Effect of lysosomal loading with Triton WR 1339 on the distribution of albumin-14C in the liver of rats with chronic hepatitis

The mechanism of the protective effect of the lysosomotropic detergent Triton WR 1339 in chronic hepatitis was examined. Assuming that the improvement in the condition is connected with potentiation of the heterophagous function of the lysosomes, the intensity of uptake of albumin-¹⁴C by the liver and its subcellular distribution in the liver of rats were studied during administration of the detergent to animals with chronic carbon tetrachloride hepatitis. Preliminary injection of the detergent did not affect the intensity of uptake of albumin-¹⁴C, but subsequent injection of Triton WR 1339 into rats with toxic hepatitis reduced the protein uptake to values obtained in intact rats. In chronic hepatitis albumin-¹⁴C is concentrated in the lysosomal fraction. After injection of Triton WR 1339 into the poisoned animals the peaks of labeled protein and lysosomal enzymes did not coincide. The selective role of lysosomes of the Kupffer cells of the liver in producing the more rapid recovery of the liver from chronic hepatitis is examined.Presented by Academician of the Academy of Medical Sciences of the USSR V. P. Kaznacheev.Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 82, No. 7, pp. 816–819, July, 1976.     

Involvement of lysosomes in the uptake of macromolecular material by bloodstream forms of Trypanosoma brucei

To investigate whether the lysosomes of Trypanosoma brucei are capable of uptake of macromolecules after internalization by the cell, we used Triton WR-1339, a non-digestible macromolecular compound, which is known to cause a marked decrease in the density of hepatic lysosomes due to massive intralysosomal storage. Intraperitoneal administration of 0.4 g/kg Triton WR-1339 to rats infected with T. brucei led to the development of a large vacuole in the trypanosomes between nucleus and kinetoplast within 22 h. Higher doses (2 g/kg) led to the disappearance of the trypanosomes from the blood and resulted in permanent cures (greater than 100 days). Lysosomes isolated from the trypanosomes of animals treated with a sub-curative dose showed a decrease in equilibrium density of 0.03 g/cm3 in sucrose gradients. These lysosomes were partly damaged as evidenced by a reduction in latency and an increase in the non-sedimentable part of lysosomal enzymes. We conclude that acid proteinase and alpha-mannosidase-containing organelles of T. brucei take up exogenous macromolecules and must therefore be considered as true lysosomes and that Triton WR-1339 acts in T. brucei as a true lysosomotropic drug. Its trypanocidal action probably results from an interference with lysosomal function.     

Hypolipidemic activity of P-methoxycinnamic diester (PCO-C) isolated from Copernicia prunífera against Triton WR-1339 and hyperlipidemic diet in mice

Carnauba wax is extracted from the leaves of the Copernicia prunífera and contains approximately 80% of esters in its composition. The purpose of the present study was evaluate the hypolipidemic effect of p-methoxycinnamic diesters (PCO-C) extracted from Copernicia prunífera in a model of acute and chronic dyslipidemia in mice. The levels of total cholesterol and triglycerides were significantly reduced plasma levels in PCO-C at the dose of 100 mg/kg in a model of acute and chronic dyslipidemia. Histological studies showed that PCO-C has no hepatotoxic effect and reduces hepatic steatosis in animals that consumed hyperlipidemic ration. Thus, it was concluded that PCO-C isolated from Copernicia Prunifera was effective in reducing total cholesterol and triglyceride levels in both dyslipidemia induction models. The finding indicates that PCO-C might be beneficial in treatment of hyperlipidemia and atherosclerosis.     

Serum insulin and lipogenesis in the suckling ‘fatty’ fa/fa rat

Summary Preobese fatty fa/fa rats identified by their decreased rectal temperature were either given access to high carbohydrate chow or maintained on a suckling only diet till 20 days of age. Serum insulin, hepatic and adipose tissue fatty acid synthesis and lipogenic enzyme activities were low in suckling preobese fa/fa. In animals with access to chow diet, hepatic lipogenesis was unaltered, serum insulin rose to similar levels in lean and preobese fa/fa (lean 62±5; preobese 69±4 U/ml), but adipose tissue lipogenesis was increased to higher levels in the preobese than lean rats (lean 0.56±0.12; preobese 1.80±0.22 mol. tissue^-1. h^-1). The activities of glucose-6-phosphate dehydrogenase, acetyl coenzyme A carboxylase and fatty acid synthetase were increased in adipose tissue of preobese fa/fa rats. Neither streptozotocin treatment nor pretreatment with Triton WR 1339 abolished the difference in adipose tissue lipogenesis between lean and preobese fa/fa rats. Preobese fa/fa rats showed an enhanced insulin secretory response to a glucose load.     

Diffuse alveolar hemorrhage following alemtuzumab

This study describes an unusual patient with X-linked Alport syndrome (XLAS) in whom diffuse alveolar hemorrhage (DAH) developed as a complication of alemtuzumab therapy following renal transplantation. A 26-year-old man with XLAS underwent retransplantation with a cadaveric renal allograft. He received alemtuzumab therapy as a part of an immunosuppressive induction protocol, and dyspnea and hemoptysis developed. A chest CT scan showed diffuse alveolar opacities. Bronchoscopy was performed to determine the cause of hemoptysis and hypoxia. BAL showed a characteristic increasingly bloody return in the sequential aliquots. There was no growth of pathogenic bacteria or evidence of opportunistic infection. Clinical improvement occurred with the initiation of steroids, and the patient required short-term mechanical ventilation for acute respiratory failure. To our knowledge, this is the first reported case of DAH associated with use of alemtuzumab therapy, although other pulmonary toxicities have been described. The prevalence of this form of pulmonary toxicity is unclear and requires further systematic study.     

Hypolipidemic activity of Phellinus rimosus against triton WR-1339 and high cholesterol diet induced hyperlipidemic rats

Patients with the risk for atherosclerotic disease will be targeted to reduce the existing hyperlipidemia. The hypolipidemic activity of Phellinus rimosus was studied using triton WR-1339 and high cholesterol diet (HCD) induced models. The triton induced elevated lipid profile was attenuated by P. rimosus or standard drug atorvastatin. Similarly, administration of P. rimosus along with HCD significantly decline serum triglyceride, total cholesterol, low-density lipoprotein, with elevating the high-density lipoprotein. Thiobarbituric acid reacting substances in heart and liver significantly decreased; where as activity of enzymatic antioxidants and level of reduced glutathione were significantly increased. In both models, P. rimosus extract showed a significant ameliorative effect on the elevated atherogenic index as well as LDL/HDL-C ratio. The hypolipidemic activity of P. rimosus can be ascribed to its inhibitory effect on the liver HMG CoA reductase activity. The results suggest the possible therapeutic potential of this fungus as hypolipidemic agent.     

苹果多酚对Triton WR-1339诱发的高脂血症小鼠抗氧化能力的影响

目的研究苹果多酚对Triton WR-1339诱发的高脂血症小鼠抗氧化能力的影响。方法采用苹果多酚（200、400 mg.kg-1）对NIH小鼠进行连续口服灌胃7 d,第6天尾静脉注射Triton WR-1339（300 mg.kg-1）诱导高脂血症,18 h后收集各组小鼠血清,测定总胆固醇和三酰甘油的含量及血清MDA和NO水平、SOD和GPx活性。结果苹果多酚（200、400 mg.kg-1）能明显降低高脂血症小鼠血清MDA的含量,升高NO水平,提高SOD、GPx活性。结论苹果多酚可以显著提高高脂血症小鼠的抗氧化能力。     

桑叶总黄酮对高脂血症动物的降血脂效应

 目的 观察桑叶总黄酮（ MTF ）的降血脂作用。 方法 用 Triton WR-1339 诱导建立急性高脂血症小鼠模型和高脂饲料建立高脂血症大鼠模型,分别测定小鼠和大鼠血清中的总胆固醇（ TC ）、甘油三脂（ TG ）、高密度脂蛋白胆固醇（ HDL-C ）和低密度脂蛋白胆固醇（ LDL-C ）的含量,并计算 HDL-C/TC 和 HDL-C/LDL-C 的比值 。 结果 MTF 能显著抵抗 Triton WR-1339 诱导的小鼠血清 TG , TC 和 LDL-C 等指标的升高,同时升高血清 HDL-C/TC 和 HDL-C/LDL-C 的比值。给药后 12 h 作用效果更明显。喂高脂饲料的大鼠模型也同样表明 MTF 具有降低血脂的作用,而且具有剂量依赖性。 结论 MTF 能剂量依赖性地降低高脂血症小鼠和大鼠的血脂水平,预防高脂血症的发生发展。     

Hovenia Dulcis Extract Reduces Lipid Accumulation in Oleic Acid‐Induced Steatosis of Hep G2 Cells via Activation of AMPK and PPARα/CPT‐1 Pathway and in Acute Hyperlipidemia Mouse Model

Hovenia dulcis Thunb. (HDT) was known to have anti‐fatigue, anti‐diabetes, neuroprotective, and hepatoprotective effects. In the present study, the anti‐fatty liver mechanism of HDT was elucidated in oleic acid (OA)‐treated Hep G2 cells and acute hyperlipidemia mouse model using Triton WR‐1339. Here, HDT activated p‐AMP‐activated protein kinase (p‐AMPK), proliferator activated receptor‐α, carnitine palmitoyltransferase and also inhibited the expression of lipogenesis and cholesterol synthesis proteins, such as 3‐hydroxy‐3‐methylglutaryl‐CoA reductase, sterol regulatory element binding protein‐1c, SREBP‐2, and fatty acid synthase in OA‐treated Hep G2 cells. Conversely, AMPK inhibitor compound C blocked the anti‐fatty liver effect of HDT to induce AMPK phosphorylation and decrease 3‐hydroxy‐3‐methylglutaryl‐CoA reductase and lipid accumulation by oil red O staining in OA‐treated Hep G2 cells. Additionally, HDT pretreatment protected against the increase of serum total cholesterol, triglyceride, low‐density lipoprotein cholesterol and phospholipid in an acute hyperlipidemia mouse model with enhancement of glutathione reductase, glutathione peroxidase, superoxide dismutase, and catalase activities. Taken together, HDT inhibits OA‐induced hepatic lipid accumulation via activation of AMPK and proliferator activated receptor‐α/carnitine palmitoyltransferase signaling and enhancement of antioxidant activity as a potent candidate for nonalcoholic fatty liver disease and hyperlipidemia. Copyright © 2016 John Wiley & Sons, Ltd.