Search

Chronic kidney failure (KF) provokes the development of immune senescent CD8+ cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8+CD31+CD45RA+CCR7+ recent thymic emigrant (CCR7+ RTE) Tregs/Tresps into CD8+CD31-CD45RA- memory (CD31- memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8+ Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps. Compared to healthy controls, KF patients revealed an age-independently decreased frequency of CCR7+ RTE Tregs/Tresps, but increased frequencies of CCR7+ MN Tregs/Tresps and CD31- memory Tregs/Tresps, suggesting an increased differentiation via CD31+CD45RA- memory (CD31+ memory) Tregs/Tresps into CD31- memory Tregs/Tresps. Intensified differentiation via CD31+ memory Tresps increased the emergence of apoptosis-resistant CM Tresps with strong Fas ligand-mediated cytotoxicity. CCR7+ RTE Tresp proliferation generated TEMRA Tresps, secreting high levels of cytotoxic mediators. In dialysis and transplant patients, CD31+ TEMRA Tregs/Tresps accumulated, proposing an impaired CCR7+ RTE Treg/Tresp differentiation via CD31+ memory Tregs/Tresps into CD31- memory Tregs/Tresps. Increased percentages of CD31- TEMRA Tresps, but not of CD31- TEMRA Tregs, were observed in all patient groups, indicating impaired proliferation of CCR7+ RTE Tresps, but not of CCR7+ RTE Tregs, into CD31- memory Tregs/Tresps. In transplant patients, CCR7+ RTE Tregs accumulated, while frequencies of CCR7+ RTE Tresps were decreased, suggesting that the immunosuppressive therapy only prevented excessive CCR7+ RTE Treg differentiation but not that of CCR7+ RTE Tresps. Presumably, this caused the accumulation of TEMRA Tresps with decreased release of cytotoxic mediators, such as perforin. In conclusion, we propose that chronic KF affects both the differentiation of CD8+ Tregs and CD8+ Tresps. However, the immunosuppressive therapy after transplantation may successfully prevent excessive Treg differentiation, but not as suffciently that of Tresps. Therefore, the risk for graft rejection may be reduced, while the susceptibility for infections and malignancies may be increased in these patients. [ABSTRACT FROM AUTHOR]

Chronic kidney failure (KF) provokes the development of immune senescent CD8+ cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8+CD31+CD45RA+CCR7+ recent thymic emigrant (CCR7+ RTE) Tregs/Tresps into CD8+CD31-CD45RA- memory (CD31- memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8+ Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps. Compared to healthy controls, KF patients revealed an age-independently decreased frequency of CCR7+ RTE Tregs/Tresps, but increased frequencies of CCR7+ MN Tregs/Tresps and CD31- memory Tregs/Tresps, suggesting an increased differentiation via CD31+CD45RA- memory (CD31+ memory) Tregs/Tresps into CD31- memory Tregs/Tresps. Intensified differentiation via CD31+ memory Tresps increased the emergence of apoptosis-resistant CM Tresps with strong Fas ligand-mediated cytotoxicity. CCR7+ RTE Tresp proliferation generated TEMRA Tresps, secreting high levels of cytotoxic mediators. In dialysis and transplant patients, CD31+ TEMRA Tregs/Tresps accumulated, proposing an impaired CCR7+ RTE Treg/Tresp differentiation via CD31+ memory Tregs/Tresps into CD31- memory Tregs/Tresps. Increased percentages of CD31- TEMRA Tresps, but not of CD31- TEMRA Tregs, were observed in all patient groups, indicating impaired proliferation of CCR7+ RTE Tresps, but not of CCR7+ RTE Tregs, into CD31- memory Tregs/Tresps. In transplant patients, CCR7+ RTE Tregs accumulated, while frequencies of CCR7+ RTE Tresps were decreased, suggesting that the immunosuppressive therapy only prevented excessive CCR7+ RTE Treg differentiation but not that of CCR7+ RTE Tresps. Presumably, this caused the accumulation of TEMRA Tresps with decreased release of cytotoxic mediators, such as perforin. In conclusion, we propose that chronic KF affects both the differentiation of CD8+ Tregs and CD8+ Tresps. However, the immunosuppressive therapy after transplantation may successfully prevent excessive Treg differentiation, but not as suffciently that of Tresps. Therefore, the risk for graft rejection may be reduced, while the susceptibility for infections and malignancies may be increased in these patients.

Light at wavelength 405 nm is an effective bactericide. Previous studies showed that exposing mammalian cells to 405 nm light at 36 J/cm 2 (a bactericidal dose) had no significant effect on normal cell function, although at higher doses (54 J/cm 2 ), mammalian cell death became evident. This research demonstrates that mammalian and bacterial cell toxicity induced by 405 nm light exposure is accompanied by reactive oxygen species production, as detected by generation of fluorescence from 6-carboxy-2′,7′-dichlorodihydrofluorescein diacetate. As indicators of the resulting oxidative stress in mammalian cells, a decrease in intracellular reduced glutathione content and a corresponding increase in the efflux of oxidised glutathione were observed from 405 nm light treated cells. The mammalian cells were significantly protected from dying at 54 J/cm 2 in the presence of catalase, which detoxifies H 2 O 2 . Bacterial cells were significantly protected by sodium pyruvate (H 2 O 2 scavenger) and by a combination of free radical scavengers (sodium pyruvate, dimethyl thiourea ( OH scavenger) and catalase) at 162 and 324 J/cm 2 . Results therefore suggested that the cytotoxic mechanism of 405 nm light in mammalian cells and bacteria could be oxidative stress involving predominantly H 2 O 2 generation, with other ROS contributing to the damage. [ABSTRACT FROM AUTHOR]

Chronic kidney failure (KF) provokes the development of immune senescent CD8 + cytotoxic T cells, affecting the occurrence of graft rejection, viral infections, and malignancies after kidney transplantation. In this study, we analyzed the impact of KF, subsequent dialysis treatment, and kidney transplantation on the differentiation of CD8 + CD31 + CD45RA + CCR7 + recent thymic emigrant (CCR7 + RTE) Tregs/Tresps into CD8 + CD31 - CD45RA - memory (CD31 - memory) Tregs/Tresps and its effect on the release of cytokines, Fas receptor, Fas ligand as well as cytotoxic mediators by naïve, central memory (CM), effector memory (EM), and terminally differentiated effector memory (TEMRA) Tresps. We found that normal age-dependent differentiation of CD8 + Tregs/Tresps generally differs in the way that TEMRA cells only arise in Tresps. Compared to healthy controls, KF patients revealed an age-independently decreased frequency of CCR7 + RTE Tregs/Tresps, but increased frequencies of CCR7 + MN Tregs/Tresps and CD31 - memory Tregs/Tresps, suggesting an increased differentiation via CD31 + CD45RA - memory (CD31 + memory) Tregs/Tresps into CD31 - memory Tregs/Tresps. Intensified differentiation via CD31 + memory Tresps increased the emergence of apoptosis-resistant CM Tresps with strong Fas ligand-mediated cytotoxicity. CCR7 + RTE Tresp proliferation generated TEMRA Tresps, secreting high levels of cytotoxic mediators. In dialysis and transplant patients, CD31 + TEMRA Tregs/Tresps accumulated, proposing an impaired CCR7 + RTE Treg/Tresp differentiation via CD31 + memory Tregs/Tresps into CD31 - memory Tregs/Tresps. Increased percentages of CD31 - TEMRA Tresps, but not of CD31 - TEMRA Tregs, were observed in all patient groups, indicating impaired proliferation of CCR7 + RTE Tresps, but not of CCR7 + RTE Tregs, into CD31 - memory Tregs/Tresps. In transplant patients, CCR7 + RTE Tregs accumulated, while frequencies of CCR7 + RTE Tresps were decreased, suggesting that the immunosuppressive therapy only prevented excessive CCR7 + RTE Treg differentiation but not that of CCR7 + RTE Tresps. Presumably, this caused the accumulation of TEMRA Tresps with decreased release of cytotoxic mediators, such as perforin. In conclusion, we propose that chronic KF affects both the differentiation of CD8 + Tregs and CD8 + Tresps. However, the immunosuppressive therapy after transplantation may successfully prevent excessive Treg differentiation, but not as suffciently that of Tresps. Therefore, the risk for graft rejection may be reduced, while the susceptibility for infections and malignancies may be increased in these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Leonhard, Schaier, Kälble, Eckstein, Zeier and Steinborn.)

Abstract: Aiming to investigate the role of cytotoxic mechanisms in neuroborreliosis (NB), the cytokines IL-2, IL-7, IL-10, IL-12p70, IL-15, GM-CSF and the Th17-cytokine IL-17 were analyzed in cerebrospinal fluid (CSF) and plasma from NB-patients. NB-patients showed increased levels in CSF compared to controls of all analyzed cytokines except IL-15 but not in plasma. Blood lymphocytes from three NB-patients showed functional cytotoxicity in response to autologous Borrelia-infected macrophages. The findings support a role for cytotoxic mechanisms in the local immune response in NB and in addition suggest an increase of IL-17. [Copyright &y& Elsevier]

Saponins are natural glycosides which possess a wide range of pharmacological properties including cytotoxic activity. In this review, the recent studies (2005–2009) concerning the cytotoxic activity of saponins have been summarized. The correlations between the structure and the cytotoxicity of both steroid and triterpenoid saponins have been described as well as the most common mechanisms of action. [ABSTRACT FROM AUTHOR]

Abstract: Diallyl disulfide (DADS) and diallyl sulfide (DAS) are the major metabolites found in garlic oil and have been reported to lower cholesterol and prevent cancer. The molecular cytotoxic mechanisms of DADS and DAS have not been determined. The cytotoxic effectiveness of hydrogen versus allyl sulfides towards hepatocytes was found to be as follows: NaHS>DADS>DAS. Hepatocyte mitochondrial membrane potential was decreased and reactive oxygen species (ROS) and TBARS formation was increased by all three allyl sulfides. (1) DADS induced cytotoxicity was prevented by the H2S scavenger hydroxocobalamin, which also prevented cytochrome oxidase dependent mitochondrial respiration suggesting that H2S inhibition of cytochrome oxidase contributed to DADS hepatocyte cytotoxicity. (2) DAS cytotoxicity on the other hand was prevented by hydralazine, an acrolein trap. Hydralazine also prevented DAS induced GSH depletion, decreased mitochondrial membrane potential and increased ROS and TBARS formation. Chloral hydrate, the aldehyde dehydrogenase 2 inhibitor, however had the opposite effects, which could suggest that acrolein contributed to DAS hepatocyte cytotoxicity. [Copyright &y& Elsevier]

Aspects of insulin secretory mechanisms and models of diabetogenic B cell damage are discussed. Measurements of fluxes ofH-labelled triphenylmethylphosphonium ion,Rb,K,Na, andCa in isolated islets indicate that the triggering of insulin release depends on alterations in the interaction of ions with the B cells. One difficulty in the detailed analysis of these alterations are uncertainties which arise when macroscopic concepts for homogenous phases are applied to microscopic and heterogenous compartments, as exemplified by the meaning of pH in insulin secretory granules and of membrane electric potential. Nonetheless, the importance of an apparent decreased K permeability in mediating the insulin-releasing action of glucose, and of an apparent increased Na+ permeability in mediating the potentiating action of acetylcholine is emphasized. Fluorescent probing of Ca by chlorotetracycline revealed effects of glucose alone as well as glucose-dependent and atropine-sensitive effects of acetylcholine. Although acetylcholine, sulfonylureas, and certain thiol-blocking agents may stimulate insulin release by direct effects on the B cell plasma membrane, a high capacity for D-glucose transmembrane transport has probably evolved in order that the interior of the B cells can always sense the circulating glucose concentration. A signal to secretion is thought to be transmitted from glucose metabolism to altered ion fluxes by intervention of reduced pyridine nucleotides and a hypothetical redox protein for which thioredoxin may be a model. The insulin secretory defect in hereditary diabetic C57BL/KsJ- db/ db-mice is apparently linked to a decreased basal permeability for K and a failure of the B cells to decrease further this permeability in response to glucose. Functioning B cells are acutely damaged when exposed to heterologous serum or alloxan in vitro; cytotoxic activation of complement by the alternative pathway could perhaps occur during islet inflammation. Protection experiments with free-radical scavangers in vitro and in vivo support the theory that hydroxyl radicals are instrumental in the production of alloxan diabetes. Rapid reduction of alloxan by thioredoxin in the presence of molecular oxygen and NADPH leads to strong chemiluminescence from luminol indicative of an intense radical production. The sensitivity of B cells to alloxan may be due to physiological specializations of their plasma membranes, involving the highly effective glucose carrier or the hypothetical oxidation/reduction systems or both. [ABSTRACT FROM AUTHOR]

T- and K-cell cytotoxic activity has been measured in groups of type I diabetic patients and comparable groups of healthy control subjects. The mean cytotoxic indices for T-cell activity were 0.72 for 13 type I diabetics and −2.38 for a control group. These values are not significantly different. K-cell cytotoxic activity was measured using both chicken red blood cells and Chang liver cells coated with appropriate xenogenic antibodies. Using the chicken red blood cell system the percentage specific chromium release was 55.3 for 17 type I diabetics and 50.0 for a control group. These values are not significantly different. Using the Chang liver cell system the percentage specific chromium release was 13.9 for 37 type I diabetics and 9.7 for a control group. This difference is statistically significant (p<0.05). [ABSTRACT FROM AUTHOR]

The current study was carried out by a bioguided fractionation of a hexane extract of the latex of Euphorbia umbellata against leukemic cells. Samples were analyzed by NMR, GC/MS, triterpenes quantification, and MTT reduction assay. Morphological, cell cycle, mitochondrial membrane potential and caspases 3/7 analyses were performed for the dichloromethane and ethanol fractions, and selectivity index for the dichloromethane fraction. NMR analysis presented characteristic signals of terpenes and steroids, data were confirmed by the quantification of triterpenes and GC/MS analysis. MTT reduction assay demonstrated that HL-60 was the most sensitive cell lineage against dichloromethane and ethanol fractions. Compounds of these matrices caused morphological changes compatible with apoptosis induction, altered cell cycle, increment of depolarized population cells and activation of caspases 3/7. Selectivity indices were higher than 22.44. Bioguided-fractionation study showed that samples of the latex of E. umbellata raised the activity of the phytocomplex against leukemic cells, and the cytotoxicity can be associated with an apoptosis pathway., (© 2020 Wiley-VHCA AG, Zurich, Switzerland.)