and selective COX-2-I groups with reference to the treatment they received, whereas arthritics with no history of COX-I treatment were included as controls. CV risk factors like blood pressure (BP), blood sugar level (BSL), lipid profile, and body mass index (BMI) were assessed and compared; the demography of CV risk factors was also studied. Data obtained were analyzed with Student’s t-test using OpenEpi statistical software (Andrew G. Dean and Kevin M. Sullivan, Atlanta, GA, USA). Results: The study clearly revealed that all NSAIDs exhibit potential CV risk; however, selective COX-2-Is were found to exhibit more CV risk. BMI, BP and lipid profile, the potential CV risk factors, showed significant impairment in a selective COX-2-I group: p<0.01, p<0.001 and p<0.05, respectively, vs. baseline and p<0.05 for BMI and triglycerides vs. nonselective COX-Is. Conclusions: This study depicts the impending CV risk of selective COX-2-Is and confirms and reevaluates the results of earlier studies in this regard.

Background: Currently there are no studies on γ-glutamyltransferase (γGT) levels at high altitude or on the relationship between γGT, uric acid and several dysfunctions. The aim of the study was to determine the association between serum γGT and uric acid levels in subjects at high altitude with hemoglobin, glycemia, and lipidic, hepatic and kidney markers. Methods: The present study was performed in 487 subjects aged 30–75 years living at 4100 m of altitude. A venous blood sample was drawn from each subject to measure hemoglobin, glucose, and lipid levels and markers of liver and kidney function. Quartiles for serum γGT and uric acid were calculated and associated with different physiological variables. A p-value <0.05 was considered statistically significant. Results: Serum γGT values were higher in men (38.35± 2.54 IU/L) than in women (30.33±1.76 IU/L) (p<0.01). Similarly, serum uric acid levels were higher in men (5.78± 0.12 mg/dL) than in women (4.29±0.08 mg/dL; p<0.001). Serum γGT levels in the top quartile were associated with higher glycemia, overweight/obesity, increased levels of non-high-density lipoprotein (non-HDL) cholesterol, triglycerides, alanine aminotransferase, alkaline phosphatase, uric acid, creatinine, and hemoglobin. Levels of uric acid in the top quartile were associated with overweight/obesity, elevated non-HDL cholesterol, triglycerides, creatinine, γGT and hemoglobin. Higher arterial blood pressure was associated with high levels of uric acid but not with γGT levels. Conclusions: At high altitude, increased γGT levels were associated with hyperglycemia; increased uric acid levels were associated with overweight/obesity, hemoglobin, dyslipidemia, high blood pressure and kidney disease.

Background: Phyllanthus amarus has a history of use in Ayurvedic medicine for over 2000 years as well as a wide variety of traditional applications and has gained popularity in many continents as a herbal remedy; hence, it is being assessed for its safety potential and anti-inflammatory and analgesic properties in some laboratory animals. Methods: Standard phytochemical methods were used to test for the presence of phytoactive compounds in the plant. Acute toxicity testing was carried out in mice to determine safe doses for the extract. The anti-inflammatory activity of the leaf extract of this plant was assessed using carrageenan-induced and histamine-induced paw edema. The analgesic effect was determined using the acetic acid writhing method as well as formalin test. Results: The extract at 100 and 200 mg/kg body weight reduced significantly, the formation of edema induced by carrageenan and histamine. In the acetic acid-induced writhing model, the extract showed a good analgesic effect characterized by reduction in the number of writhes when compared to the control. The extract caused dose-dependent decrease of licking time in rats injected with 2.5% formalin, signifying its analgesic effect. These results were also comparable to those of ibuprofen, the reference drug used in this study. Conclusions: The plant extract reduced significantly the formation of edema induced by carrageenan and histamine as well as reducing the number of writhes in acetic acid-induced writhing models and dose-dependent decrease of licking time in rats injected with 2.5% formalin. The results have validated the basis for the traditional use of P. amarus as a medicinal plant.

Background: Turmeric ( Curcuma longa ) and ginger ( Zingiber officianale ) are widely used in Asian countries as traditional medicine and food ingredients. In the present study, we have evaluated the gastroprotective activity of turmeric essential oil (TEO) and ginger essential oil (GEO) in rats. Methods: Turmeric and ginger were evaluated for their antiulcer activity against ethanol-induced ulcers in male Wistar rats at different doses: 100, 500 and 1000 mg/kg body weight. Ethanol was used to induce gastric ulcer in Wistar rats. Parameters such as ulcer index, histopathology and levels of antioxidant enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD), catalase and glutathione (GSH) levels were measured to assess the degree of protection produced by the essential oils. Results: TEO and GEO inhibited ulcer by 84.7% and 85.1%, respectively, as seen from the ulcer index. Reduced antioxidant enzymes such as GPx, SOD, catalase and GSH produced by alcohol administration were significantly (p<0.001) increased by simultaneous administration of TEO and GEO. Histopathological examination showed that ethanol-induced lesions such as necrosis, erosion and hemorrhage of the stomach wall were significantly reduced after oral administration of essential oils. Conclusions: Results suggest that TEO and GEO could reduce the gastric ulcer in rat stomach as seen from the ulcer index and histopathology of the stomach. Moreover, oxidative stress produced by ethanol was found to be significantly reduced by TEO and GEO.

Background: Hepatic metabolism of drugs has been rarely studied in children with malnutrition. Caffeine breath test (CBT) has been used to determine the activity of cytochrome P450 1A2 (CYP1A2) enzymes in children. We used the CBT to assess how marasmus and kwashiorkor differentially affect 13 C-caffeine metabolism. Methods: A total of 45 children composed of 15 children per group of malnutrition (marasmus, marasmic-kwashiorkor, and kwashiorkor) were studied during malnutrition and after nutritional recovery. After an overnight fast, patients ingested 3 mg/kg 13 C-caffeine at 0900 h. Duplicate breath samples were collected into an Exetainer bottle at –20, –10, and –1 min and at 15-min intervals for 2 h. The mean cumulative percent dose recovered (CPDR) of 13 C-caffeine in the expired 13 CO 2 was determined over the study period. Results: The CPDR in the expired 13 CO 2 in 2 h significantly increased after nutritional recovery in children with marasmus (from 6.80%±3.00% to 7.67%±2.81%; Student’s t-test, p=0.001), marasmic-kwashiorkor (from 6.61%±2.26% to 7.56%±2.46%, p=0.041), and kwashiorkor (from 6.29%±1.06% to 7.20%±1.80%, p=0.002). When the three groups of malnutrition were compared, there was no significant difference in their mean CPDR in 2 h during malnutrition [p=0.820, analysis of variance (ANOVA)] and after nutritional recovery (p=0.810, ANOVA). Conclusions: Hepatic metabolism of caffeine significantly decreased in children with marasmus, marasmic-kwashiorkor, and kwashiorkor compared to after they had recovered nutritionally. This suggests a decreased CYP1A2 activity in all categories of malnutrition.