Upregulation Of Antiapoptotic Protein BCL-XL Research Articles

Acute Antiapoptotic Effects of Hydrocortisone in the Hippocampus of Neonatal Rats

Natural glucocorticoid hydrocortisone was suggested as a potent substitution for dexamethasone in the treatment of bronchopulmonary dysplasia in neonates. The aim of this study was to investigate whether hydrocortisone is able to affect the expression of apoptotic genes and the intensity of naturally occurring cell death in the developing rat hippocampus. Hormone treatment decreased procaspase-3 and active caspase-3 levels as well as DNA fragmentation intensity in the hippocampal formation of one-week-old rats in 6 h after injection. These changes were accompanied by an upregulation of antiapoptotic protein Bcl-XL, while expression of proapoptotic protein Bax remained unchanged. The action of hydrocortisone was glucocorticoid receptor-independent, as the selective glucocorticoid receptor agonist dexamethasone did not affect either apoptotic protein levels or DNA fragmentation intensity in the hippocampal region. The data are the first evidences for in vivo antiapoptotic effects of hydrocortisone in the developing hippocampus.

Granulocyte Colony-Stimulating Factor (G-CSF) Protects Oligpdendrocyte and Promotes Hindlimb Functional Recovery after Spinal Cord Injury in Rats

BackgroundGranulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of cells in the granulocytic lineage. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction and we previously reported the same effect in studies of murine spinal cord injury (SCI). The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for SCI in rats.MethodsAdult female Sprague-Dawley rats were used in the present study. Contusive SCI was introduced using the Infinite Horizon Impactor (magnitude: 200 kilodyne). Recombinant human G-CSF (15.0 µg/kg) was administered by tail vein injection at 1 h after surgery and daily the next four days. The vehicle control rats received equal volumes of normal saline at the same time points.ResultsUsing a contusive SCI model to examine the neuroprotective potential of G-CSF, we found that G-CSF suppressed the expression of pro-inflammatory cytokine (IL-1 beta and TNF- alpha) in mRNA and protein levels. Histological assessment with luxol fast blue staining revealed that the area of white matter spared in the injured spinal cord was significantly larger in G-CSF-treated rats. Immunohistochemical analysis showed that G-CSF promoted up-regulation of anti-apoptotic protein Bcl-Xl on oligpodendrocytes and suppressed apoptosis of oligodendrocytes after SCI. Moreover, administration of G-CSF promoted better functional recovery of hind limbs.ConclusionsG-CSF protects oligodendrocyte from SCI-induced cell death via the suppression of inflammatory cytokines and up-regulation of anti-apoptotic protein. As a result, G-CSF attenuates white matter loss and promotes hindlimb functional recovery.

Neuroprotective effects of salidroside against beta-amyloid-induced oxidative stress in SH-SY5Y human neuroblastoma cells

Beta-amyloid (Aβ) peptide, the hallmark of Alzheimer's disease (AD), invokes a cascade of oxidative damages to neurons and eventually leads to neuronal death. In this study, salidroside (Sald), an active compound isolated from a traditional Chinese medicinal plant, Rhodiola rosea L., was investigated to assess its protective effects and the underlying mechanisms against Aβ-induced oxidative stress in SH-SY5Y human neuroblastoma cells. Aβ25–35-induced neuronal toxicity was characterized by the decrease of cell viability, the release of lactate dehydrogenase (LDH), morphological alterations, neuronal DNA condensation, and the cleavage of poly(ADP-ribose) polymerase (PARP) by activated caspase-3. Pretreatment with salidroside markedly attenuated Aβ25–35-induced loss of cell viability and apoptosis in a dose-dependent manner. The mechanisms of salidroside protected neurons from oxidative stress included the induction of antioxidant enzymes, thioredoxin (Trx), heme oxygenase-1 (HO-1), and peroxiredoxin-I (PrxI); the downregulation of pro-apoptotic protein Bax and the upregulation of anti-apoptotic protein Bcl-XL. Furthermore, salidroside dose-dependently restored Aβ25–35-induced loss of mitochondrial membrane potential (MMP) as well as suppressed the elevation of intracellular reactive oxygen species (ROS) level. It was also observed that Aβ25–35 stimulated the phosphorylation of mitogen-activated protein (MAP) kinases, including c-Jun NH2-terminal kinase (JNK) and p38 MAP kinase, but not extracellular signal-regulated kinase1/2 (ERK1/2). Salidroside inhibited Aβ25–35-induced phosphorylation of JNK and p38 MAP kinase, but not ERK1/2. These results suggest that salidroside has protective effects against Aβ25–35-induced oxidative stress, which might be a potential therapeutic agent for treating or preventing neurodegenerative diseases.

Rapamycin reverses TLR4 signaling-triggered tumor apoptosis resistance by disrupting Akt-mediated Bcl-xL upregulation

Toll-like receptor 4 (TLR4) signaling in tumor cells can promote tumor escape and tumor progression, for which TLR4-triggered resistance of tumor cells to apoptosis has been proposed as one of the mechanisms. Rapamycin is an immunosuppressant agent widely used for treatment of transplantation rejection and autoimmune diseases, and recently used for cancer therapy. However, the underlying mechanisms responsible for antitumor effects of rapamycin remain to be fully elucidated. Here we report that rapamycin can reverse TLR4-triggered resistance of colon cancer cells to oxaloplatin- or doxorubicin-induced apoptosis by disrupting Akt and subsequent NF-κB activation, suppressing upregulation of anti-apoptotic protein Bcl-xL. Furthermore, Akt/NF-κB inhibitors also reverses the apoptosis resistance, accordingly, Akt constitutive activation rescues NF-κB activation and Bcl-xL expression in rapamycin-pretreated colon cancer cells, suggesting Akt disruption is critical to the process. Therefore, rapamycin may abrogate TLR4-triggered tumor apoptosis resistance by inhibiting Akt/NF-κB pathways and Bcl-xL expression, providing experimental evidence for the anti-tumor effect of rapamycin.

Inhibition of apoptosis, activation of NKT cell and upregulation of CD40 and CD40L mediated by M. leprae antigen(s) combined with Murabutide and Trat peptide in leprosy patients

Protective immunity against intracellular pathogen Mycobacterium leprae is dependent on the activation of T cells. Repeated stimulation of T cells by M. leprae antigens MLCwA (M. leprae total cell wall antigen) and ManLAM (mannose-capped lipoarabinomannan), may lead to apoptosis in leprosy patients. In the present study, inhibition of the Fas-induced apoptosis of peripheral blood mononuclear cells of leprosy patients was investigated using above M. leprae antigen(s), in combination with immunomodulators murabutide (MB) and a Trat peptide in particulate form (liposome). Incubation of the cells with antigen containing the two immunomodulators in particulate form (liposomes) led to decrease in percentage of propidium iodide positive cells and T cells expressing Fas-FasL as well as decreased caspase-8/-3 activities in lepromatous patients, thereby inhibiting apoptosis, while converse was true upon stimulation with soluble antigen. Concurrently, there was an upregulation of antiapoptotic protein Bcl-xL in lepromatous patients, leading to the inhibition of apoptosis. It was also observed that same formulation upregulated the expression of CD40 on B cells and monocytes-macrophages and CD40L on T cells of lepromatous leprosy patients. The same liposomal formulation significantly increased the expression of CD1b and CD1d on monocytes-macrophages as well as percentage of NKT cells secreting IFN-gamma in lepromatous leprosy patients. Thus, the liposomal formulation of antigen with the immunomodulators in vitro promoted the activation of CD40:CD40L pathways and NKT cell function involved in providing cell-mediated immunity to these patients. The same formulation also caused reversal of T cell anergy by inhibiting apoptosis through decreased expression of death receptors (Fas-FasL) and caspase activities (3 and 8) and increased expression of antiapoptotic protein Bcl-xL in these patients.