During the current corona pandemic, new therapeutic options against this viral disease are urgently desired. Due to the rapid spread and immense number of affected individuals worldwide, ...cost-effective, globally available, and safe options with minimal side effects and simple application are extremely warranted. This review will therefore discuss the potential of zinc as preventive and therapeutic agent alone or in combination with other strategies, as zinc meets all the above described criteria. While a variety of data on the association of the individual zinc status with viral and respiratory tract infections are available, study evidence regarding COVID-19 is so far missing but can be assumed as was indicated by others and is detailed in this perspective, focusing on re-balancing of the immune response by zinc supplementation. Especially, the role of zinc in viral-induced vascular complications has barely been discussed, so far. Interestingly, most of the risk groups described for COVID-19 are at the same time groups that were associated with zinc deficiency. As zinc is essential to preserve natural tissue barriers such as the respiratory epithelium, preventing pathogen entry, for a balanced function of the immune system and the redox system, zinc deficiency can probably be added to the factors predisposing individuals to infection and detrimental progression of COVID-19. Finally, due to its direct antiviral properties, it can be assumed that zinc administration is beneficial for most of the population, especially those with suboptimal zinc status.
Zinc supplementation enhances NK cell activity by increasing perforin expression. Furthermore, zinc supplementation increased the interleukin (IL)-2 enhanced NK cell activity additively. In contrast, ...zinc deficiency reduced NK cell activity and dampened the IL-2 medicated enhancing effect on NK cells.
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•The trace element zinc has an enhancing effect on YTS cell killing activity.•Zinc supplementation induces killing activity of primary NK cells from healthy donors.•A rapid zinc influx after zinc deficiency boosts the NK cell cytotoxicity.•Pre-incubation of malignant target cells with zinc facilitates apoptosis resistance.
Knowledge about the role of zinc on natural killer (NK) cell activity and function is limited and needs further instigation. Hence, in this study, the influence of interleukin (IL)-1, IL-2, zinc, and the zinc-chelator N,N,N′,N′-tetrakis(2-pyridylmethyl)ethane-1,2-diamine (TPEN) on the human NK cell line (YTS cell line) and primary NK cells were examined. We mainly focused on NK cell killing activity by using the K562 cell line as target cells. We uncovered a significantly increased NK cell killing activity due to 1 h zinc pre-incubation and contact to zinc-rich medium in physiological concentrations. Moreover, co-stimulation of zinc and IL-2 provoked an additive increase in NK cell killing activity. In contrast, zinc deficiency induced by 1 h TPEN pre-incubation significantly decreased the killing activity of primary NK cells. Temporary elevated intracellular zinc levels in target cells act contrary to the destruction by NK cells.
Thoracoabdominal aortic aneurysm (TAAA) repair is related to a relevant morbidity and in-hospital mortality rate. In this retrospective observational single-center study including serum zinc levels ...of 33 patients we investigated the relationship between zinc and patients' outcome following TAAA repair. Six patients died during the hospital stay (18%). These patients showed significantly decreased zinc levels before the intervention (zinc levels before intervention: 60.09 µg/dl survivors vs. 45.92 µg/dl non-survivors). The post-interventional intensive care SOFA-score (Sepsis-related organ failure assessment) (at day 2) as well as the SAPS (Simplified Acute Physiology Score) (at day 2) showed higher score points in case of low pre-interventional zinc levels. No significant correlation between patient comorbidities and zinc level before intervention, except for peripheral arterial disease (PAD), which was significantly correlated to reduced baseline zinc levels, was observed. Septic shock, pneumonia and urinary tract infections were not associated to reduced zinc levels preoperatively as well as during therapy. Patients with adverse outcome after TAAA repair showed reduced pre-interventional zinc levels. We speculate that decreased zinc levels before intervention may be related to a poorer outcome because of poorer physical status as well as negatively altered perioperative inflammatory response.
Dyskeratosis congenita (DKC) is a rare inherited disease of impaired telomere maintenance that progressively leads to multi-organ failure, including the bone marrow. By enhancing telomerase activity, ...androgen derivatives (ADs) are a potential therapeutic option able to re-elongate previously shortened telomeres. Danazol, oxymetholone, and nandrolone are ADs most frequently used to treat DKC. However, no direct in vitro analyses comparing the efficacy of these ADs have been conducted so far. We therefore treated mononuclear cells derived from peripheral blood and bone marrow of four patients with mutations in telomerase reverse transcriptase (
,
= 1),in the telomerase RNA component (TERC,
= 2) and in dyskerin pseudouridine synthase 1 (
,
= 1) and found no substantial differences in the activity of these three agents in patients with
mutations. All AD studied produced comparable improvements of proliferation rates as well as degrees of telomere elongation. Increased
expression levels were shown with danazol and oxymetholone. The beneficial effects of all ADs on proliferation of bone marrow progenitors could be reversed by tamoxifen, an estrogen antagonist abolishing estrogen receptor-mediated
expression, thereby underscoring the involvement of
in AD mechanism of action. In conclusion, no significant differences in the ability to functionally enhance telomerase activity could be observed for the three AD studied in vitro. Physicians therefore might choose treatment based on patients' individual co-morbidities, e.g., pre-existing liver disease and expected side-effects.
Obesity has negative effects on comorbidities, health-related quality of life and survival. Telomere length (TL) changes after bariatric surgery have been reported, but the studies are contradictory, ...and analyses using state-of-the art techniques for TL measurement, such as flow-FISH, are sparse. We measured TL dynamics via flow-FISH in patients undergoing bariatric surgery and compared their TL with 105 healthy individuals. Patients with obesity who underwent bariatric surgery were included. Lymphocyte and granulocyte absolute and age-adjusted (aa) TL were analyzed by flow-FISH before (preoperative cohort, n = 45) and after surgery (follow-up cohort, n = 35) at month 5.5 ± 3.9 (mean ± standard deviation SD). The initial lymphocyte aaTL was significantly shorter (-0.37 kb ± 0.18 kb, P = 0.045) in patients with obesity, while the granulocyte aaTL was not different from that in the healthy comparison population (0.28 kb ± 0.17 kb, P = 0.11). The telomere dynamics after surgery showed an increase in mean TL in both lymphocytes and granulocytes of patients with a pronounced BMI loss of ≥ 10 kg/m
. We did not find any association between TL increase after surgery and age, sex or the type of procedure selected for bariatric surgery. We confirmed that patients suffering from obesity have significantly shorter lymphocyte TL using flow-FISH. Along with and dependent on the degree of weight reduction after bariatric surgery, TL significantly increased in both lymphocytes and granulocytes after a mean of 5.5 months. Our results show that bariatric surgery affects not only body weight but also biomarkers of aging, such as TL.
Phosphatidylserines are known to sustain skeletal muscle activity during intense activity or hypoxic conditions, as well as preserve neurocognitive function in older patients. Our previous studies ...pointed out a potential cardioprotective role of phosphatidylserine in heart ischemia. Therefore, we investigated the effects of phosphatidylserine oral supplementation in a mouse model of acute myocardial infarction (AMI). We found out that phosphatidylserine increases, significantly, the cardiomyocyte survival by 50% in an acute model of myocardial ischemia-reperfusion. Similar, phosphatidylserine reduced significantly the infarcted size by 30% and improved heart function by 25% in a chronic model of AMI. The main responsible mechanism seems to be up-regulation of protein kinase C epsilon (PKC-ε), the main player of cardio-protection during pre-conditioning. Interestingly, if the phosphatidylserine supplementation is started before induction of AMI, but not after, it selectively inhibits neutrophil's activation, such as Interleukin 1 beta (IL-1β) expression, without affecting the healing and fibrosis. Thus, phosphatidylserine supplementation may represent a simple way to activate a pre-conditioning mechanism and may be a promising novel strategy to reduce infarct size following AMI and to prevent myocardial injury during myocardial infarction or cardiac surgery. Due to the minimal adverse effects, further investigation in large animals or in human are soon possible to establish the exact role of phosphatidylserine in cardiac diseases.
Immune checkpoint inhibitor (ICI) therapy represents a new standard of care for an increasing number of malignancies. Nevertheless, response rates and outcome of ICI treatment vary between ...individuals and the identification of predictive markers or hints towards immune cell exhaustion during therapy has remained a major challenge. Leukocyte telomere length is an established predictive biomarker of replicative aging and cellular proliferative potential in various hematological diseases. However, its relevance in the context of ICI therapy has not been investigated to date. Here, we analyze the age-adapted delta telomere length (ΔTL) of peripheral leukocytes as a potential predictive and prognostic marker in patients undergoing ICI therapy.
Age-adapted delta telomere length (ΔTL) of 84 patients treated with ICIs for solid malignancies was measured
quantitative real-time PCR. ΔTL was correlated with outcome and clinical data.
ΔTL was not significantly altered between patients with different tumor entities or tumor stages and did not predict tumor response to ICI therapy. However, ΔTLs at initiation of treatment were a prognostic marker for overall survival (OS). When using a calculated ideal cut-off value, the median OS in patients with shorter ΔTL was 5.7 months compared to 18.0 months in patients showing longer ΔTL. The prognostic role of age-adapted ΔTL was further confirmed by uni- and multivariate Cox-regression analyses.
In the present study, we demonstrate that shorter telomere lengths in peripheral blood leukocytes are associated with a significantly impaired outcome in patients receiving ICI therapy across different malignancies. We explain our findings by hypothesizing an older replicative age in peripheral leukocytes of patients with an impaired overall survival, reflected by a premature TL shortening. Whether this association is ICI-specific remains unknown. Further follow-up studies are needed to provide insights about the exact mechanism of how shortened telomeres eventually affect OS and could help guiding therapeutic decisions in future.
Purpose of Review
Myeloproliferative neoplasms (MPNs) are chronic hematological malignancies characterized by increased proliferation of MPN stem and myeloid progenitor cells with or without bone ...marrow fibrosis that typically lead to increased peripheral blood cell counts. The genetic and cytogenetic alterations that initiate and drive the development of MPNs have largely been defined, and we summarize these here.
Recent Findings
In recent years, advances in understanding the pathogenesis of MPNs have defined a long-preclinical phase in
JAK2
-mutant MPN, identified genetic loci associated with MPN predisposition and uncovered mechanistic insights in
CALR
-mutant MPN. The integration of molecular genetics into prognostic risk models is well-established in myelofibrosis and ongoing studies are interrogating the prognostic implications of concomitant mutations in ET and PV. Despite all these advances, the field is deficient in clonally selective therapies to effectively target the MPN clone at any stage of disease, from pre-clinical to advanced.
Summary
Although the biological understanding of the pathogenesis of MPNs has progressed quickly, substantial knowledge gaps remain, including in the molecular mechanisms underlying MPN progression and myelofibrotic transformation. An ongoing goal for the MPN field is to translate advances in biological understanding to improved treatments for patients.
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