Synergistic renal protection by combining alkaline-diuresis with lipid peroxidation inhibitors in rhabdomyolysis: possible interaction between oxidant and non-oxidant mechanisms

BACKGROUND AND PURPOSE.: Heme-proteins, besides causing renal tubular obstruction, maycontribute to rhabdomyolysis-induced renal injury through aheme-iron-mediated lipid peroxidation process. In the presentstudy, we compared the combined therapy of a lipid peroxidationinhibitor, 21-aminosteroid (21-AS) and fluid-alkaline-mannitol(FAM) diuresis with either of them alone to determine the efficacyof the combination therapy and to delineate the roles of lipidperoxidation and cast formation. METHODS AND RESULTS.: Employing Raman spectroscopy, we confirmed in vitro the abilityof 21-AS to inhibit iron-induced fatty acid peroxidation. 21-ASwas then administered to rats developing renal failure fromglycerol-induced rhabdomyolysis. Although 21-AS inhibited rhabdomyolysis-inducedplasma and renal lipid peroxidation, renal protection was incomplete.Administration of FAM to inhibit cast formation afforded a betterrenal protection. However, when these therapies were combinedto inhibit both lipid peroxidation and cast formation, therewas a synergistic renal functional protection. This was accompaniedby a maximum inhibition of renal and plasma lipid peroxidation,as well as, renal tubular necrosis and cast formation. Comparedto combination therapy, FAM therapy alone, despite identicalvolume, was accompanied by a higher tubular necrosis and castformation. CONCLUSIONS.: That combining a lipid peroxidation inhibitor with fluid-alkalinediuresis in rhabdomyolysis further lowers renal lipid peroxidation,tubular necrosis and cast formation and synergistically limitsrenal dysfunction (i) supports a role for lipid peroxidationin the pathophysiology of rhabdomyolysis ARF, (ii) underscoresthe role of intratubular heme retention, a cause for tubularobstruction as well a source for prodigious amount of iron,likely involved in the lipid peroxidation, and (iii) raisesthe possibility of interactions between non-oxidant and oxidantmechanisms.     

Fatal intoxications in Denmark following intake of morphine from opium poppies

Summary In Denmark it is legal to grow opium poppies for the production of poppy seeds and until 1986 for decoration purposes, too. Danish poppy capsules contain 0.3–5 mg morphine per capsule and the content of morphine in opium exuded from the capsules may amount to 24%. This has resulted in misuse as both fresh and dried poppy capsules have been used for the production of opium tea. During the period 1982–1985, seven casualties occurred among drug addicts in Denmark which were solely or partly caused by these opium poppies.     

Induction of light hydrocarbon nephropathy by p-dichlorobenzene

In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150–600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man.     

SNHG6靶向miR-101/TGFBR1促进AMI小鼠左心室心肌纤维化

目的探讨SNHG6对急性心肌梗死(AMI)小鼠左心室心肌的影响。 方法将30只雄性C57/BL6小鼠构建成AMI小鼠后随机均分为AMI组、AMI+SNHG6组、AMI+miR-101-3p组、AMI+SNHG6+miR-101-3p组、AMI+miR-101-3p+TGFBR1组,另设正常小鼠6只为假手术组。qRT-PCR检测AMI小鼠SNHG6、miR-101-3p表达水平。心脏彩超检测各组小鼠左室射血分数(LVEF);马松和天狼星红染色法以及免疫组化分析各组小鼠左心室心肌纤维化变化。将H9C2细胞株分为阴性对照组(转染空质粒)、SNHG6组(转染质粒SNHG6)、miR-101-3p组(转染质粒miR-101-3p)。Western blotting检测各组TGFBR1蛋白表达;采用双荧光素酶报告基因法预测并验证SNHG6/miR-101-3p/TGFBR1荧光素酶活性及调控机制。 结果AMI小鼠较假手术组SNHG6表达显著增加,miR-101-3p降低(P＜0.05)。与AMI组比较,AMI+SNHG6组小鼠LVEF降低,心肌纤维化程度加重(P＜0.05);AMI+miR-101-3p组LVEF升高,心肌纤维化程度减轻(P＜0.05)。AMI+SNHG6+miR-101-3p组较AMI+SNHG6组LVEF升高、心肌纤维化程度减轻(P＜0.05),而AMI+miR-101-3p+TGFBR1组较AMI+miR-101-3p组LVEF降低、心肌纤维化程度加重(P＜0.05)。双荧光素酶报告基因法验证显示,miR-101-3p组SNHG6、TGFBR1野生型质粒的荧光素酶活性较阴性对照组明显降低(P＜0.05)。 结论SNHG6抑制miR-101-3p上调TGFBR1加重AMI小鼠左心室心肌纤维化。     

Diffuse type of senile plaques in the cerebellum of Alzheimer-type dementia demonstrated byβ protein immunostain

Summary We studied senile plaques (SP) in the cerebella of six autopsied subjects with Alzheimer-type dementia (ATD) and ten non-ATD autopsied subjects between the ages of 78 and 90. Neither SP nor amyloid angiopathy (AA) was observed in any of the non-ATD subjects. In the four of the six ATD subjects, diffuse plaques in the molecular layer were seen as ill-defined areas of fine fibrillar materials by protein immunostaining with formic acid pretreatment, the modified Bielschowsky stain, and periodic acid-methenamine silver (PAM) stain. The plaques were not visible with Bodian, Congo red, or periodic acid-Schiff stains. Compact plaques in the Purkinje cell or in the granular cell layers were found in three of the six subjects. Their amyloid core was often surrounded by areolar amyloid deposits. AA was observed in three of the six subjects. The argyrophilia of the diffuse and compact plaques, demonstrated by the modified Bielschowsky and PAM stains, became undetectable when the sections were first treated with formic acid. Such treatment made the plaques immunoreactive with protein antiserum. The findings suggested that cerebellar diffuse plaques and compact plaques consist mainly of an amyloid component, and are characteristic of ATD.     

Testosterone in a Cyclodextrin-Containing Formulation: Behavioral and Physiological Effects of Episode-like Pulses in Rats

Testosterone, administered in the form of an inclusion complex with 2-hydroxypropyl--cyclodextrin by subcutaneous injection, enters the circulation in a manner markedly similar to the natural episodic release by the testes. The effects of a regimen of once-a-day administration of complexed testosterone to adult (castrated or intact) rats and to senescent (intact) rats were investigated. Although this procedure left the castrated animals with concentrations of circulatory hormone far below physiological levels for much of the day, a significant improvement in androgen-sensitive behavior and physiology was obtained. Furthermore, the testosterone effects were more pronounced when high doses were used periodically rather than when the same total amount of testosterone was equally divided among doses. The same supplementation to intact rats intensified androgen-sensitive behavior and physiology over normal levels. In senescent rats uniform pulses of the testosterone complex also improved behavior and physiology. Specifically, spermatogenesis was stimulated and, notably, the treatment increased muscle weight without substantial enlargement of the prostate. Since the testosterone–cyclodextrin complex also can be effectively administered as a sublingual tablet, the data suggest that similar regimens may be recommended for elderly men suffering from decreases in muscle mass.     

Drug Binding to α1-Acid Glycoprotein Studied by Circular Dichroism

The interactions of acidic and basic drugs with ₁-acid glycoprotein (₁-AGP) were investigated using circular dichroism (CD) measurements. Extrinsic Cotton effects were generated by the binding of drugs to ₁-AGP. The CD data suggested the presence of a single binding site on the ₁-AGP molecule. The induced ellipticities of the acidic drug–₁-AGP system decreased with increasing pH, while the ellipticities for the basic drugs increased with pH. The ellipticities for all drugs were reduced by the addition of fatty acids. Furthermore, the induced ellipticities decreased in the presence of cesium chloride for basic drugs bound to ₁-AGP. The extrinsic Cotton effects therefore appear to result from hydrophobic interaction with ₁-AGP for the acidic drugs and from hydrophobic and electrostatic interactions for the basic drugs.     

Compartmentation of cardiac adenine nucleotides and formation of adenosine

Summary After prelabeling the adenine nucleotides (ATP, ADP, AMP) of isolated perfused guinea pig hearts with either¹⁴C-adenine or¹⁴C-adenosine for 35 min, labeled adenosine, inosine, hypoxanthine and cyclic 35-AMP (cAMP) were continuously released into the cardiac perfusate. Determination of the specific activities (SA) of the adenine nucleotides, cAMP, and their breakdown products (adenosine, inosine, hypoxanthine) in tissue and perfusate revealed: Under steady state conditions the SA of adenosine and cAMP in the perfusate were of the same order of magnitude and proved to be many times higher than the SA of the respective precursor adenine nucleotides. This difference was observed regardless whether adenine or adenosine was used as prelabeling substance. The SA of inosine and hypoxanthine in the perfusate were constantly lower than the SA of adenosine. Cardiac ischemia of 6 min, which resulted in a markedly increased formation of adenosine, led to a pronounced decrease in the SA of adenosine released from the heart.Our findings provide evidence that at least two different adenine nucleotide compartments of the heart serve as precursors for the formation of adenosine and cAMP, one characterized by a high, the other by a lower SA. Under normoxic conditions adenosine and cAMP released into the cardiac perfusate are derived mainly from a nucleotide fraction of high SA, which appears to be rather small. During ischemia a second compartment of much lower SA in addition contributes to the formation of adenosine.A preliminary report of part of this work appeared in Biochemistry and Pharmacology of Myocardial Hypertrophy, Hypoxia and Infarction Vol. 7 of Recent advances in studies on cardiac structure and metabolism. (P. Harris, R. J. Bing, A. Fleckenstein, eds.), pp. 171–175. München: Urban & Schwarzenberg 1976A preliminary report of part of this work appeared in Biochemistry and Pharmacology of Myocardial Hypertrophy, Hypoxia and Infarction Vol. 7 of Recent advances in studies on cardiac structure and metabolism. (P. Harris, R. J. Bing, A. Fleckenstein, eds.), pp. 171–175. München: Urban & Schwarzenberg 1976