The role of Fas-mediated apoptosis in thyroid disease

Recent evidence has emphasized the importance of apoptosis in the maintenance of tissue homeostasis and the pathogenesis of malignant and immune diseases. Autoimmune thyroid diseases such as Hashimoto's thyroiditis and Graves' disease, as well as other autoimmune endocrine diseases, have been associated with dysregulation of apoptotic signaling pathways. In particular, dysfunction of the Fas apoptotic pathway or production of soluble factors including soluble Fas and soluble Fas ligand may be involved in the pathogenesis of these disorders. On the other hand, malignant thyroid cells may avoid Fas-mediated suicide possibly by expression of inhibitors of apoptosis and evade the immune system by inducing apoptosis on infiltrating lymphocytes. The delicate balance between cell proliferation and cell death through the Fas pathway may also play an important role in the control of thyroid cell mass and goitrogenesis. This review analyzes the current evidence on the role of Fas-mediated apoptosis in the pathogenesis of thyroid diseases including Hashimoto's thyroiditis, Graves' disease, thyroid cancer and goiter. However, the exact mechanisms involved in the regulation of apoptosis in thyroid disease remain unclear. Further investigation is needed.     

Involvement of epithelial cell apoptosis in interstitial lung diseases

Lung epithelium is the primary site of lung damage in interstitial lung diseases. Although there are various initiating factors, the terminal stages are characterized by pulmonary fibrosis. Conventional therapy consisting of glucocorticoids or immunosuppressive drugs is usually ineffective. Epithelial cell apoptosis have been considered to be initial events in interstitial lung diseases. The death receptor-mediated signaling pathway directly induces caspase activation and apoptosis. Other stresses induce the release of cytochrome from mitochondria and caspase activation. Endoplasmic reticulum stress also induces apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of the coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymal interaction plays important roles in these processes. Further understanding of apoptosis signaling may lead to effective strategies against devastating lung diseases. We review the role of epithelial cell apoptosis in the molecular mechanisms of pulmonary fibrosis.     

Extracorporeal photopheresis reverses experimental graft-versus-host disease through regulatory T cells

Extracorporeal photopheresis (ECP), a technique that exposes isolated white blood cells to photoactivatable 8-methoxypsoralen and ultraviolet A radiation, is used clinically to treat cutaneous T-cell lymphoma and immune-mediated diseases such as graft-versus-host disease (GVHD). ECP is thought to control these diseases in part through direct induction of lymphocyte apoptosis, but its effects on the immune system beyond apoptosis remain poorly characterized. We have developed a novel method for incorporating ECP treatment into well-established and clinically relevant murine models of GVHD to examine its effects during an ongoing immune response. We demonstrate that the transfer of cells treated with ECP reverses established GVHD by increasing donor regulatory T cells and indirectly reducing the number of donor effector lymphocytes that themselves had never been exposed to psoralen and ultraviolet A radiation.     

外周型苯二氮受体与中枢神经系统疾病

中枢神经系统内的外周型苯二氮受体(PBR)主要分布在小胶质细胞线粒体外膜,参与调控神经类固醇的合成以及神经元的凋亡过程。最近的研究表明,PBR在各种中枢神经系统疾病,如神经变性、肿瘤、炎症、脱髓鞘、脑缺血、脑创伤、癫癎和肝性脑病中表达明显上调。PBR已成为反映体内外神经病理学改变的一种敏感而特异的定量指标。深入研究PBR在中枢神经系统疾病中的作用机制,有可能为这些疾病的治疗找到一条新的途径。     

Apoptosis in hepatic pathophysiology

Apoptosis is a fundamental biologic process that is important in many physiologic and pathophysiologic processes in the liver. Although dysregulation of apoptosis may contribute to a wide range of diseases, the role of this process in liver disease and pathophysiology has only recently begun to be recognized and remains to be fully defined. Several important questions remain unanswered: How does excessive apoptosis in response to injury contribute to inflammation and fibrogenesis in the liver? How does control of apoptosis contribute to the regulation of hepatic structure following injury? What is the role of death receptors in hepatic disease? Can an understanding of apoptosis be helpful in therapeutic modulation of specific liver diseases or liver cancer? The identification of target molecules involved in apoptosis raises the prospect of pharmacologic modulation that may result in better treatment options for patients with liver diseases. Inhibition of apoptosis is likely to be useful in treating fulminant hepatic failure or in organ preservation before transplantation. In these situations, treatment is for a limited period, and the potential hazards of nonselective long-term inhibition of apoptosis are minimized. Safe and organ-specific inhibitors of apoptosis would be required for prolonged treatment of chronic liver diseases. For treatment of liver tumors, the goal is to induce apoptosis selectively in cancer cells. Drugs that decrease the apoptotic threshold by modulating the intracellular regulatory mechanisms and drugs that enhance the susceptibility of cancer cells to undergo immune-mediated apoptosis will be useful in the treatment of liver cancers. The rapid advances in the understanding of the intracellular mechanisms and the regulation of apoptosis will ultimately result in a better understanding of the role of apoptosis in the pathophysiology of liver diseases and may allow therapeutic modulation of this process.     

CD95 engagement induces disseminated endothelial cell apoptosis in vivo: immunopathologic implications

Fas (CD95) is a death receptor involved in apoptosis induction on engagement by Fas ligand (CD95L). Although CD95L-mediated apoptosis has been proposed as a pathogenic mechanism in a wide range of diseases, including graft-versus-host disease, systemic CD95 engagement in mice by agonistic CD95-specific antibodies or by soluble multimeric CD95L (smCD95L), though lethal, has been reported to cause apoptosis only in a limited range of cell types, that is, hepatocytes, hepatic sinusoidal endothelial cells, and lymphocytes. Another member of the tumor necrosis factor (TNF)/CD95L family, TNF-alpha, induces disseminated vascular endothelial cell apoptosis, which precedes apoptosis of other cell types and lethal multiorgan failure. Here we show that systemic CD95 engagement in vivo by agonistic CD95-specific antibody or smCD95L causes rapid, extensive, and disseminated endothelial cell apoptosis throughout the body, by a mechanism that does not depend on TNF-alpha. Disseminated endothelial cell apoptosis was also the first detectable lesion in a murine model of acute tissue damage induced by systemic transfer of allogeneic lymphocytes and did not occur when allogeneic lymphocytes were from CD95L-defective mice. Both vascular and additional tissue lesions induced by agonistic CD95-specific antibody, smCD95L, or allogeneic lymphocytes were prevented by treatment with an inhibitor of caspase-8, the upstream caspase coupled to CD95 death signaling. Vascular lesions are likely to play an important role in the pathogenesis of allogeneic immune responses and of other diseases involving circulating CD95L-expressing cells or smCD95L, and the prevention of CD95-mediated death signaling in endothelial cells may have therapeutic implications in these diseases.     

Hyperthermia induces platelet apoptosis and glycoprotein Ibα ectodomain shedding

Hemorrhage is a significant pathological feature of some fever or hyperthermia-related diseases, such as dengue fever and heatstroke. Although the mechanisms of hemorrhage in these diseases are thought to be complex, whether there is an association between hemorrhage and hyperthermia or fever remains unclear. Platelets play a central role in maintaining integrity of endothelium and biological hemostasis. To explore the effect of hyperthermia on platelet physiology, platelet-rich plasma or washed platelets were incubated at hypothermia (22°C), normothermia (37°C) or hyperthermia (40 and 42°C) for 1 or 2 hours. ADP and α-thrombin induced platelet aggregations were obviously reduced in platelets incubated at hyperthermia. Hyperthermia induced apoptotic events in platelets, including depolarization of mitochondrial inner transmembrane potential, caspase-3 dependent gelsolin cleavage and phosphatidylserine exposure. Furthermore, hyperthermia incurred platelet glycoprotein Ibα ectodomain shedding. Thus, these data suggest that hyperthermia induces platelet apoptosis and dysfunction. These findings have important implications for the pathogenesis of hemorrhage in fever or hyperthermia-related diseases, and also suggest that attention should be paid to platelet apoptosis under relatively high temperature conditions.     

激活素A与肝脏疾病

激活素A是一种具有广泛生物学作用的细胞因子,在肝脏其作用主要表现为抑制细胞增殖、诱导细胞凋亡、促进细胞外基质合成分泌、抑制肿瘤细胞增殖及转移.研究发现急、慢性肝炎、肝纤维化、肝硬化、肝癌及肝功能衰竭等疾病发生发展中均有激活素A表达异常,提示激活素A信号异常可能参与了这些肝脏疾病的发生发展过程.     

Lysosomal destabilization in p53-induced apoptosis

The tumor suppressor wild-type p53 can induce apoptosis. M1-t-p53 myeloid leukemic cells have a temperature-sensitive p53 protein that changes its conformation to wild-type p53 after transfer from 37 degrees C to 32 degrees C. We have now found that these cells showed an early lysosomal rupture after transfer to 32 degrees C. Mitochondrial damage, including decreased membrane potential and release of cytochrome c, and the appearance of apoptotic cells occurred later. Lysosomal rupture, mitochondrial damage, and apoptosis were all inhibited by the cytokine IL-6. Some other compounds can also inhibit apoptosis induced by p53. The protease inhibitor N-tosyl-l-phenylalanine chloromethyl ketone inhibited the decrease in mitochondrial membrane potential and cytochrome c release, the Ca(2+)-ATPase inhibitor thapsigargin inhibited only cytochrome c release, and the antioxidant butylated hydroxyanisole inhibited only the decrease in mitochondrial membrane potential. In contrast to IL-6, these other compounds that inhibited some of the later occurring mitochondrial damage did not inhibit the earlier p53-induced lysosomal damage. The results indicate that apoptosis is induced by p53 through a lysosomal-mitochondrial pathway that is initiated by lysosomal destabilization, and that this pathway can be dissected by using different apoptosis inhibitors. These findings on the induction of p53-induced lysosomal destabilization can also help to formulate new therapies for diseases with apoptotic disorders.     

Advances in apoptosis research

Apoptosis, also called programmed cell death, has attracted great attention in recent years. After its discovery by Carl Vogt in 1842, apoptosis research was dormant for more than a century. Its rediscovery in the second half of this century, and the coining of the term apoptosis in 1972 by Kerr, Wyllie, and Currie, ignited an unparalleled interest in this field of science. The number of publications related to apoptosis has been growing exponentially every year ever since. This is mainly due to three major advances, two of which have been made recently and one that is currently seen. First, studies with the small nematode Caenorhabditis elegans have identified a number of apoptosis regulating genes—the first evidence that cell death is an active process under genetic control. Many of these genes have mammalian homologs that, like their worm counterparts, seem to regulate mammalian apoptosis. Second, elucidation of the signal transduction pathways of apoptosis has lead especially to the identification of specific death signaling molecules such as a new family of cysteine proteases, the caspases. Third, it has now become clear that many diseases are characterized by dysregulation of apoptotic programs. Many of these programs involve a family of receptors and their ligands, the death receptor/ligand family. The hope now is to interfere with apoptosis regulation in these systems and to develop new therapeutic concepts.     

Apoptosis in cardiovascular remodeling--effect of medication

In the last decade, apoptosis has emerged as a key determinant of target organ damage in cardiovascular diseases. The suggestion that increased cardiomyocyte apoptosis participates in the etiology of heart failure probably contributed to the negative view of the prevalence of apoptosis in the field of cardiovascular diseases. However, we and others have shown that up-regulation of apoptosis in certain cardiovascular cells may contribute to the beneficial action of antihypertensive drugs on target-organ structure. As an explanation for this apparent discrepancy, the same stimulus, e.g. angiotensin II, can induce apoptosis or stimulate cell growth in different cell types (e.g., cardiomyocytes and fibroblasts, respectively). Using the angiotensin pathway as a paradigm, this review proposes an integrative view of cell growth and cell death regulation in cardiovascular cells in order to illustrate how cell-specific responses to the same stimulus may in part explain the patterns of cell population dynamics during the development and treatment of target organ damage in hypertension.     

Mechanism of ASK1 involvement in liver diseases and related potential therapeutic targets: A critical pathway molecule worth investigating

Since the discovery of apoptosis signal-regulated kinase 1 (ASK1), the signal transduction mechanism and pathophysiological process involved in its regulation have been continuously revealed. Many previous studies have identified that ASK1 is involved and plays a critical role in the development of diseases affecting the nervous, cardiac, renal, and other systems. As a mitogen-activated protein kinase (MAPK) kinase kinase, ASK1 mediates apoptosis, necrosis, inflammation, and other pathological processes by activating its downstream c-Jun N-terminal kinase (JNK)/p38 MAPK. Owing to the important role of ASK1, an increasing number of studies in recent years have focused on its status in liver-related diseases. In this paper, we review the mechanisms and targets of ASK1 in liver-related diseases to emphasize its important role in the development of liver disease.     

Role of p53 in lung tissue remodeling

The tumor suppressor gene p53 regulates a wide range of cellular processes including cell cycle progression, proliferation, apoptosis and tissue development and remodeling. Lung cell apoptosis and tissue remodeling have critical roles in many lung diseases. Abnormal proliferation or resistance to apoptosis of lung cells will lead to structural changes of many lung tissues, including the pulmonary vascular wall, small airways and lung parenchyma. Among the many lung diseases caused by vascular cell apoptosis and tissue remodeling are chronic obstructive pulmonary disease, bronchial asthma and pulmonary arterial hypertension. Recent advances in biology and medicine have provided new insights and have resulted in new therapeutic strategies for tissue remodeling in human and animal models. This review is focused on lung disease susceptibility associated with the p53 pathway and describes molecular mechanisms upstream and downstream of p53 in lung tissue remodeling. Improved understanding of structural changes associated with pulmonary vascular remodeling and lung cell apoptosis induced by the p53 pathway may new provide therapeutic targets.     

氯离子通道与缺血性卒中

缺血性卒中是发病率和致残率最高的疾病之一.高血压是公认的缺血性卒中最重要的独立危险因素,在高血压发展过程中出现的血管重构是引发缺血性卒中的病理学基础.研究表明,血管平滑肌细胞异常增殖和凋亡都将导致血管重构.此外,脑缺血再灌注可导致神经元损伤和凋亡.近来的研究表明,血管重构和神经元凋亡都与氯离子通道有关.至少3种氯离子通道参与这些过程:容积调控的氯离子通道、钙激活的氯离子通道以及囊性纤维跨膜电导调节体.文章就这3种氯离子通道在血管重构、神经元凋亡以及缺血性卒中中的作用进行了综述.     

Melatonin and endoplasmic reticulum stress: relation to autophagy and apoptosis

Endoplasmic reticulum (ER) is a dynamic organelle that participates in a number of cellular functions by controlling lipid metabolism, calcium stores, and proteostasis. Under stressful situations, the ER environment is compromised, and protein maturation is impaired; this causes misfolded proteins to accumulate and a characteristic stress response named unfolded protein response (UPR). UPR protects cells from stress and contributes to cellular homeostasis re‐establishment; however, during prolonged ER stress, UPR activation promotes cell death. ER stressors can modulate autophagy which in turn, depending of the situation, induces cell survival or death. Interactions of different autophagy‐ and apoptosis‐related proteins and also common signaling pathways have been found, suggesting an interplay between these cellular processes, although their dynamic features are still unknown. A number of pathologies including metabolic, neurodegenerative and cardiovascular diseases, cancer, inflammation, and viral infections are associated with ER stress, leading to a growing interest in targeting components of the UPR as a therapeutic strategy. Melatonin has a variety of antioxidant, anti‐inflammatory, and antitumor effects. As such, it modulates apoptosis and autophagy in cancer cells, neurodegeneration and the development of liver diseases as well as other pathologies. Here, we review the effects of melatonin on the main ER stress mechanisms, focusing on its ability to regulate the autophagic and apoptotic processes. As the number of studies that have analyzed ER stress modulation by this indole remains limited, further research is necessary for a better understanding of the crosstalk between ER stress, autophagy, and apoptosis and to clearly delineate the mechanisms by which melatonin modulates these responses.     

miRNA与消化系统肿瘤的关系

微小RNA(miRNA)是一类广泛存在于多种生物体内的长度约22个核苷酸的非编码小分子RNA,能够在后转录水平负调控基因表达.miRNA在细胞产生、增殖及凋亡过程中发挥特有的负性调控作用,与人类许多疾病(包括肿瘤)的发生发展密切相关.近来的研究证实miRNA在人类肿瘤中可能是潜在的癌基因或抑癌基因,本文就miRNA与消化系统肿瘤的关系的研究进展作一综述.     

Apoptosis and myofibroblasts in the pathogenesis of systemic sclerosis

Tissue fibrosis is the result of a complex series of events focusing on regulation of fibroblast proliferation, synthesis of extracellular matrix, and apoptosis. Transforming growth factor-beta is important for the stimulation of the fibrotic response by promoting the production of extracellular matrix proteins, by promoting the differentiation of the myofibroblast cell morphology, and by protecting these cells against apoptotic stimuli. Other cytokines such as interleukin-1 may have stimulatory and counter-regulatory effects on fibrosis. The effects of these signaling molecules depend on cellular environment and are organ specific. Furthermore, intercellular interactions and cell-matrix interactions can stimulate or inhibit the apoptotic pathway. Through selective inhibition of apoptosis in myofibroblasts, fibrosis can become dysregulated and lead to diseases such as systemic sclerosis.     

Intracellular signaling pathways, apoptosis and neurodegenerative diseases

Progressive regional loss of neurons underlies the irreversible pathology of various neurodegenerative brain diseases. In mature organisms, neurons die either by necrosis or apoptosis. Apoptotic neuronal cell death is the cardinal feature of aging and neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's diseases, but its mechanisms remain unsolved. Cysteine proteases like caspases are known to be critical effectors in the central nervous system cellular apoptosis. More recently, the calcium-dependent protease, calpains, have been implicated in cellular apoptotic processes. Moreover, for most neurodegenerative diseases, aggregation of full length or truncated proteins is central but the mechanisms involved still remain a mystery. With the identification of the mechanisms which promote or prevent cell apoptosis, new approaches for preventing and treating neurodegenerative disorders could be proposed. This article reviews our understanding of intracellular signaling pathways which lead to apoptosis in the nervous system, concentrating on its possible roles in chronic neurodegenerative disorders.