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.     

Enhancement of Oral Bioavailability of Tripterine Through Lipid Nanospheres: Preparation,Characterization, and Absorption Evaluation

Oral delivery of anticancer drugs remains challenging because of limited water-solubility and/or poor permeability. Here, we aimed to enhance the oral bioavailability of tripterine (TRI, a plant-derived anticancer compound) using lipid nanospheres (LNs) and to determine the mechanisms of oral absorption. TRI-loaded LNs (TRI-LNs) were prepared by rapid dispersion of an ethanol mixture of TRI, lecithin, sodium oleate, and soybean oil into water. The obtained LNs were 150 nm in size with a high value of entrapment efficiency (99.95%). TRI-LNs were fairly stable and the drug release was negligible (< 0.2%) in simulated physiological fluid. The pharmacokinetic results showed that LNs significantly enhanced the oral bioavailability of TRI with a relative bioavailability of 224.88% (TRI suspensions was used as a reference). The mechanistic studies demonstrated that improved intestinal permeability and post-enterocyte lymphatic transport were mainly responsible for the enhanced oral absorption. Our findings suggested that LNs may be a viable oral carrier for poorly bioavailable drugs. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:171 1-1719, 2014     

Iso-suillin from the mushroom Suillus flavus induces cell cycle arrest and apoptosis in K562 cell line

Iso-suillin, an isomer of suillin that belongs to the prenylphenol class of fungal derivatives, was isolated from petroleum ether extracts of Suillus flavus. The IC₅₀ value of iso-suillin in K562 cells was 0.87 μM, which was lower than the positive control cisplatin (19.33 μM). Iso-suillin-treated K562 cells exhibited an increased rate of apoptosis, mitochondrial membrane potential (MMP) depolarization, and G0/G1 arrest. Western blot analysis revealed that these cells displayed significantly upregulated expression of several apoptosis-related proteins, including cytochrome c, caspase 9, FADD (Fas-associating protein with a novel death domain), caspase 8, caspase 3, and Bax. Moreover, the expression of two anti-apoptosis proteins, NF-κB and Bcl-2, was downregulated. Inhibitors of caspase 9 and caspase 8 protected the K562 cells from apoptosis. Taken together, our results suggest that iso-suillin induces K562 apoptosis through the mitochondrial and death receptor pathways and that iso-suillin may represent a candidate anti-leukemia treatment.     

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.     

低剂量口服避孕药、高血压及其联合作用对女性脑卒中发病危险性的影响

目的探讨低剂量口服避孕药、高血压及其联合作用对女性脑卒中发病危险l生的影响。方法应用病例对照研究方法,共收集了453例脑卒中病例,按照年龄与地区等分布特征1：2匹配919例对照。通过问卷调查收集基本资料,并采集了静脉血用于脂代谢测定。结果多因素Logistic回归分析显示：不同类型脑卒中的主要风险因素不同,出血型脑卒中的风险因素有高血压、复方口服避孕药（combinedoralcontraceptives,COC）使用和脑卒中家族史;而梗塞型脑卒中的风险因素则包括：高血压、高脂血症及脑卒中家族史。联合作用分析结果显示：COC使用与高血压的联合作用使女性出血型脑卒中的风险增加18．51倍（OR=19．51,95％C／：9．70～39．23）,梗塞型脑卒中的风险增加14．49倍（OR=15．49,95％C／：8．87～27．67）。结论COC使用与高血压的联合作用可以显著升高女性出血型及梗塞型脑卒中的发病危险。     

PIVAS细胞毒性药物调配及输注质量安全探讨

目的 探讨细胞毒性药物集中调配的方法及注意事项,降低医务人员的潜在身体损害。方法 以药物说明书和相关药学专业资料为基础,分析出细胞毒性药物最适宜的调配方法,明确溶媒、溶媒量、药物输注滴速、用药时限及输注注意事项等。结果 明确各类细胞毒性药物调配方法、使用注意事项、用药潜在风险,严格按照输液流程操作,确保用药安全。结论 规范的细胞毒性药物调配方法及操作是药物使用安全、降低医务人员意外损害的重要举措。