Protective mechanisms of coenzyme-Q10 may involve up-regulation of testicular P-glycoprotein in doxorubicin-induced toxicity

The anticancer drug; doxorubicin (DOX), causes testicular toxicity as an adverse effect. P-glycoprotein (P-gp) is a multidrug resistance efflux transporter expressed in blood-testis barrier, which extrudes DOX from the testis. We investigated whether DOX-induced gonadal injury could be prevented by the use of antioxidant; coenzyme-Q10 (CoQ10). The involvement of P-gp expression, as a possible protective mechanism, was also investigated. CoQ10 was administered orally for 8 days, and DOX toxicity was induced via a single i.p. dose of 15 mg/kg at day 4. Concomitant administration of CoQ10 with DOX significantly restored testicular oxidative stress parameters and the distorted histopathological picture, reduced the up-regulation of caspase 3 caused by DOX, and increased P-gp expression. We show for the first time that CoQ10 up-regulates P-gp as a novel mechanism for gonadal protection. In conclusion, CoQ10 protects against DOX-induced testicular toxicity in rats via ameliorating oxidative stress, reducing apoptosis and up-regulating testicular P-gp.     

Combined effects of oxytetracycline and Pb on earthworm Eisenia fetida

Combined effects of oxytetracycline (OTC) and Pb on lysosomal membrane stability and coelomocyte apoptosis of earthworm were studied in the paper. Compared with control, the lysosomal membrane stability decreased and coelomocyte apoptosis increased in the treatments of single OTC and Pb contamination. As for compound pollution, combined effect of (5 mg/kg OTC + 50 mg/kg Pb) treatment on earthworm lysosomal was synergistic (except 28 d). However, it was antagonistic at higher concentration of (10 mg/kg OTC + 50 mg/kg Pb) and (20 mg/kg OTC + 50 mg/kg Pb) treatment. In addition, coelomocyte apoptosis of earthworm decreased significantly compared with single OTC, indicating an antagonistic reaction. And joint toxicity of OTC and Pb decreased significantly with the increasing OTC concentration.     

Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: Role of oxidative stress and caspase-3

Cadmium (Cd) is an environmental and industrial pollutant that can induce a broad spectrum of toxicological effects that affect various organs in humans and experimental animals. This study aims to investigate the effect of betaine supplementation on cadmium-induced oxidative impairment in rat kidney. The animals were divided into four groups (n = 10 per group): control, cadmium, betaine and betaine + cadmium (1) saline control group; (2) cadmium group in which cadmium chloride (CdCl₂) was given orally at a daily dose of 5 mg/kg body weight for four weeks; (3) betaine group, in which betaine was given to rats at a dose of 250 mg/kg/day, orally via gavage for six weeks; (4) cadmium + betaine group in which betaine was given at a dose of 250 mg/kg/day, orally via gavage for two weeks prior to cadmium administration and concurrently during cadmium administration for four weeks. Cadmium nephrotoxicity was indicated by elevated blood urea nitrogen (BUN) and serum creatinine levels. Kidneys from cadmium-treated rats showed an increase in lipid peroxidation measured as thiobarbituric acid-reactive substances (TBARS) concentration and reductions in total antioxidant status (TAS), reduced glutathione (GSH) content, glutathione peroxidase (GSH-Px) activity, superoxide dismutase concentration (SOD) and catalase activity. Caspase-3 activity, a marker of DNA damage was also elevated in renal tissues of cadmium-treated rats. Pre-treatment of rats with betaine substantially attenuated the increase in BUN and serum creatinine levels. Betaine also inhibited the increase in TBARS concentration and reversed the cadmium-induced depletion in total antioxidant status, GSH, GSH-Px, SOD and catalase concentrations in renal tissues. Renal caspase-3 activity was also reduced with betaine supplementation. These data emphasize the importance of oxidative stress and caspase signaling cascade in cadmium nephrotoxicity and suggest that betaine pretreatment reduces severity of cadmium nephrotoxicity probably via antioxidant action and suppression of apoptosis.     

Studies on the effect of sodium arsenate on the enzymes of carbohydrate metabolism,brush border membrane,and oxidative stress in the rat kidney

Arsenic is an environmental pollutant and its contamination in drinking water poses serious world wide environmental health threats. It produces multiple adverse effects in various tissues, including the kidney. However, biochemical mechanism and renal response to its toxic insult are not completely elucidated. We hypothesized that sodium arsenate (ARS) induces oxidative stress and alters the structure and metabolic functions of kidney. Male Wistar rats were administered ARS (10 mg/kg body weight/day), intraperitoneally daily for 10 days. ARS administration increased blood urea nitrogen, serum creatinine, cholesterol, glucose, and phospholipids but decreased inorganic phosphate, indicating kidney toxicity. The activity of brush border membrane (BBM) enzymes significantly lowered in both cortex and medulla. Activity of hexokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenases, and NADP-malic enzyme significantly increased whereas malate dehydrogenase, glucose-6-phosphatase, and fructose 1,6 bis phosphatase decreased by ARS exposure. The activity of superoxide dismutase, GSH-peroxidase, and catalase were selectively altered in renal tissues along with an increase in lipid peroxidation. The present results indicated that ARS induced oxidative stress caused severe renal damage that resulted in altered levels of carbohydrate metabolism and BBM enzymes.     

Estrogen receptors are involved in polychlorinated biphenyl-induced apoptosis on mouse spermatocyte GC-2 cell line

Polychlorinated biphenyls (PCBs) are widespread persistent environmental contaminants which have been shown to have reproductive toxicity and to disturb spermatogenesis. But the precise mechanism is not clear. A mouse pachytene spermatocyte-derived cell line, GC-2 cells were used in the present study to investigate the toxic effect of PCBs (Aroclor 1254) and explore the underlying molecular mechanism. Results showed that Aroclor 1254 inhibited cell proliferation, caused the arrest of cells in G0/G1 phase and induced apoptosis which might be partly explained by the decreased expression of Bcl-2 and cell cycle regulator cyclin D1 together with the activation of caspase-3. Besides, the treatment of Aroclor 1254 decreased the protein expression of estrogen receptor (ER)-α while increasing that of ERβ. Then the administration of selective ERα agonist PPT partly reversed Aroclor 1254-induced alteration in Bcl-2, caspase-3 and cyclin D1 protein expression while selective ERβ agonist DPN accelerated it. These results suggest that Aroclor 1254, working through ERα and ERβ, interferes with the expression of proteins involved in the balance between cellular apoptosis and proliferation.     

Glutaminase1 heterozygous mice show enhanced trace fear conditioning and Arc/Arg3.1 expression in hippocampus and cingulate cortex

Mice heterozygous for a mutation in the glutaminase (GLS1) gene (GLS1 HZ mice), with reduced glutamate recycling and release, display reduced hippocampal function as well as memory of contextual cues in a delay fear conditioning (FC) paradigm. Here, we asked whether this deficit reflects an inability to process contextual information or a selective alteration in salience attribution. In addition, we asked whether baseline and activity-induced hippocampal activity were diminished in GLS1 HZ mice. For this purpose, we manipulated the relative salience of the conditioned stimulus (CS) and contextual cues in FC tasks, and examined gene expression of the immediate early gene Arc (Arc/Arg3.1) in hippocampus and anterior cingulate cortex (ACC) following trace FC (tFC). The results indicate that GLS1 HZ mice succeed in processing contextual information when the salient CS is absent or less predictive. In addition, in the hippocampus-dependent tFC paradigm GLS1 HZ mice display enhanced CS learning. Furthermore, while baseline arc activation was reduced in GLS1 HZ mice in the hippocampus, in line with previous fMRI findings, it was enhanced in the hippocampus and anterior cingulate cortex following tFC. These findings suggest that GLS1 HZ mice have a pro-cognitive profile in the tFC paradigm, and this phenotype involves activation of both hippocampus and ACC.Taken together with previous work on the GLS1 HZ mouse, this study sheds light on the importance of glutamate transmission to memory processes that require the allocation of attentional resources, and extends our understanding of the underpinnings of attention deficits in SZ.     

Impact of infliximab therapeutic drug level monitoring on outcomes of patients with inflammatory bowel disease: A real-world experience from a Middle Eastern cohort

Background and study aimTherapeutic drug monitoring (TDM) through measurement of infliximab (IFX) trough levels and antibodies to infliximab (ATI) is performed to guide IFX intensification strategies and improve its efficacy. We conducted this study to explore the relationship between clinical and endoscopic/radiological remission and IFX and ATI levels in patients with inflammatory bowel disease (IBD) treated with IFX and to evaluate the appropriateness of treatment decision post TDM.Patients and methodsThis was a cross-sectional study of a cohort of adult patients with IBD. Serum IFX trough concentrations and ATI were measured.ResultsA total of 129 patients [104] with ulcerative colitis (UC) and 25 with Crohn’s disease (CD)] were included in this study, of whom 61.2% were men. The mean disease duration was 6.7 years, and 72% of patients with UC had extensive colitis. The mean serum IFX trough level was 4.1 µg/mL; the IFX trough levels were subtherapeutic in 75 patients (58%), therapeutic in 37 patients (29%), and supratherapeutic in 17 patients (13%). Positivity to ATI was found in 16 patients (12.4%). Only 43 patients (33.3%) underwent an appropriate change in therapy after TDM, patients with penetrating CD disease had low IFX levels and higher C-reactive protein levels at 12 months before TDM.ConclusionsPatients with IBD with therapeutic IFX levels tend to have increased endoscopic/radiological remission rates. However, an appropriate change in management based on TDM was absent in the majority of patients, potentially reflecting the need to have a dashboard to support and guide clinicians in decision-making.     

The analysis of cell-free DNA concentrations and integrity in serum of initial and treated of lymphoma patients

ObjectiveTo evaluate cell-free DNA (cfDNA) in plasma as a promising biomarker for lymphoma, altered levels of cfDNA and its association with clinical parameters are investigated in patients suffered from lymphomas.MethodsPeripheral blood specimens were collected from 60 patients with lymphoma during initial diagnosis and those of another 107 patients with lymphoma during treated stage were also collected, 93 healthy volunteers were selected as control group. Quantitative PCR was used to detect cfDNA level in each group, cfDNA level in different groups was analyzed to understand its relationship with lymphoma patients' clinical features. After correlation analysis between cfDNA and clinical characteristics, Receiver operator characteristic curve was performed to analyze sensitivity and specificity of cfDNA and LDH.ResultscfDNA concentration and integrity in initial stage of lymphoma patients were significantly higher than those in treated stage, and cfDNA concentration in treated phase was significantly higher than cfDNA concentration in control group. There was no significant difference in cfDNA integrity at treated stage compared with control group. There was no significant correlation between patient's age, gender, extranodal invasion and lymphoma pathological type and cfDNA concentration and integrity; In contrast, there was a significant correlation between ECOG score, LDH content, Ann Arbor stage, IPI, B-symptoms, Ki-67 expression and radiotherapy and cfDNA concentration and integrity, both at the time of initial diagnosis and treated stage. cfDNA concentration detection is an optimal diagnostic indicator, followed by cfDNA integrity detection, the sensitivity and specificity of both are superior to the traditional LDH detection.ConclusioncfDNA level is significantly increased in lymphomas patient plasma and may help lymphoma screening. cfDNA level may serve as a potential indicator of lymphomas treatment efficacy.     

Regulation of alternative splicing of tau exon 10

The neuronal microtubule-associated protein tau is abnormally hyperphosphorylated and aggregated into neurofibrillary tangles in the brains of individuals with Alzheimer’s disease and related neurodegenerative disorders. The adult human brain expresses six isoforms of tau generated by alternative splicing of exons 2, 3, and 10 of its pre-mRNA. Exon 10 encodes the second microtubule-binding repeat of tau. Its alternative splicing produces tau isoforms with either three or four microtubule-binding repeats, termed 3R-tau and 4Rtau. In the normal adult human brain, the level of 3R-tau is approximately equal to that of 4R-tau. Several silent and intronic mutations of the tau gene associated with FTDP-17T (frontotemporal dementia with Parkinsonism linked to chromosome 17 and specifically characterized by tau pathology) only disrupt exon 10 splicing, but do not influence the primary sequence of the tau protein. Thus, abnormal exon 10 splicing is sufficient to cause neurodegeneration and dementia. Here, we review the regulation of tau exon 10 splicing by cis-elements and trans-factors and summarize all the mutations associated with FTDP-17T and related tauopathies. The findings suggest that correction of exon 10 splicing may be a potential target for tau exon 10 splicing-related tauopathies.