Genotoxic impact of di-n-butyl phthalate on DNA: A comparative study of three generations in the neuronal tissue of Wistar rats.

Di-n-butyl phthalate (DBP), one of the plasticizers, is considered a ubiquitous environmental contaminant due to its widespread application in personal-care products and serves as a raw material in many industries for the generation of many plastic products. Several scientific investigations have shown that DBP caused embryotoxicity and cognitive impairments. However, there is less understanding of the genotoxic potential of DBP in neuronal tissue when exposure happens continuously for several generations. The present study was undertaken to investigate the impact of DBP on the nucleic acids of neuronal tissue in one-month-old rats by performing a comet assay and biochemical analyses. By oral gavage, the parental generation (F0) was administered DBP (500 mg/kg/day) during gestation (GD6-20) and lactation, and exposures were continued for three consecutive generations until the pups were grown to one-month-old. The oxidative stress assessments carried out in discrete brain regions isolated from one-month-old rats (F1-F3) following DBP exposure indicated significant inhibition in the levels of antioxidant enzymes (superoxide dismutase and catalase) while oxidant status (malondialdehyde) was elevated significantly. The extent of DNA damage using the comet assay, as measured by the olive moment, tail DNA percentage and tail length, was greater in DBP-treated rats compared with the control group, but RNA/DNA content decreased significantly. The results of this study suggested a strong link between oxidative stress and genetic integrity in the neuronal tissue of rats exposed to DBP generationally. To summarise, DBP exposure during pregnancy caused oxidative stress, which resulted in genetic instability in specific discrete brain regions of the third generation.

Publisher Correction: Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Synthesis of Saccharumoside-B analogue with potential of antiproliferative and pro-apoptotic activities.

A new series of phenolic glycoside esters, saccharumoside-B and its analogs (9b-9n, 10) have been synthesized by the Koenigs-Knorr reaction. Antiproliferative activities of the compounds (9b-9n, 10) were evaluated on various cancer cell lines including, MCF-7 breast, HL-60 leukemia, MIA PaCa-2 pancreatic, DU145 prostate, HeLa cervical and CaCo-2 colon, as well as normal human MCF10A mammary epithelial and human peripheral blood mononuclear cells (PBMC) by MTT assay. Compounds (9b-9n, 10) exhibited considerable antiproliferative effects against cancer cells with IC50 range of 4.43 ± 0.35 to 49.63 ± 3.59 µM, but they are less cytotoxic on normal cells (IC50 > 100 µM). Among all the compounds, 9f showed substantial antiproliferative activity against MCF-7 and HL-60 cells with IC50 of 6.13 ± 0.64 and 4.43 ± 0.35, respectively. Further mechanistic studies of 9f were carried out on MCF-7 and HL-60 cell lines. 9f caused arrest of cell cycle of MCF-7 and HL-60 cells at G0/G1 phase. Apoptotic population elevation, mitochondrial membrane potential loss, increase of cytosolic cytochrome c and Bax levels, decrease of Bcl-2 levels and enhanced caspases-9 and -3 activities were observed in 9f-treated MCF-7 and HL-60 cells. These results demonstrate anticancer and apoptosis-inducing potentials of 9f in MCF-7 and HL-60 cells via intrinsic pathway.

5-Lipoxygenase and cyclooxygenase inhibitory dammarane triterpenoid 1 from Borassus flabellifer seed coat inhibits tumor necrosis factor-α secretion in LPSInduced THP-1 human monocytes and induces apoptosis in MIA PaCa-2 pancreatic cancer cells.

Phospholipase A2 (PLA2), Cyclooxygenase (COX) and 5-Lipoxygenase (5-LOX) are arachidonic acid metabolizing enzymes and their inhibitors have been developed as therapeutic molecules for cancer and inflammation related disorders. In the present study, PLA2, COX 1&2 and 5-LOX inhibitory studies of Borassus flabellifer seed coat extract were carried out and substantial 5-LOX inhibitory activity was found. Dammarane triterpenoid 1 (Dammara-20,23-diene-3,25-diol) was isolated according to 5-LOX activity guided isolation, and screened for COX (1 & 2) inhibitory activities. Dammarane triterpenoid 1 inhibited carrageenan-induced rat paw edema and TNF-α secretion levels in lipopolysaccharide (LPS)-induced THP-1 human monocytes. Anticancer activity studies demonstrated the antiproliferative effect of dammarane triterpenoid 1 on various cancer cell lines including MIA PaCa-2 pancreatic, DU145 prostate, HL-60 leukemia and Caco-2 colon cancers. Dammarane triterpenoid 1 showed good antiproliferative activity on MIA PaCa-2 pancreatic cancer cell line with IC50 of 12.36±0.33 µM, among other tested cell lines. Apoptosis inducing activity of dammarane triterpenoid 1 was confirmed based on increased sub-G0 phase cell population in cell cycle analysis, loss of mitochondrian membrane potential, elevated levels of cytochrome c, nuclear morphological changes and DNA fragmentation in MIA PaCa-2 pancreatic cancer cells. Therefore, dammarane triterpenoid skeleton may raise the hope of developing novel anti-inflammatory and anticancer drugs in the future.

A Saudi Patient with an Interstitial Deletion of Short Arm of Chromosome 3 (p13 to p21) and its Association with Joubert's Syndrome Features.

We report a case of 4 weeks old girl with a de novo interstitial deletion of the short arm of chromosome 3 (p13-p21) and clinical findings typical of proximal 3p deletion together with heart defects, choanal atresia, ear anomalies, central nervous system anomalies, renal anomalies and associated Joubert's syndrome (JS). Family history is unremarkable and parenteral chromosomes were normal. The clinical manifestations of the patient are compared with those of 11 patients previously described with a proximal 3p deletion. The additional JS features associated with this syndrome were described. This is the first case report in English literature describing 3p deletion associated with additional JS features.

Influence of fluoride on streptozotocin induced diabetic nephrotoxicity in mice: protective role of Asian ginseng (Panax ginseng) & banaba (Lagerstroemia speciosa) on mitochondrial oxidative stress.

BACKGROUND & OBJECTIVES: Chronic fluoride intoxication through drinking water is a serious health problem. Patients with diabetes are known to have impaired renal function and elimination of fluoride from the body is mainly done through kidney. Fluoride toxicity in diabetes patients may aggravate complications. In this study, the influence of fluoride was assessed on streptozotocin (STZ) induced diabetes in mice as also the efficacy/protective effective of oral supplementation of ginseng (GE) and banaba leaf extracts (BLE). METHODS: The efficacy of plant extracts, GE and BLE at doses of 50, 150, 250 mg/kg b.w./day alone and in combination, was tested for a period of 15 days on fluoride treated STZ induced diabetic animals. RESULTS: Fluoride exposure to mice with STZ-induced diabetes produced significant changes in OSI (organo-somatic index), fluoride content, blood glucose, urea, serum creatinine and oxidative stress indices in kidney tissues with evident histological alterations. Among the antioxidant treatments, combination therapy of GE and BLE at 150 mg/kg b.w. significantly normalized the impaired biochemical variables in kidney tissues of fluoride toxicated diabetic mice. INTERPRETATIONS & CONCLUSIONS: High fluoride uptake was found to be diabetogenic and further aggravated the renal oxidative damage and thereby the toxicity in mice with STZ induced diabetes mice. GE and BLE exposure individually or in combination at a dose of 150 mg/kg b.w./day for 15 days exhibited protective effects on fluoride toxicated STZ induced nephrotoxicity in mice.

Neuroprotective Actions of Clinoptilolite and Ethylenediaminetetraacetic Acid Against Lead-induced Toxicity in Mice Mus musculus.

OBJECTIVES: Oxidative stress is considered as a possible molecular mechanism involved in lead (Pb(2+)) neurotoxicity. Very few studies have been investigated on the occurrence of oxidative stress in developing animals due to Pb(2+) exposure. Considering the vulnerability of the developing brain to Pb(2+), this study was carried out to investigate the effects of Pb(2+) exposure in brain regions especially on antioxidant enzyme activities along with ameliorative effects of ethylenediaminetetraacetic acid (EDTA) and clinoptilolite. METHODS: Three-week old developing Swiss mice Mus musculus were intraperitoneally administered with Pb(2+) acetate in water (w/v) (100 mg/kg body weight/day) for 21 days and control group was given distilled water. Further Pb(2+)-toxicated mice were made into two subgroups and separately supplemented with EDTA and clinoptilolite (100 mg/kg body weight) for 2 weeks. RESULTS: In Pb(2+)-exposed mice, in addition to increased lipid peroxidation, the activity levels of catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione (GSH) found to decrease in all regions of brain indicating, existence of severe oxidative stress due to decreased antioxidant function. Treatment of Pb(2+)-exposed mice with EDTA and clinoptilolite lowered the lipid peroxidation (LPO) levels revealing their antioxidant potential to prevent oxidative stress. Similarly their administration led to recover the level of catalase, SOD, and GPx enzymes affected during Pb(2+) toxicity in different regions of brain. CONCLUSIONS: The protection of brain tissue against Pb(2+)-induced toxicity by clinoptilolite and EDTA in the present experiment might be due to their ability to react faster with peroxyl radicals there by reducing the severity of biochemical variable indicative of oxidative damage. Thus, the results of present study indicate the neuroprotective potential of clinoptilolite and EDTA against Pb(2+) toxicity.

Cold stress offered modulation on chlorpyrifos toxicity in aging rat central nervous system.

The adverse effects produced by chlorpyrifos (CPF) or cold stress alone in humans and animals are well documented, but there is no information available relating to the consequences of their co- exposure in an age-related manner. In this study, effects of sublethal doses of CPF were carried out in vivo, for 48 h to assess the biochemical perturbations in relation to interactions with cold stress (15°C and 20°C) in different age group rat CNS. A positive interaction of CPF with age of animal and cold exposure was observed resulting in marked decrease in the activity levels of AChE (P<0.05), ChAT (P<0.05), Na(+), K(+)-ATPase (P<0.05), Ca(2+)-ATPase (P<0.05), and Mg(2+)-ATPase (P<0.05). The ANOVA and posthoc analysis showed that regulatory enzymes decreased significantly (P<0.05) on CPF exposure. Overall, the effect of co-exposure was appreciably different from either of the exposures. Synergistic interaction of CPF and cold stress at 15°C showed higher inhibition in comparison with CPF and cold stress alone and together at 20°C. Further, this study reveals that young animals are significantly vulnerable and sensitive than adults.

Chronic fluoride toxicity and myocardial damage: antioxidant offered protection in second generation rats.

This experiment was designed to investigate the extent of peroxidative changes and histological alterations in the myocardium of rats exposed to high fluoride for two generations, in addition to ameliorative role of selenium and vitamin E on the above indices. Adult albino Wistar rats were given fluoride through drinking water (200 ppm F) and maintained subsequently for two generations, while they were exposed to fluoride throughout the experiment. Fluoride treatment significantly increased the lipid peroxidation and decreased the activity of antioxidant enzymes, viz., catalase, superoxide dismutase, and glutathione level in auricle and ventricle regions of the heart. Decreased feed and water consumption, organ somatic index and marginal drop in body growth rate were observed. Decreased antioxidant enzymes and increased malondialdehyde levels might be related to oxidative damage that occurs variably in the myocardium of rats. Biochemical changes were supported by the histological observations, which also revealed that chronic exposure to fluoride causes damage to the myocardium. Results of this study can be taken as an index of cardio-toxicity in rats exposed to water fluoridation. Further, oral supplementation of selenium and vitamin E not only inhibited oxidative stress but also enhanced the activities of antioxidant enzymes. Administration of antioxidants during fluoride exposure significantly overcame cardiac fluoride toxicity and therefore may be a therapeutic strategy for fluorotic victims.

Urinary bladder perforation in a premature infant with Down syndrome.

Urinary bladder perforation due to bladder catheterization in neonates is a rare iatrogenic complication. It has been reported secondary to various causes and a variety of surgical settings in neonates. A case of urinary bladder perforation due to catheterization in a premature baby with Down syndrome, who presented with progressive renal failure and mild-to-moderate ascites, is reported. Urinary bladder perforation should be considered in a case of neonatal ascites with renal failure, which is unexplainable by other causes. We recommend that bladder catheterization in a baby with Down syndrome, whose urinary bladder may be at an increased risk for perforation as part of their generalized hypotonia, should be performed cautiously. To our knowledge, this is the first case report of bladder perforation due to urinary bladder catheterization in a case of Down syndrome.