Human Herpesvirus-8 (HHV-8)-Associated Primary Effusion Lymphoma in two Renal Transplant Recipients Receiving Rapamycin

The Akt/mammalian target of rapamycin (mTOR) signaling cascade has been demonstrated to be constitutively activated in several malignancies, including Kaposi sarcoma (KS) and human herpesvirus-8 (HHV-8)-associated primary effusion lymphoma (PEL). In organ transplant recipients, therapeutic change from cyclosporin to the mTOR inhibitor rapamycin can lead to regression of KS lesions. Recent experiments using PEL cell lines and murine xenograft PEL models suggested that rapamycin could inhibit the growth of PEL cells. In the present report, we describe the cases of two HIV-1-negative males of African origin who underwent renal transplantation and developed PEL while receiving rapamycin as immunosuppressive treatment. Both patients were retrospectively found to be HHV-8 seropositive before renal transplantation. The present case report suggests that rapamycin may not protect HHV-8-infected renal transplant recipients from occurrence of PEL or progression of pre-existing PEL.     

Rapamycin prevents Concanavalin A-induced liver injury by inhibiting lymphocyte activation

Background and Aims:  Liver injury induced by Concanavalin A (Con A) is often used as a model to study the pathophysiology of immune mediated liver injury. Rapamycin (Rapa) is an effective immunosuppressant widely used for preventing immune activation and transplant rejection. However, the effect of Rapa on liver injury caused by Con A has not been carefully examined. In the present study, we examined the effect of Rapa on liver injury caused by Con A.
Methods:  Mice received intraperitoneal Rapa injection before Con A intravenous administration. The liver injury was examined by measuring serum transaminase and pathology, and the level of cytokines was detected by enzyme linked immunosorbent assay (ELISA).
Results:  In the present study, we examined the effect of Rapa on liver injury after Con A injection in mice. We found that the treatment of mice with Rapa protected the liver from Con A-induced injury. Pretreatment with Rapa dramatically ameliorated Con A-induced mortality. This protection was associated with reduced transaminase levels in the blood and further confirmed by liver histology. ELISA showed that Rapa suppressed pro-inflammatory cytokines IFN-γ and TNF-α production as compared with the untreated controls. Furthermore, intrahepatic lymphocyte proliferation was significantly inhibited.
Conclusion:  These findings suggested that Rapa has the therapeutic potential for treatment of immune-mediated liver injury in the clinic.     

Ras homologue enriched in brain is a critical target of farnesyltransferase inhibitors in non-small cell lung cancer cells

The purpose of this work is to study mechanisms underlying anti-tumor effects of farnesyltransferase inhibitors (FTIs) in non-small cell lung cancer (NSCLC). We demonstrate that mRNA and protein levels of Ras homologue enriched in brain (Rheb) are highly expressed both in NSCLC tissues and in NSCLC cell lines. Rheb expression levels correlate with phosphorylation of its downstream target S6 and the sensitivity of NSCLC cells to FTIs (R115777 and SCH66336)-induced growth inhibition and apoptosis. FTIs effectively and preferentially inhibited Rheb downstream signaling in NSCLC cells. Moreover, inhibition of Rheb functions by FTIs or dominant-negative Rheb mutants enhance the effects of cisplatin on NSCLC cells. Rheb-CSVL, a FTIs-resistant mutant, reduces the effects of FTIs on NSCLC cells. Our results suggest that Rheb is a critical target for FTIs therapy in NSCLC.     

mTOR inhibitor everolimus ameliorates progressive tubular dysfunction in chronic renal failure rats

Responsible factors in progressive tubular dysfunction in chronic renal failure have not been fully identified. In the present study, we hypothesized that the mammalian target of rapamycin, mTOR, was a key molecule in the degenerative and progressive tubular damage in chronic renal failure. Everolimus, an mTOR inhibitor, was administered for 14 days in 5/6 nephrectomized (Nx) rats at 2 and 8 weeks after renal ablation. Marked activation of the mTOR pathway was found at glomeruli and proximal tubules in remnant kidneys of Nx rats. The reduced expression levels of the phosphorylated S6 indicated the satisfactory pharmacological effects of treatment with everolimus for 14 days. Everolimus suppressed the accumulation of smooth muscle alpha actin, infiltration of macrophages and expression of kidney injury molecule-1 in the proximal tubules. In addition, everolimus-treatment restored the tubular reabsorption of albumin, and had a restorative effect on the expression levels of membrane transporters in the polarized proximal tubular epithelium, when its administration was started at 8 weeks after Nx. These results indicate that the constitutively activated mTOR pathway in proximal tubules has an important role in the progressive tubular dysfunction, and that mTOR inhibitors have renoprotective effects to improve the proximal tubular functions in end-stage renal disease.     

亲免素结合类免疫抑制剂作用的分子机理

随着环孢素、FK5 0 6及雷帕霉素等生物制剂类免疫抑制剂在器官移植时的免疫抑制及治疗自身免疫性疾病的成功应用 ,对其生物作用机理有了一定认识。发现了生物体内存在其天然配基亲免素 ,并通过形成药物 亲免素复合物发挥免疫抑制作用 ,故又称为亲免素结合类免疫抑制剂。近年来研究证实 ,药物 亲免素复合物分别作用于细胞信号传递体系中的钙调磷酸酶与雷帕霉素靶蛋白 ,从而影响免疫细胞的蛋白质生物合成 ,细胞的增殖和生存 ,达到免疫抑制的作用。     

Time course of MPTP toxicity on translational control protein expression in mice brain

The present study investigated in mice brain, the time course of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity on the expression of translational control proteins.     

Hormesis as a Pro-Healthy Aging Intervention in Human Beings?

Hormesis is a phenomenon in which adaptive responses to low doses of otherwise harmful factors (also called mild stressors) make cells and organisms more robust. Aging is a complex and poorly understood process. This review explores the positive effects of hormesis on aging in animal models and human cell cultures, and discusses whether it might apply to humans. As an example, repeated mild heat stress confers anti-aging benefits to normal human cells in culture. Calorie restriction and xenohormetic compounds such as resveratrol, in large part via activation of sirtuins, decrease risk of common age-related conditions, such as cancer, cardiovascular disease, type 2 diabetes, and neurological diseases, so lengthening lifespan. Mild stressors and xenohormetic dietary components have diverse molecular targets and affect many pathways. Despite experimental advances in aging research, findings in humans are still quite limited. Moderate-intensity exercise, weight management and healthy diet ameliorate diseases of aging to increase lifespan and this could involve hormesis.     

干预癫痫大鼠自噬活性对小胶质细胞激活状态及肿瘤坏死因子-α分泌的影响及意义

目的观察干预癫痫大鼠自噬活性对小胶质细胞激活状态及分泌肿瘤坏死因子-α(TNF-α)水平变化的影响,探讨其对神经元以及癫痫状态的影响。方法 Wistar大鼠随机分为正常对照组(6只)与癫痫组(24只);癫痫组大鼠采用戊四氮制作癫痫模型,造模成功后随机分为致痫对照组、3-甲基嘌呤(3-MA)组及雷帕霉素(RAPA)组,每组各6只。观察记录各组大鼠行为学及脑电图变化,采用HE及Nissl染色观察CA1区神经元损伤情况,免疫荧光染色及Western blot检测海马组织LC3、CD68及TNF-α的表达。结果致痫对照组显示癫痫可导致神经元损伤,LC3、CD68、TNF-α的表达较正常对照组显著增加(P0.05)。3-MA组与致痫对照组相比癫痫发作等级降低;神经元损伤数目减少;LC3、CD68、TNF-α的表达显著降低(P0.05)。RAPA组大鼠癫痫发作等级、CD68和TNF-α的表达较致痫对照组无明显变化(P0.05);但神经元损伤数目及LC3的表达进一步增加(P0.05)。结论癫痫过程中存在自噬现象,其可激活小胶质细胞,促进TNF-α分泌,导致神经元损伤;而抑制自噬活性可调控小胶质细胞,减少TNF-α的分泌,保护神经元,从而减轻癫痫发作状态。