■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

Stem cells are defined as cells able to both extensively self-renew and differentiate into progenitors. Research data show that more resistant stem cells than common cancer cells exist in cancer patients.To identify unrecognized differences between cancer stem cells and cancer cells might be able to develope effective classification,diagnose and treat ment for cancer.

Stem Cells,Cancer and Cancer Stem Cells

Disorders characterized by ischemia/reperfusion (I/R), such as myocardial infarction, stroke, and peripheral vascular disease, continue to be among the most frequent causes of debilitating disease and death. Tissue injury and/or death occur as a result of the initial ischemic insult, which is determined primarily by the magnitude and duration of the interruption in the blood supply, and then subsequent damage induced by reperfusion. During prolonged ischemia, ATP levels and intracellular pH decrease as a result of anaerobic metabolism and lactate accumulation. As a consequence, ATPase-dependent ion transport mechanisms become dysfunctional, contributing to increased intracellular and mitochondrial calcium levels (calcium overload), cell swelling and rupture, and cell death by necrotic, necroptotic, apoptotic, and autophagic mechanisms. Although oxygen levels are restored upon reperfusion, a surge in the generation of reactive oxygen species occurs and proinflammatory neutrophils infiltrate ischemic tissues to exacerbate ischemic injury. The pathologic events induced by I/R orchestrate the opening of the mitochondrial permeability transition pore, which appears to represent a common end-effector of the pathologic events initiated by I/R. The aim of this treatise is to provide a comprehensive review of the mechanisms underlying the development of I/R injury, from which it should be apparent that a combination of molecular and cellular approaches targeting multiple pathologic processes to limit the extent of I/R injury must be adopted to enhance resistance to cell death and increase regenerative capacity in order to effect long-lasting repair of ischemic tissues.

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Cell Biology of Ischemia/Reperfusion Injury

A report of two cases

Although they were originally defined as haematopoietic-cell growth factors, colony-stimulating factors (CSFs) have been shown to have additional functions by acting directly on mature myeloid cells. Recent data from animal models indicate that the depletion of CSFs has therapeutic benefit in many inflammatory and/or autoimmune conditions and as a result, early-phase clinical trials targeting granulocyte/macrophage colony-stimulating factor and macrophage colony-stimulating factor have now commenced. The distinct biological features of CSFs offer opportunities for specific targeting, but with some associated risks. Here, I describe these biological features, discuss the probable specific outcomes of targeting CSFs in vivo and highlight outstanding questions that need to be addressed.

Colony-stimulating factors in inflammation and autoimmunity.

As a result of ischemia or hemorrhage, blood supply to neurons is disrupted which subsequently promotes a cas-cade of pathophysiological responses resulting in cell loss. Many mechanisms are involved solely or in combination in this disorder including excitotoxicity, mitochondrial death pathways, and the release of free radicals, protein misfolding, apopto-sis, necrosis, autophagy and inflammation. Besides neuronal cell loss, damage to and loss of astrocytes as well as injury to white matter contributes also to cerebral injury. The core problem in stroke is the loss of neuronal cells which makes recov-ery difficult or even not possible in the late states. Acute treatment options that can be applied for stroke are mainly targeting re-establishment of blood flow and hence, their use is limited due to the effective time window of thrombolytic agents. How-ever, if the acute time window is exceeded, neuronal loss starts due to the activation of cell death pathways. This review will explore the most updated cellular death mechanisms leading to neuronal loss in stroke. Ischemic and hemorrhagic stroke as well as subarachnoid hemorrhage will be debated in the light of cell death mechanisms and possible novel molecular and cel-lular treatment options will be discussed.

/pdf/cell-death-mechanisms-in-stroke-and-novel-molecular-and-582yxycxe5.pdf

Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options.

Lipid peroxidation has been reported to play an important role in spinal cord injury (SCI). Erythropoietin (EPO) is a hematopoietic growth factor that stimulates proliferation and differentiation of erythroid precursor cells and is also known to exert neurotrophic activity in the central nervous system. The purpose of this study was to investigate the effectiveness of recombinant human EPO in attenuating the severity of experimental SCI. Rats were divided into seven groups. Controls (1) received only laminectomy. The trauma-only group (2) underwent 50-g/cm contusion injury and had no medication. In group 3, 30 mg/kg of methylprednisolone was introduced. The vehicle group (4) received vehicle solution containing human serum albumin, which is a solvent of EPO. Groups 5, 6, and 7 received 100 IU/kg, 1,000 IU/kg, and 5,000 IU/kg of EPO, respectively. All treatments were given as single doses, intraperitoneally, immediately after injury. Thiobarbituric acid-reactive substances were estimated to demonstrate lipid peroxidation, and ultrastructure was evaluated by electron microscopy. The results showed that lipid peroxidation by-products increased after injury. Administration of EPO and methylprednisolone sodium succinate (MPSS) reduced thiobarbituric acid-reactive substances after trauma. The best biochemical results were obtained with 5,000 IU/kg of EPO. Electron microscopic findings showed that EPO protected the spinal cord from injury. Although 1,000 IU/kg and 5,000 IU/kg of EPO inhibited lipid peroxidation better than MPSS, ultrastructural neuroprotection was similar.

Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat.

Background and Purpose— Granulocyte-colony stimulating factor (G-CSF) is a growth factor that orchestrates the proliferation, differentiation, and survival of hematopoietic progenitor cells. It has been used for many years in clinical practice to accelerate the recovery of patients from neutropenia after cytotoxic therapy. However, there is a growing body of evidence from experimental studies suggesting that G-CSF also has important nonhematopoietic functions in the central nervous system. Summary of Review— The presence of the G-CSF/G-CSF–receptor system in the brain and its role in neuroprotection and neural tissue repair has been investigated in many recent studies. The neuroprotective actions of G-CSF have mainly been attributed to its anti-inflammatory and antiapoptotic effects. Furthermore, it induces neurogenesis and angiogenesis and improves functional recovery. In this review, we summarize the role of G-CSF and the corresponding signal transduction pathways regulated by G-CSF in neuroprotection. ...

A Novel Neuroprotectant Granulocyte-Colony Stimulating Factor


Objective. The aim of this study was to show the effect of erythropoietin on ischemia-reperfusion-induced oxidative damage in fetal rat brain. 
Methods. Fetal brain ischemia was induced by clamping the utero-ovarian artery bilaterally for 20 min, and reperfusion was achieved by removing the clamps for 30 min. The control group was made up of noninjured rats that were 19 days pregnant. In the ischemia-reperfusion group no treatment was given, while 0.4 ml of human serum albumin solution and 5,000 U/kg recombinant human erythropoietin (r-Hu-EPO) were administered in the vehicle and treatment groups 30 min before ischemia-reperfusion injury. Lipid peroxidation in the brain tissue was determined as the concentration of thiobarbituric acid-reactive substances (TBARS) for each fetal rat. A one-way analysis of variance and the post-hoc test were used for statistical analysis. 
Results. TBARS increased to statistically significantly higher levels in fetal rat brain after ischemia-reperfusion injury than were found in the control group. Recombinant human erythropoietin prevented the increase in TBARS after ischemia-reperfusion injury. 
Conclusion. Recombinant human erythropoietin has been shown to have neuroprotective effect in intrauterine ischemia-reperfusion-induced fetal brain damage in rats.

Ihsan Solaroglu

Papers

Cell Death Mechanisms in Stroke and Novel Molecular and Cellular Treatment Options.

Erythropoietin exerts neuroprotection after acute spinal cord injury in rats: effect on lipid peroxidation and early ultrastructural findings

Anti-apoptotic effect of granulocyte-colony stimulating factor after focal cerebral ischemia in the rat.

A Novel Neuroprotectant Granulocyte-Colony Stimulating Factor

Erythropoietin prevents ischemia-reperfusion from inducing oxidative damage in fetal rat brain.