The Deubiquitinating Enzyme Cylindromatosis Dampens CD8 T Cell Responses and Is a Critical Factor for Experimental Cerebral Malaria and Blood-Brain Barrier Damage.

Cerebral malaria is a severe complication of human malaria and may lead to death of -infected individuals. Cerebral malaria is associated with sequestration of parasitized red blood cells within the cerebral microvasculature resulting in damage of the blood-brain barrier and brain pathology. Although CD8 T cells have been implicated in the development of murine experimental cerebral malaria (ECM), several other studies have shown that CD8 T cells confer protection against blood-stage infections.

Receptor-Interacting Protein Kinase-2 Inhibition by CYLD Impairs Antibacterial Immune Responses in Macrophages.

Upon infection with intracellular bacteria, nucleotide oligomerization domain protein 2 recognizes bacterial muramyl dipeptide and binds, subsequently, to receptor-interacting serine/threonine kinase 2 (RIPK2), which activates immune responses via the nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) and extracellular signal-regulated kinase (ERK) pathways. Activation of RIPK2 depends on its K63 ubiquitination by E3 ligases, whereas the deubiquitinating enzyme A20 counter regulates RIPK2 activity by cleaving K63-polyubiquitin chains from RIPK2. Here, we newly identify the deubiquitinating enzyme CYLD as a new inhibitor of RIPK2.

Protective dendritic cell responses against listeriosis induced by the short form of the deubiquitinating enzyme CYLD are inhibited by full-length CYLD.

The deubiquitinating enzyme CYLD is an important tumor suppressor and inhibitor of immune responses. In contrast to full-length CYLD, the immunological function of the naturally occurring short splice variant of CYLD (sCYLD) is insufficiently described. Previously, we showed that DCs, which lack full-length CYLD but express sCYLD, exhibit augmented NF-κB and DC activation.

Mineralocorticoid receptor-mediated DNA damage in kidneys of DOCA-salt hypertensive rats.

Epidemiological studies exploring the connection between hypertension and cancer demonstrate a higher cancer incidence, especially of kidney cancer, and a higher cancer mortality in hypertensive patients. Hormones elevated in hypertension, i.e.

Angiotensin II induces DNA damage in the kidney.

Increased activity of the renin angiotensin system with enhanced levels of angiotensin II leads to oxidative stress with endothelial dysfunction, hypertension, and atherosclerosis. Epidemiologic studies revealed a higher cancer mortality and an increased kidney cancer incidence in hypertensive patients. Because elevated angiotensin II levels might contribute to carcinogenesis, we tested whether angiotensin II induces DNA damage in the kidney.

Benfotiamine reduces genomic damage in peripheral lymphocytes of hemodialysis patients.

Hemodialysis patients have an elevated genomic damage in peripheral blood lymphocytes (PBLs) and an increased cancer incidence, possibly due to accumulation of uremic toxins like advanced glycation end products (AGEs). Because the vitamin B1 prodrug benfotiamine reduces AGE levels in experimental diabetes, and dialysis patients often suffer from vitamin B1 deficiency, we conducted two consecutive studies supplementing hemodialysis patients with benfotiamine. In both studies, genomic damage was measured as micronucleus frequency of PBLs before and at three time-points after initiation of benfotiamine supplementation.

Reduction of the genomic damage level in haemodialysis patients by folic acid and vitamin B12 supplementation.

Background: Cancer incidence and genomic damage of peripheral lymphocytes are elevated in patients with end-stage renal failure. Among other uraemic toxins, homocysteine (Hcy) levels are increased in most of these patients. In healthy individuals, plasma Hcy correlates with the degree of genomic damage observed in peripheral blood lymphocytes (PBL).

Benfotiamine exhibits direct antioxidative capacity and prevents induction of DNA damage in vitro.

Background: Complications in diabetes mellitus are partially mediated by enhanced formation of reactive oxygen species. Among the factors involved in reactive oxygen species formation, advanced glycation end products play a key role. Owing to a reduced activity of the enzyme transketolase, which requires diphosphorylated thiamine (vitamin B(1)) as cofactor, an accumulation of those deleterious glucose metabolites especially in diabetic patients can be observed.

Rosuvastatin protects against oxidative stress and DNA damage in vitro via upregulation of glutathione synthesis.

Statins, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, exert various beneficial effects independent of serum cholesterol reduction; among others is antioxidative action. Human promyelocytic cells (HL-60) were used to examine the effect of the statin rosuvastatin on reactive oxygen species-induced DNA damage, formation of oxidative stress and expression of glutathione metabolising enzymes. Rosuvastatin from 10nM significantly reduced DNA damage induced by phorbol 12-myristate 13-acetate (PMA) or by hydrogen peroxide, as assessed by the comet assay.

New approaches for the treatment of genomic damage in end-stage renal disease.

Objective: Patients with end-stage renal disease (ESRD) exhibit an enhanced genomic damage which may have pathophysiological relevance for cancer development and cardiovascular complications. The DNA damage has been shown both in the pre-dialysis and dialysis phase by micronucleus (MN) frequency test and single cell gel electrophoresis in peripheral blood lymphocytes (PBLs). A major cause of DNA damage is oxidative stress, which may be induced by various uremic toxins, including advanced glycation end products (AGEs), as well as by activation of the renin-angiotensin system.

Antigenotoxic effects of the phytoestrogen pelargonidin chloride and the polyphenol chlorogenic acid.

Pelargonidin (PEL), a common anthocyanidin with estrogenic activity, was tested in HL-60 cells for its genotoxicity and possible antigenotoxic effects against 4-nitroquinoline 1-oxide (NQO), a potent mutagen and carcinogen which induces oxidative stress. To take into account potential interactions between phytochemicals within normal human nutrition, we evaluated a combination of PEL with the nonestrogenic phytochemical chlorogenic acid (CLA), one of the most abundant polyphenols in the human diet. PEL (< or = 2 microM) and CLA (< or = 800 microM) were nongenotoxic in the micronucleus test.

Angiotensin II-induced genomic damage in renal cells can be prevented by angiotensin II type 1 receptor blockage or radical scavenging.

Hypertensive patients exhibit elevated cancer incidence, especially of cancers of the kidney. Elevated levels of ANG II, the active peptide of the renin-angiotensin system, regulating blood pressure and cardiovascular homeostasis, are known to cause hypertension and kidney diseases. There is evidence that ANG II is an activator of NAD(P)H oxidase, leading to the formation of free radicals, which are known to participate in the induction of DNA damage.