Alterations of glycosaminoglycans in human liver and kidney tumors

Glycosaminoglycans were investigated in surgically removed human liver and kidney tumours by applying biochemical methods. Four liver adenoma, 6 focal nodular hyperplasia and 9 primary hepatocellular carcinoma samples were compared with normal liver from autopsy cases and also with liver tissue adjacent to PHC. The studies on kidney included 14 renal cell carcinoma and 4 wilms' tumour samples. Three findings emerged from the quantitative and qualitative characterization of the tumours with epithelial origin. 1) The rise in the amount of total GAG was not limited to the malignant lesion. Similar increase was observed in benign liver tumours and also in the tissue adjacent to liver or kidney malignant tumours. 2) The dominant type of the GAG subclasses varies with the histology of the tumours. In benign liver tumours dermatan sulfate, in PHC and renal cell carcinoma chondroitin sulfate, but in Wilms' tumour hyaluronate was the prominent GAG subclass. 3) In all tumour-affected tissues dermatan and chondroitin sulfates had lower degree of sulfation. However, in the histologically different tumours various disaccharides showed reduced level of sulfation. The GAG alteration in renal cell carcinoma was compared with the prognostic factors of each individual case. This analysis showed a good correlation between HS/CS ratio and the prognostic factors of the kidney tumour cases.     

Stimulation of cadmium uptake by estradiol in the kidney of male rats treated with cadmium

The present study was carried out to analyze the sex differences in the retention of Cd in rats treated with a small amount of Cd, and its mechanisms. Cd and Zn concentrations in the kidney and liver of female rats treated with 28 nmol Cd or 1 nmole Zn were significantly higher than those in male rats. Pretreatment with estradiol (1.8 mumol/kg of b.w., twice a day, 6 consecutive days) increased the Cd and Zn concentrations in the kidney of male rats treated with Cd or Zn. Incubation of MDCK cells with 10(-5) M estradiol, 10(-5) M stilboestrol and 10(-5) M progesterone caused a significant increase in Cd uptake. These results suggest that endogenous female sex hormones may play a role in a higher concentration of Cd and Zn in the kidney of female rats than that in male rats. The basal level of metallothionein (MT) in the liver and kidney of control female rats was within the same range as that in the control male rats. Cd and Zn accumulations caused by pretreatment with estradiol in the kidney of male rats treated with Cd or Zn were so low (Cd: 38 ppb, Zn: 1.0 ppb) as to be probably unable to induce the synthesis of MT. An increase in the concentration of Cd in the cultured renal cells occurred 1 hr after treatment with estradiol and Cd. Pretreatment with estradiol alone also resulted in a modification of the concentration of Na and K, which cannot be bound to MT. Together, all of the above findings suggest that estradiol directly increases the accumulation of Cd into the renal cells without inducing the synthesis of MT.     

肝肾功能衰竭患者行连续性肾脏替代治疗的护理

目的对应用护理干预模式对接受连续性肾脏替代治疗的肝肾功能衰竭患者进行治疗的临床效果进行研究分析。方法抽取84例接受连续性肾脏替代治疗的肝肾功能衰竭患者病例,将其分为对照组和干预组,平均每组42例。对照组患者在接受治疗期间进行常规护理;干预组患者在治疗期间进行护理干预。结果干预组患者肝肾衰竭症状的改善效果明显优于对照组;治疗时间明显短于对照组;治疗期间患者并发症发生率明显低于对照组。结论应用护理干预模式对接受连续性肾脏替代治疗的肝肾功能衰竭患者进行治疗的临床效果非常明显。     

Lipid peroxidation and antioxidant status in kidney and liver of rats treated with sulfasalazine

Sulfasalazine (SASP) is a drug commonly used in the treatment of inflammatory bowel diseases (IBD). In this study, the changes in endogenous antioxidant capacity and oxidative damage in liver and kidney of SASP-treated rats were investigated. Adult male Sprague–Dawley rats were orally given 0, 300, or 600 mg SASP/kg body weight for 14 days. One half of the animals in each group remained 14 additional days without SASP treatment. At the end of the experimental period, rats were euthanized and liver and kidney were removed. In both organs, the following stress markers were determined: reduced glutathione (GSH), oxidized glutathione (GSSG), glutathione reductase (GR), glutathione peroxidase (GPx), glutathione-S-transferase (GST), superoxide dismutase (SOD), catalase (CAT), and thiobarbituric acid-reactive substances (TBARS). Moreover, histological examination of kidneys showed phagolysosomes after 14 days of SASP withdrawal. A dropsical degeneration was also observed in renal tissue. Oral SASP administration induced a significant increase in TBARS levels in both liver and kidney. After 2 weeks without SASP administration, a recovery of these levels was noted. SOD activity was significantly reduced, while CAT activity significantly increased at 600 mg SASP/(kg day). In kidney, GPx activity significantly increased, while GST activity and GSH levels were significantly reduced at 600 mg SASP/(kg day). These results suggest that in male rats, oxidative damage can be a mechanism for nephro- and hepatotoxicity related with SASP treatment.     

Interaction of estrone and estradiol with DNA and protein of liver and kidney in rat and hamster in vivo and in vitro

[6,7-³H] Estrone (E) and [6,7-³H]estradiol-17 (E₂) have been synthesized by reduction of 6-dehydroestrone and 6-dehydroestradiol with tritium gas. Tritiated E and E₂ were administered by oral gavage to female rats and to male and female hamsters on a dose level of about 300 g/kg (54 mCi/kg). After 8 h, the liver was excised from the rats; liver and kidneys were taken from the hamsters. DNA was purified either directly from an organ homogenate or via chromatin. The radioactivity in the DNA was expressed in the units of the Covalent Binding Index, CBI = (mol chemical bound per mol DNA-P)/(mmol chemical administered per kg b.w.). Rat liver DNA isolated via chromatin exhibited the very low values of 0.08 and 0.09 for E and E₂, respectively. The respective figures in hamster liver were 0.08 and 0.11 in females and 0.21 and 0.18 in the males. DNA isolated from the kidney revealed a detectable radioactivity only in the female, with values of 0.03 and 0.05 for E and E₂, respectively. The values for male hamster kidney were < 0.01 for both hormones. The minute radioactivity detectable in the DNA samples does not represent covalent binding to DNA, however, as indicated by two sets of control experiments. (A) Analysis by HPLC of the nucleosides prepared by enzyme digest of liver DNA isolated directly or via chromatin did not reveal any consistent peak which could have been attributed to a nucleoside-steroid adduct. (B) All DNA radioactivity could be due to protein contaminations, because the specific activity of chromatin protein was determined to be more than 3,000 times higher than of DNA. The high affinity of the hormone to protein was also demonstrated by in vitro incubations, where it could be shown that the specific activity of DNA and protein was essentially proportional to the concentration of radiolabelled hormone in the organ homogenate, regardless of whether the animal was treated or whether the hormone was added in vitro to the homogenate.Carcinogens acting by covalent DNA binding can be classified according to potency on the basis of the Covalent Binding Index. Values of 10³–10⁴ have been found for potent, 10² for moderate, and 1–10 for weak carcinogens. Since estrone is moderately carcinogenic for the kidney of the male hamster, a CBI of about 100 would be expected. The actually measured limit of detection of 0.01 places covalent DNA binding among the highly unlikely mechanisms of action. Similar considerations can be made for the liver where any true covalent DNA binding must be below a level of 0.01. It is concluded that an observable tumor induction by estrone or estradiol is unlikely to be due to DNA binding.Paper presented at the Satellite Symposium of the European Society of Toxicology, Rome, March 29, 1983     

Glucose homeostasis in rats treated acutely and chronically with quinine

Glucose homeostasis in normal rats was studied after chronic or acute administration of quinine. Male rats received a daily dose of 10-30 mg/kg of quinine in the drinking water for 20 weeks. The high dose caused a slight decrease in food intake and weight gain. Though basal plasma insulin levels were increased in treated rats, their plasma glucose levels were only slightly and not consistently decreased. After oral or intravenous administration of glucose, the plasma insulin levels were higher and the disappearance rate of glucose was greater in rats receiving quinine than in the controls. The insulin content of the pancreas was not affected by quinine treatment. Intraperitoneal injection of a high dose of quinine (30 mg/kg) transiently increased plasma glucose and insulin levels. The insulin response was increased during a subsequent administration of glucose but the glucose levels were not modified. This study shows that chronic administration of quinine increases plasma insulin levels, accelerates disposal of oral or intravenous glucose but does not cause hypoglycaemia in normal rats.     

Altered nuclear factor kappa-B activity and mercury-induced kidney tubule cell apoptosis: implications for renal failure.

The article highlighted in this issue is ‘Nuclear FactorB Activity Determines the Sensitivity of Kidney Epithelial Cellsto Apoptosis: Implications for Mercury-Induced Renal Failure,’by Francisco J. Dieguez-Acuña, William W. Polk, MaureenE. Ellis, P. Lynne Simmonds, John V. Kushleika, and James S.Woods. This article appeared in the November issue (pp. 114–123). The great power of understanding mechanisms of cell injury andcell death rests in providing valuable insights into how drugsand/or chemical agents may interact with target cell populationsto produce clinical disease (Fowler, 1987). Once these insightsare understood, they may     

The role of NPY in metabolic homeostasis: implications for obesity therapy

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide which has now emerged as an important regulator of feeding behaviour. Upon intracerebroventricular (icv.) administration, NPY produces a pronounced feeding response in a variety of species. The actions of NPY are believed to be mediated by a family of receptor subtypes named Y1 - y6. Recent studies suggest that the Y1 and Y5 receptor subtypes are intimately involved in NPY induced feeding. This review presents preclinical data obtained with receptor subtype selective agonists and antagonists as well as findings from knockout mice. These new data suggest that NPY receptor antagonists may become an additional option for treating human obesity.     

The role of NPY in metabolic homeostasis: implications for obesity therapy

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide which has now emerged as an important regulator of feeding behaviour. Upon intracerebroventricular (icv.) administration, NPY produces a pronounced feeding response in a variety of species. The actions of NPY are believed to be mediated by a family of receptor subtypes named Y1 - y6. Recent studies suggest that the Y1 and Y5 receptor subtypes are intimately involved in NPY induced feeding. This review presents preclinical data obtained with receptor subtype selective agonists and antagonists as well as findings from knockout mice. These new data suggest that NPY receptor antagonists may become an additional option for treating human obesity.     

GABA-related enzymes in the hypothalamus of rats treated with estradiol

In a naloxone-reversible, dose-dependent manner, morphine (10-50 mg/kg i.p.) protected against seizures induced by maximal electroshock and increased the incidence and severity of seizures induced by bicuculline, in rats. Morphine also potentiated seizures induced by isoniazid and by picrotoxin. Thus, opiate activity influences the expression of seizures in contrasting ways depending upon the mode of seizure induction. Since morphine consistently potentiated seizures induced by interference with GABA transmission, it appears that GABAergic systems may be of particular significance for the elucidation of the varied effects of morphine on seizure susceptibility.     

七氟醚静吸复合麻醉对肝叶切除术患者肝肾功能的影响

目的 探讨七氟醚静吸复合麻醉对肝叶切除术患者肝肾功能的影响。方法 85例择期行开腹肝叶切除术患者随机分为七氟醚组(n=44)和丙泊酚组(n=41),麻醉诱导:七氟醚组所有患者吸入8%七氟醚,等意识丧失后,用0.2 mg·kg-1顺苯磺酸阿曲库胺和0.4 μg·kg-1舒芬太尼静脉注射;丙泊酚组所有患者将1～2 mg·kg-1丙泊酚、0.2 mg·kg-1顺苯磺酸阿曲库胺和0.4 μg·kg-1舒芬太尼静脉注射。麻醉维持:七氟醚组患者持续吸入2%～3%七氟醚,丙泊酚组患者将0.5～0.8 mg·kg-1·h-1丙泊酚持续静脉输注,维持BIS值在40～60之间。记录两组患者手术一般情况,分别于麻醉诱导前(T₀)、术毕(T₁)、术后1 d(T₂)、3 d(T₃)和5 d(T₄)时,检测两组患者肝肾功能指标。结果 与T₀时相比,两组患者T1～4时ALT升高,T1～3时AST升高,T2～4时TBil和DBil升高,T₂时ALB降低,差异均有统计学意义(P<0.05);七氟醚组患者T2～4时ALT、TBil和DBil均低于丙泊酚组,T2～3时AST低于丙泊酚组,T₂时ALB高于丙泊酚组,差异均有统计学意义(P<0.05);与T₀时相比,两组患者T2～4时Cystatin C和24 h尿微量白蛋白均升高,差异均有统计学意义(P<0.05);七氟醚组患者T2～4时Cystatin C和24 h尿微量白蛋白均低于丙泊酚组,差异均有统计学意义(P<0.05)。结论 相比于丙泊酚复合麻醉,七氟醚静吸复合麻醉更有利于减轻肝叶切除术中缺血—再灌注损伤对患者肝肾功能的影响。     

Amino Acid requirements in critically ill patients with acute kidney injury treated with continuous renal replacement therapy

Acute kidney injury in critically ill patients is often a complication of an underlying condition such as organ failure, sepsis, or drug therapy. In these patients, stress-induced hypercatabolism results in loss of body cell mass. Unless nutrition support is provided, malnutrition and negative nitrogen balance may ensue. Because of metabolic, fluid, and electrolyte abnormalities, optimization of nutrition to patients with acute kidney injury presents a challenge to the clinician. In patients treated with conventional intermittent hemodialysis, achieving adequate amino acid intake can be limited by azotemia and fluid restriction. With the use of continuous renal replacement therapy (CRRT), however, better control of azotemia and liberalization of fluid intake allow amino acid intake to be maximized to support the patient's metabolic needs. High amino acid doses up to 2.5 g/kg/day in patients treated with CRRT improved nitrogen balance. However, to our knowledge, no studies have correlated increased amino acid intake with improved outcomes in critically ill patients with acute kidney injury. Data from large, prospective, randomized, controlled trials are needed to optimize the dosing of amino acids in critically ill patients with acute kidney injury who are treated with CRRT and to study the safety of high doses and their effects on patient morbidity and survival.     

Structure of estradiol metal chelate and estrogen receptor complex: the basis for designing a new class of selective estrogen receptor modulators

Selective estrogen receptor modulators, such as 17β-estradiol derivatives bound to metal complexes, have been synthesized as targeted probes for the diagnosis and treatment of breast cancer. Here, we report the detailed 3D structure of estrogen receptor α ligand-binding domain (ERα-LBD) bound with a novel estradiol-derived metal complex, estradiol-pyridine tetra acetate europium(III), at 2.6 ? resolution. This structure provides important information pertinent to the design of novel functional ERα targeted probes for clinical applications.     

Development of hepatocytes in the pancreas of hamsters treated with 2,3,7,8-tetrachlorodibenzo-p-dioxin

Transdifferentiation is a process in which one differentiated cell type is converted to another. A unique example of transdifferentiation is the development of hepatocytes from pancreatic cells in adult hamsters and rats. In this communication we report the induction of pancreatic hepatocytes in hamsters that were given 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Two or 6 intraperitoneal (ip) injections of TCDD at a dose of 100 micrograms/kg body weight at 4-wk intervals induced pancreatic hepatocytes in 75% and 89% of the animals respectively. In animals given only two doses of TCDD each pancreas contained one to two hepatic foci, whereas when six injections were administered multiple hepatic foci were observed. By hematoxylin and eosin stain and by periodic acid Schiff stain, the pancreatic hepatocytes were morphologically identical to those in normal liver. Although the exact mechanism by which TCDD induces the transformation is not clear, it is conceivable that TCDD acting through receptor-mediated mechanisms is activating the repressed liver-specific genes in the pancreas.     

MicroRNAs in platelet biogenesis and function: implications in vascular homeostasis and inflammation

Platelets are involved in vascular homeostasis and inflammation through interaction with circulating blood cells and vascular wall. MiRNAs are small, conserved and non-coding RNA molecules, which interact directly with specific mRNAs regions regulating gene expression. The purpose of this review is to gather all known platelet miRNAs and summarize their role in platelet biogenesis and function. Increasing evidence supports the role of miR-34a and miR-150 in megakaryocytopoiesis and platelet production. Although 284 miRNAs are described to be present in platelets, their role is mostly unknown. The most abundant miRNA in platelets is miR-223 followed by miR-126. The miR-96, miR-200b, miR- 495, miR-107 and miR-223 are critically involved in platelet reactivity, aggregation, secretion and adhesion. The presence of miRNAs known to regulate angiogenesis in platelets is also discussed. Furthermore, platelet-derived microvesicles and microparticles contain several miRNAs, which may facilitate the communication between platelets with other vascular cells, a mechanism that may play an important role in vascular homeostasis and inflammation. Further studies are needed to elucidate the exact roles of platelet miRNAs in platelet function and vascular biology.     

雌激素对大鼠趋化因子受体CXCR2表达的影响：动脉粥样硬化的指征

目的：研究17β-雌二醇对体内单核细胞趋化因子受体CXCR2表达的影响．方法：流式细胞仪测定单核细胞趋化因子受体CXCR2的蛋白表达、逆转录PCR测定其mRNA水平．结果：在卵巢完整和切除卵巢的大鼠中,喂养富含胆固醇饮食6周增加单核细胞趋化因子受体CXCR2 mRNA和蛋白水平．在切除卵巢的大鼠,注射17β-雌二醇(5和20μg．kg^-1．d^-1)显著减少了胆固醇诱导的CXCR2 mRNA及蛋白表达的增加．正常饮食的大鼠,切除卵巢增加了趋化因子受体CXCR2 mRNA和蛋白水平的表达,但是注射17β-雌二醇可以防止它表达的增加．结论：生理性浓度的雌激素调节基础及胆固醇诱导的趋化因子受体CXCR2表达．     

Genetic polymorphisms of estrogen receptor-alpha: possible implications for targeted osteoporosis therapy

Genetic factors play an important role in the determination of bone mass and osteoporosis. A number of candidate genes have been implicated in osteoporosis, including genes encoding type 1 collagen, vitamin D receptor, estrogen receptor-alpha (ERalpha), and others. A number of association studies have been performed with single nucleotide polymorphisms in the ERalpha gene to assess their relation with bone mineral density in pre- and postmenopausal women, as well as the rate of bone loss after menopause and skeletal response to estrogen administration. The polymorphisms studied thus far mostly involved intronic polymorphisms in intron 1. Other less frequently studied polymorphisms include those in exons 1, 4, and 8. Although most studies demonstrated associations with various bone-related parameters, the results are still disputed. Assessing genetic factors including ERalpha polymorphisms, if their significances are confirmed, can be helpful in targeting preventive measures to individuals with higher risk of developing osteoporosis and render the preventive effort more cost-effective. Moreover, pharmacogenetically, it may help identify postmenopausal women who tend to have better skeletal responses after estrogen replacement. It is not known, however, if patients who possess favorable polymorphisms in terms of skeletal responsiveness will also have an undesirably higher risk of adverse effects. This issue needs to be further investigated before clinical decisions based on the balance between benefits and risks can be made.     

Changes in glucose-6-phosphatase activity in liver and kidney of rats treated with a single large dose of fluoride

Changes in glucose-6-phosphatase activities in the liver and kidney were investigated in rats after ip administration of a large dose of fluoride (NaF, 35 mg/kg body wt). The glucose-6-phosphatase activity in the liver and kidney of fluoride-treated rats increased 2.37 and 3.42 times that of respective control values. These elevations in hepatic and renal glucose-6-phosphatase activity were suppressed by pretreatments of actinomycin D or cycloheximide.