Natural causes of programmed death of yeast Saccharomyces cerevisiae

The existence of cell death program in unicellular organisms has been reported for a number of species. Nevertheless, the question why the ability to commit suicide has been maintained throughout evolution is far from being solved. While it is believed that altruistic death of individual yeast cells could be beneficial for the population, it is generally not known (i) what is wrong with the individuals destined for elimination, (ii) what is the critical value of the parameter that makes a cell unfit and (iii) how the cell monitors this parameter. Studies performed on yeast Saccharomyces cerevisiae allow us to hypothesize on ways of possible solutions of these problems. Here we argue that (a) the main parameter for life-or-death decision measured by the cell is the degree of damage to the genetic material, (b) its critical value is dictated by quorum sensing machinery, and (c) it is measured by monitoring delays in cell division.     

Lycopene in atherosclerosis prevention: An integrated scheme of the potential mechanisms of action from cell culture studies

Increasing evidence suggests that lycopene may protect against atherosclerosis, although, the exact mechanism(s) is still unknown. Because lycopene is an efficient antioxidant, it has been proposed for a long time that this property may be responsible for its beneficial effects. Consistent with this, the carotenoid has been demonstrated to inhibit ROS production in vitro and to protect LDL from oxidation. However, recently, other mechanisms have been evoked and include: prevention of endothelial injury; modulation of lipid metabolism through a control of cholesterol synthesis and oxysterol toxic activities; reduction of inflammatory response through changes in cytokine production; inhibition of smooth muscle cell proliferation through regulation of molecular pathways involved in cell proliferation and apoptosis. Focusing on cell culture studies, this review summarizes the experimental evidence for a role of lycopene in the different phases of atherosclerotic process.     

人参悬浮细胞系的建立及其生长特性的研究

从人参幼叶的培养中,筛选出了质地松疏、生长迅速、易于分散、可以长期进行继代培养的淡黄色半透明状愈伤组织系。将这种愈伤组织接种在液体培养基中进行振荡培养．建立起分散程度好的人参悬浮细胞系。在此基础上,测定了人参细胞悬浮培养物的生长曲线。实验表明,水解酪蛋白（ＬＨ）对人参悬浮细胞的生长有利。滋养培养可以使人参悬浮细胞的愈伤组织形成率提高,并在低密度下达到较高的植板率。这为有效地筛选出适合于工业化生产的高产人参细胞株提供了方便。     

Peripheral blood mononuclear cell secretome for tissue repair

For almost two decades, cell-based therapies have been tested in modern regenerative medicine to either replace or regenerate human cells, tissues, or organs and restore normal function. Secreted paracrine factors are increasingly accepted to exert beneficial biological effects that promote tissue regeneration. These factors are called the cell secretome and include a variety of proteins, lipids, microRNAs, and extracellular vesicles, such as exosomes and microparticles. The stem cell secretome has most commonly been investigated in pre-clinical settings. However, a growing body of evidence indicates that other cell types, such as peripheral blood mononuclear cells (PBMCs), are capable of releasing significant amounts of biologically active paracrine factors that exert beneficial regenerative effects. The apoptotic PBMC secretome has been successfully used pre-clinically for the treatment of acute myocardial infarction, chronic heart failure, spinal cord injury, stroke, and wound healing. In this review we describe the benefits of choosing PBMCs instead of stem cells in regenerative medicine and characterize the factors released from apoptotic PBMCs. We also discuss pre-clinical studies with apoptotic cell-based therapies and regulatory issues that have to be considered when conducting clinical trials using cell secretome-based products. This should allow the reader to envision PBMC secretome-based therapies as alternatives to all other forms of cell-based therapies.     

How an organism dies affects the fitness of its neighbors

Programmed cell death (PCD), a genetically regulated cell suicide program, is ubiquitous in the living world. In contrast to multicellular organisms, in which cells cooperate for the good of the organism, in unicells the cell is the organism and PCD presents a fundamental evolutionary problem. Why should an organism actively kill itself as opposed to dying in a nonprogrammed way? Proposed arguments vary from PCD in unicells being maladaptive to the assumption that it is an extreme form of altruism. To test whether PCD could be beneficial to nearby cells, we induced programmed and nonprogrammed death in the unicellular green alga Chlamydomonas reinhardtii. Cellular contents liberated during non-PCD are detrimental to others, while the contents released during PCD are beneficial. The number of cells in growing cultures was used to measure fitness. Thermostability studies revealed that the beneficial effect of the PCD supernatant most likely involves simple heat-stable biomolecules. Non-PCD supernatant contains heat-sensitive molecules like cellular proteases and chlorophyll. These data indicate that the mode of death affects the origin and maintenance of PCD. The way in which an organism dies can have beneficial or deleterious effects on the fitness of its neighbors.     

Successful therapy of heart disease by high potassium together with low sodium in accord with predictions from the associated cation, structured water concept of the cell

High potassium together with low sodium in diet and intravenous fluids has been observed clinically by Sodi-Pallares to have a beneficial effect on chronic heart failure and on acute myocardial infarction. Recent studies from the laboratory of Ling indicate that high potassium, low sodium environments can partially restore damaged cell proteins to their normal undamaged configuration. It follows that by this mechanism cell proteins damaged by the chronic or acute hypoxia of heart disease are probably partly repaired when high potassium, low sodium therapy is used.     

Nicotine stimulation of nerve growth factor receptor expression

Previous studies have suggested that nicotine may have beneficial actions in neurodegenerative disease models. The purpose of the experiments described in this study was to determine whether the long lasting and beneficial effects of nicotine observed previously could be expressed through actions upon nerve growth factor (NGF) receptors. Using a differentiated PC-12 neuronal cell model, we have detected an increase in expression of cell surface NGF receptor protein after acute exposure to nicotine in the micromolar range. In addition, we have also observed a persistent effect upon NGF receptor expression which lasted even after nicotine (nanomolar range) was removed from the tissue culture medium. This increase in cell surface NGF receptor protein was blocked in the presence of mecamylamine, indicating that this effect is likely nicotinic receptor mediated. These results are consistent with the hypothesis that the lasting and beneficial actions of nicotine previously observed in vivo may involve an indirect effect upon the level of neuronal cell surface NGF receptor expression. Our observations offer one possible mechanism for a potential neurotrophic effect of nicotine.     

Transgenic expression of dominant-negative Fas-associated death domain protein in beta cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice

In type 1 diabetes, many effector mechanisms damage the beta cell, a key one being perforin/granzyme B production by CD8(+) T cells. The death receptor pathway has also been implicated in beta cell death, and we have therefore generated NOD mice that express a dominant-negative form of the Fas-associated death domain protein (FADD) adaptor to block death receptor signaling in beta cells. Islets developed normally in these animals, indicating that FADD is not necessary for beta cell development as it is for vasculogenesis. beta cells from the transgenic mice were resistant to killing via the Fas pathway in vitro. In vivo, a reduced incidence of diabetes was found in mice with higher levels of dominant-negative FADD expression. This molecule also blocked signals from the IL-1R in culture, protecting isolated islets from the toxic effects of cytokines and also marginally reducing the levels of Fas up-regulation. These data support a role for death receptors in beta cell destruction in NOD mice, but blocking the perforin/granzyme pathway would also be necessary for dominant-negative FADD to have a beneficial clinical effect.     

Many faces of DAMPs in cancer therapy

A new concept of immunogenic cell death (ICD) has recently been proposed. The immunogenic characteristics of this cell death mode are mediated mainly by molecules called ‘damage-associated molecular patterns'' (DAMPs), most of which are recognized by pattern recognition receptors. Some DAMPs are actively emitted by cells undergoing ICD (e.g. calreticulin (CRT) and adenosine triphosphate (ATP)), whereas others are emitted passively (e.g. high-mobility group box 1 protein (HMGB1)). Recent studies have demonstrated that these DAMPs play a beneficial role in anti-cancer therapy by interacting with the immune system. The molecular pathways involved in translocation of CRT to the cell surface and secretion of ATP from tumor cells undergoing ICD are being elucidated. However, it has also been shown that the same DAMPs could contribute to progression of cancer and promote resistance to anticancer treatments. In this review, we will critically evaluate the beneficial and detrimental roles of DAMPs in cancer therapy, focusing mainly on CRT, ATP and HMGB1.     

In vitro anticancer properties of anthocyanins: A systematic review

Anthocyanins have been associated with beneficial effects on human health. Cancer has been one of the main public health issues due to its aggressiveness and high mortality rate. This systematic review aimed to address recent research (from January 2000 to September 2021) on the anticancer activity of anthocyanins assessed by in vitro assays. The selected studies revealed that anthocyanins have anticancer potential by inhibiting cancer cell viability and proliferation, controlling cell cycle, and promoting apoptosis.,     

Total amino acid stabilization during cell-free protein synthesis reactions

Limitations in amino acid supply have been recognized as a substantial problem in cell-free protein synthesis reactions. Although enzymatic inhibitors and fed-batch techniques have been beneficial, the most robust way to stabilize amino acids is to remove the responsible enzymatic activities by genetically modifying the source strain used for cell extract preparation. Previous work showed this was possible for arginine, serine, and tryptophan, but cysteine degradation remained a major limitation in obtaining high protein synthesis yields. Through radiolabel techniques, we confirmed that cysteine degradation was caused by the activity of glutamate-cysteine ligase (gene gshA) in the cell extract. Next, we created Escherichia coli strain KC6 that combines a gshA deletion with previously described deletions for arginine, serine, and tryptophan stabilization. Strain KC6 grows well, and active cell extract can be produced from it for cell-free protein synthesis reactions. The extract from strain KC6 maintains stable amino acid concentrations of all 20 amino acids in a 3-h batch reaction. Yields for three different proteins improved 75-250% relative to cell-free expression using the control extract.     

Betaine enhances the cellular survival via mitochondrial fusion and fission factors,MFN2 and DRP1

Betaine is a key metabolite of the methionine cycle and known for attenuating alcoholic steatosis in the liver. Recent studies have focused on the protection effect of betaine in mitochondrial regulation through the enhanced oxidative phosphorylation system. However, the mechanisms of its beneficial effects have not been clearly identified yet. Mitochondrial dynamics is important for the maintenance of functional mitochondria and cell homeostasis. A defective mitochondrial dynamics and oxidative phosphorylation system have been closely linked to several pathologies, raising the possibility that novel drugs targeting mitochondrial dynamics may present a therapeutic potential to restore the cellular homeostasis. In this study, we investigated betaine’s effect on mitochondrial morphology and physiology and demonstrated that betaine enhances mitochondrial function by increasing mitochondrial fusion and improves cell survival. Furthermore, it rescued the unbalance of the mitochondrial dynamics from mitochondrial oxidative phosphorylation dysfunction induced by oligomycin and rotenone. The elongation properties by betaine were accompanied by lowering DRP1 and increasing MFN2 expression. These data suggest that betaine could play an important role in remodeling mitochondrial dynamics to enhance mitochondrial function and cell viability.     

Mesenchymal stem cells from different sources and their derived exosomes: A pre-clinical perspective

Since the introduction of cell therapy as a strategy for the treatment of many diseases, mesenchymal stem cells have emerged as ideal candidates, yet the underlying mechanisms of their beneficial effects are only partially understood.At the start of the 21 st century, a paracrine effect was proposed as a mechanism of tissue repair by these cells. In addition, a role was suggested for a heterogeneous population of extracellular vesicles in cell-to-cell communication.Some of these vesicles including exosomes have been isolated from most fluids and cells, as well as from supernatants of in vitro cell cultures. Recent research in the field of regenerative medicine suggests that exosomes derived from mesenchymal stem cells could be a powerful new therapeutic tool. This review examines the therapeutic potential of these exosomes obtained from the sources most used in cell therapy: bone marrow, adipose tissue, and umbilical cord.     

Dendritic cell recovery post-lymphodepletion: a potential mechanism for anti-cancer adoptive T cell therapy and vaccination

Adoptive transfer of autologous tumor-reactive T cells holds promise as a cancer immunotherapy. In this approach, T cells are harvested from a tumor-bearing host, expanded in vitro and infused back to the same host. Conditioning of the recipient host with a lymphodepletion regimen of chemotherapy or radiotherapy before adoptive T cell transfer has been shown to substantially improve survival and anti-tumor responses of the transferred cells. These effects are further enhanced when the adoptive T cell transfer is followed by vaccination with tumor antigens in combination with a potent immune adjuvant. Although significant progress has been made toward an understanding of the reasons underlying the beneficial effects of lymphodepletion to T cell adoptive therapy, the precise mechanisms remain poorly understood. Recent studies, including ours, would indicate a more central role for antigen presenting cells, in particular dendritic cells. Unraveling the exact role of these important cells in mediation of the beneficial effects of lymphodepletion could provide novel pathways toward the rational design of more effective anti-cancer immunotherapy. This article focuses on how the frequency, phenotype, and functions of dendritic cells are altered during the lymphopenic and recovery phases post-induction of lymphodepletion, and how they affect the anti-tumor responses of adoptively transferred T cells.     

Cardiac stem cells: paradigm shift or broken promise? A view from developmental biology

For several decades, it has been known that many tissues of the human body replenish themselves with the help of specialized stem cells. Although the role of stem cells for organs with a rapid cellular turnover is well established, other organs have seemed to be exempt from stem cell-based repair. Recent studies have suggested that the heart has an inherent ability to replace its parenchymal cells continuously either by resident stem cells or by other cells that are recruited into the heart. The evidence for this acclaimed paradigm shift, however, is limited. The basis of the acclaimed beneficial effects of stem cell therapies must be investigated carefully and the fates of potential cardiac stem cells need to be studied by established cell tracing techniques.     

Beneficial fitness effects are not exponential for two viruses

The distribution of fitness effects for beneficial mutations is of paramount importance in determining the outcome of adaptation. It is generally assumed that fitness effects of beneficial mutations follow an exponential distribution, for example, in theoretical treatments of quantitative genetics, clonal interference, experimental evolution, and the adaptation of DNA sequences. This assumption has been justified by the statistical theory of extreme values, because the fitnesses conferred by beneficial mutations should represent samples from the extreme right tail of the fitness distribution. Yet in extreme value theory, there are three different limiting forms for right tails of distributions, and the exponential describes only those of distributions in the Gumbel domain of attraction. Using beneficial mutations from two viruses, we show for the first time that the Gumbel domain can be rejected in favor of a distribution with a right-truncated tail, thus providing evidence for an upper bound on fitness effects. Our data also violate the common assumption that small-effect beneficial mutations greatly outnumber those of large effect, as they are consistent with a uniform distribution of beneficial effects.     

Cell shrinkage and monovalent cation fluxes: role in apoptosis

The loss of cell volume or cell shrinkage has been a morphological hallmark of the programmed cell death process known as apoptosis. This isotonic loss of cell volume has recently been term apoptotic volume decrease or AVD to distinguish it from inherent volume regulatory responses that occurs in cells under anisotonic conditions. Recent studies examining the intracellular signaling pathways that result in this unique cellular characteristic have determined that a fundamental movement of ions, particularly monovalent ions, underlie the AVD process and plays an important role on controlling the cell death process. An efflux of intracellular potassium was shown to be a critical aspect of the AVD process, as preventing this ion loss could protect cells from apoptosis. However, potassium plays a complex role as a loss of intracellular potassium has also been shown to be beneficial to the health of the cell. Additionally, the mechanisms that a cell employs to achieve this loss of intracellular potassium vary depending on the cell type and stimulus used to induce apoptosis, suggesting multiple ways exist to accomplish the same goal of AVD. Additionally, sodium and chloride have been shown to play a vital role during cell death in both the signaling and control of AVD in various apoptotic model systems. This review examines the relationship between this morphological change and intracellular monovalent ions during apoptosis.     

Host-pathogen interactions during apoptosis

Host pathogen interaction results in a variety of responses, which include phagocytosis of the pathogen, release of cytokines, secretion of toxins, as well as production of reactive oxygen species (ROS). Recent studies have shown that many pathogens exert control on the processes that regulate apoptosis in the host. The induction of apoptosis upon infection results from a complex interaction of parasite proteins with cellular host proteins. Abrogation of host cell apoptosis is often beneficial for the pathogen and results in a successful host invasion. However, in some cases, it has been shown that induction of apoptosis in the infected cells significantly imparts protection to the host from the pathogen. There is a strong correlation between apoptosis and the host protein translation machinery: the pathogen makes all possible efforts to modify this process so as to inhibit cell suicide and ensure that it can survive and, in some cases, establish latent infection. This review discusses the significance of various pathways/steps during virus-mediated modulation of host cell apoptosis.     

Cystamine treatment is neuroprotective in the YAC128 mouse model of Huntington disease

Huntington disease (HD) is an adult onset neurodegenerative disorder characterized by selective atrophy and cell loss within the striatum. There is currently no treatment that can prevent the striatal neuropathology. Transglutaminase (TG) activity is increased in HD patients, is associated with cell death, and has been suggested to contribute to striatal neuronal loss in HD. This work assesses the therapeutic potential of cystamine, an inhibitor of TG activity with additional potentially beneficial effects. Specifically, we examine the effect of cystamine on striatal neuronal loss in the YAC128 mouse model of HD. We demonstrate here for the first time that YAC128 mice show a forebrain-specific increase in TG activity compared with wild-type (WT) littermates which is decreased by oral delivery of cystamine. Treatment of symptomatic YAC128 mice with cystamine starting at 7 months prevented striatal neuronal loss. Cystamine treatment also ameliorated the striatal volume loss and striatal neuronal atrophy observed in these animals, but was unable to prevent motor dysfunction or the down-regulation of dopamine and cyclic adenosine monophsophate-regulated phosphoprotein (DARPP-32) expression in the striatum. While the exact mechanism responsible for the beneficial effects of cystamine in YAC128 mice is uncertain, our findings suggest that cystamine is neuroprotective and may be beneficial in the treatment of HD.     

Prostaglandin I2 reduces activation of human arterial smooth muscle cells in-vivo

Patients suffering from peripheral vascular disease have been "ultima ratio"-treated with PGI2 at a rate of 5 ng/kg/min for 6 hours a day and 5 consecutive days i.v. 20 of them underwent surgery thereafter as therapy was not sufficient. A histological examination and quantification of vascular tissue revealed that the number of activated smooth muscle cells was significantly lower in treated patients vascular segments than in untreated ones in all the different age groups. A comparable suppression was found in the intima and the media as well. It is thus concluded, that PGI2 inhibits smooth muscle cell proliferation most probably by inhibiting PDGF-release from the platelets and stimulation of smooth muscle cell cAMP. To achieve a more beneficial PGI2-effect at the vascular level, a prolonged PGI2-therapy looks rather promising.