Apoptosis resistance in Chlamydia-infected cells: a fate worse than death?

Chlamydia has long been studied as an intracellular pathogen causing widespread diseases. In the last three decades, the field of apoptosis has rapidly emerged, and as a consequence, research on infectious diseases in general and on Chlamydia –host interaction in particular shifted to apoptosis modulation. Ten years ago, the first paper describing the drastic inhibition of apoptosis in Chlamydia -infected cells was published. In a reversal of roles, here was a pathogen that was strongly protecting cells in an organism against destruction by the organism's immune system. Since then, numerous studies have described apoptosis inhibition by Chlamydia and the mechanisms involved, but still there is a lack of general consensus on the subject. With a section of studies even reporting the induction of cell death by Chlamydia and not its inhibition, the field became even more diverse and complicated. In this review, an attempt is made to discuss the recent findings on apoptosis modulation by chlamydial species.     

CD95: more than just a death factor?

The CD95 protein delivers crucial signals for lymphocyte death, and may also negatively regulate T-lymphocyte activation by preventing the influx of calcium ions from the cell's exterior. The block in calcium-ion influx occurs through the activation of acidic sphingomyelinase and the release of ceramide, a metabolite that can also induce cell death.     

Age-related memory impairment. Is the cure worse than the disease?

Aging impairs multiple memory systems. The neurochemical substrates of normal memory differ between memory systems. In this issue of Neuron, Ramos et al. find that activation of protein kinase A, which has been reported to improve hippocampal-dependent spatial memory in aged animals, has the opposite effect on prefrontal cortex-dependent working memory in aged animals.     

Different fates of mitochondria: alternative ways for degradation?

Cellular degradative processes including proteasomal and vacuolar/lysosomal (autophagic) degradation, as well as the activity of proteases (both cytosolic and mitochondrial), provide for a continuous turnover of damaged and obsolete macromolecules and organelles. Mitochondria are organelles essential for respiration and oxidative energy production in aerobic cells; they are also required for multiple biosynthetic pathways. As such, mitochondrial homeostasis is very important for cell survival. We review the evidence regarding the possible mechanisms for mitochondrial degradation. Increasingly, the evidence suggests autophagy plays a central role in the degradation of mitochondria. How mitochondria might be specifically selected for autophagy (mitophagy) remains an open question, although some evidence suggests that, under certain circumstances, in mammalian cells the Mitochondrial Permeability Transition (MPT) plays a role in initiation of the process. As more is learned about the functioning of autophagy as a degradation process, the greater the appreciation we are developing concerning its role in the control of mitochondrial degradation.     

Senescence and apoptosis: dueling or complementary cell fates?

In response to a variety of stresses, mammalian cells undergo a persistent proliferative arrest known as cellular senescence. Many senescence‐inducing stressors are potentially oncogenic, strengthening the notion that senescence evolved alongside apoptosis to suppress tumorigenesis. In contrast to apoptosis, senescent cells are stably viable and have the potential to influence neighboring cells through secreted soluble factors, which are collectively known as the senescence‐associated secretory phenotype (SASP). However, the SASP has been associated with structural and functional tissue and organ deterioration and may even have tumor‐promoting effects, raising the interesting evolutionary question of why apoptosis failed to outcompete senescence as a superior cell fate option. Here, we discuss the advantages that the senescence program may have over apoptosis as a tumor protective mechanism, as well as non‐neoplastic functions that may have contributed to its evolution. We also review emerging evidence for the idea that senescent cells are present transiently early in life and are largely beneficial for development, regeneration and homeostasis, and only in advanced age do senescent cells accumulate to an organism's detriment.     

Genome size: does bigger mean worse?

Genome sizes vary enormously. This variation in DNA content correlates with effective population size, suggesting that deleterious additions to the genome can accumulate in small populations. On this view, the increased complexity of biological functions associated with large genomes partly reflects evolutionary degeneration.     

Gap junctions in IL-1β-mediated cell survival response to strain

Mechanical stimuli play important roles in proliferation and differentiation of connective tissue cells, and development and homeostatic maintenance of tissues. However, excessive mechanical loading to a tissue can injure cells and disrupt the matrix, as occurs in tendinopathy. Tendinopathy is a common clinical problem in athletes and in many occupational settings due to overuse of the tendon. Moreover, interleukin (IL)-1β is generally considered to be a "bad" cytokine, activating NF-κb and cell death and inducing matrix metalloproteinase (MMPs 1, 2, 3) expression and matrix destruction. However, activated NF-κB can also drive a cell survival pathway. We have reported that cyclic strain induced tenocyte death in three-dimensional (3D) cultures, and IL-1β could promote cell survival under strain. Therefore, it was hypothesized that 1) cyclic strain could induce cell death in tenocytes as observed in pathologic tendons in vivo; 2) a gene expression profile indicative of tendinopathy could be identified; and 3) low-dose IL-1β could protect cells from strain-induced, tendinopathy-like changes. Human tenocytes were cultured in 3D type I collagen hydrogels and subjected to 3.5% elongation at 1 Hz for 1 h/day for up to 5 days with or without IL-1β. Real-time RT-PCR data showed that cyclic strain regulated the expression of tendinopathy marker genes in a manner similar to that found in pathological tendons from patients and that addition of IL-1β reversed the gene expression changes to control levels. Results of further studies showed that IL-1β may modulate cell survival through upregulating the expression of connexin 43, which is involved in the modulation of cell death/survival in a variety of cells and tissues. The elucidation of the mechanisms underlying strain-induced cell death and recovery from strain injury will facilitate our understanding of the pathogenesis of tendinopathy and may lead to the discovery of new molecular targets for early diagnosis and treatment of tendinopathy.     

Intercellular junctions: downstream and upstream of Ras?

Most human tumors are of epithelial origin, and these tumors gradually lose their epithelial character in a process termed the epithelial-mesenchymal transition. Approximately 40% of human tumors have activating mutations in one of the three RAS genes. Given these statistics, it is critically important to understand the role of Ras signaling in the epithelial-mesenchymal transition. This review considers the mechanisms and effectors through which Ras may regulate intercellular junction formation in epithelial cells. Conversely, intercellular junction proteins themselves may play a role in regulating Ras activation and signaling.     

Can gap junctions deliver?

In vivo delivery of small interfering RNAs (siRNAs) to target cells via the extracellular space has been hampered by dilution effects and immune responses. Gap junction-mediated transfer between cells avoids the extracellular space and its associated limitations. Because of these advantages cell based delivery via gap junctions has emerged as a viable alternative for siRNA or miRNA delivery. Here we discuss the advantages and disadvantages of extracellular delivery and cell to cell delivery via gap junction channels composed of connexins. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.     

Can gap junctions deliver?

In vivo delivery of small interfering RNAs (siRNAs) to target cells via the extracellular space has been hampered by dilution effects and immune responses. Gap junction-mediated transfer between cells avoids the extracellular space and its associated limitations. Because of these advantages cell based delivery via gap junctions has emerged as a viable alternative for siRNA or miRNA delivery. Here we discuss the advantages and disadvantages of extracellular delivery and cell to cell delivery via gap junction channels composed of connexins. This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics.     

Brain death: a durable consensus?

Is it even conceivable that this global consensus [on the whole-brain definition of death] could, in time, be regarded as a very temporary and makeshift expedient, a momentary substitute for a resolution of some profoundly difficult issues which for a time, perhaps a brief time, fit with both the technical capacities and the legal needs of those who endorsed it? And that in the long run it could linger as a footnote, or perhaps a chapter heading, in the long history of man's conceptions of life and death? This suggestion is so far from conventional wisdom today that one who espouses it risks being regarded as a crank. Nevertheless, I believe that the argument in its favor, while not conclusive, is much stronger than the argument against it (and in favor of the prevailing consensus). I will state the argument briefly, with particular reference to the landmark report in 1982 in Washington of the President's Commission for the Study of Ethical Problems in Medicine, and will situate the argument in the context of trends in contemporary bioethics. I do not expect to win over, in this one pass, those who have been convinced of the validity of the conventional view. I do hope, however, to re-open the issue; in particular, to provide reasons to regard the issue as far from settled.     

Daxx: death or survival protein?

The death domain-associated protein (Daxx) was originally cloned as a CD95 (FAS)-interacting protein and modulator of FAS-induced cell death. Daxx accumulates in both the nucleus and the cytoplasm; in the nucleus, Daxx is found associated with the promyelocytic leukaemia (PML) nuclear body and with alpha-thalassemia/mental retardation syndrome protein (ATRX)-positive heterochromatic regions. In the cytoplasm, Daxx has been reported to interact with various proteins involved in cell death regulation. Despite a significant number of studies attempting to determine Daxx function in apoptotic and non-apoptotic cell death, its precise role in this process is only partially understood. Here, we critically review the current understanding of Daxx function and shed new light on this interesting field.     

Salmonella-induced cell death: apoptosis, necrosis or programmed cell death?

Over the past several years, it has become apparent that enteropathogens activate cell death programs. For Salmonella and Shigella species, the induction of cell death is required for pathogenesis, and the mechanisms by which these bacteria induce cell death is an area of intense investigation. Although initial studies suggested that Salmonella induce cell death through an apoptotic pathway, recent studies demonstrate that cell death occurs through a unique caspase 1-dependent mechanism.     

Antifungal proteins: More than antimicrobials?

Antimicrobial proteins (AMPs) are widely distributed in nature. In higher eukaryotes, AMPs provide the host with an important defence mechanism against invading pathogens. AMPs of lower eukaryotes and prokaryotes may support successful competition for nutrients with other microorganisms of the same ecological niche. AMPs show a vast variety in structure, function, antimicrobial spectrum and mechanism of action. Most interestingly, there is growing evidence that AMPs also fulfil important biological functions other than antimicrobial activity. The present review focuses on the mechanistic function of small, cationic, cysteine-rich AMPs of mammals, insects, plants and fungi with antifungal activity and specifically aims at summarizing current knowledge concerning additional biological properties which opens novel aspects for their future use in medicine, agriculture and biotechnology.     

Antifungal proteins: More than antimicrobials?

Antimicrobial proteins (AMPs) are widely distributed in nature. In higher eukaryotes, AMPs provide the host with an important defence mechanism against invading pathogens. AMPs of lower eukaryotes and prokaryotes may support successful competition for nutrients with other microorganisms of the same ecological niche. AMPs show a vast variety in structure, function, antimicrobial spectrum and mechanism of action. Most interestingly, there is growing evidence that AMPs also fulfil important biological functions other than antimicrobial activity. The present review focuses on the mechanistic function of small, cationic, cysteine-rich AMPs of mammals, insects, plants and fungi with antifungal activity and specifically aims at summarizing current knowledge concerning additional biological properties which opens novel aspects for their future use in medicine, agriculture and biotechnology.