Oxidative stress occurs when free radicals and other reactive species overwhelm the availability of antioxidants. Reactive oxygen species (ROS), reactive nitrogen species, and their counterpart ...antioxidant agents are essential for physiological signaling and host defense, as well as for the evolution and persistence of inflammation. When their normal steady state is disturbed, imbalances between oxidants and antioxidants may provoke pathological reactions causing a range of nonrespiratory and respiratory diseases, particularly chronic obstructive pulmonary disease (COPD). In the respiratory system, ROS may be either exogenous from more or less inhalative gaseous or particulate agents such as air pollutants, cigarette smoke, ambient high-altitude hypoxia, and some occupational dusts, or endogenously generated in the context of defense mechanisms against such infectious pathogens as bacteria, viruses, or fungi. ROS may also damage body tissues depending on the amount and duration of exposure and may further act as triggers for enzymatically generated ROS released from respiratory, immune, and inflammatory cells. This paper focuses on the general relevance of free radicals for the development and progression of both COPD and pulmonary emphysema as well as novel perspectives on therapeutic options. Unfortunately, current treatment options do not suffice to prevent chronic airway inflammation and are not yet able to substantially alter the course of COPD. Effective therapeutic antioxidant measures are urgently needed to control and mitigate local as well as systemic oxygen bursts in COPD and other respiratory diseases. In addition to current therapeutic prospects and aspects of genomic medicine, trending research topics in COPD are presented.
Immune Aging and Immunotherapy in Cancer Kaiser, Melanie; Semeraro, Maria Donatella; Herrmann, Markus ...
International journal of molecular sciences,
07/2021, Letnik:
22, Številka:
13
Journal Article
Recenzirano
Odprti dostop
Immune functions decline as we age, while the incidence of cancer rises. The advent of immune checkpoint blockade (ICB) has not only revolutionized cancer therapy, but also spawned great interest in ...identifying predictive biomarkers, since only one third of patients show treatment response. The aging process extensively affects the adaptive immune system and thus T cells, which are the main target of ICB. In this review, we address age-related changes regarding the adaptive immune system with a focus on T cells and their implication on carcinogenesis and ICB. Differences between senescence, exhaustion, and anergy are defined and current knowledge, treatment strategies, and studies exploring T cell aging as a biomarker for ICB are discussed. Finally, novel approaches to improve immunotherapies and to identify biomarkers of response to ICB are presented and their potential is assessed in a comparative analysis.
Atherosclerosis (AS) leading to myocardial infarction and stroke remains worldwide the main cause for mortality. Vulnerable atherosclerotic plaques are responsible for these life-threatening clinical ...endpoints. Atherosclerosis is a chronic, complex, inflammatory disease with interactions between metabolic dysfunction, dyslipidemia, disturbed microbiome, infectious triggers, vascular, and immune cells. Undoubtedly, the immune response is a most important piece of the pathological puzzle in AS. Although macrophages and T cells have been the focus of research in recent years, B cells producing antibodies and regulating T and natural killer (NKT) cell activation are more important than formerly thought. New results show that the B cells exert a prominent role with atherogenic and protective facets mediated by distinct B cell subsets and different immunoglobulin effects. These new insights come, amongst others, from observations of the effects of innovative B cell targeted therapies in autoimmune diseases like systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). These diseases associate with AS, and the beneficial side effects of B cell subset depleting (modifying) therapies on atherosclerotic concomitant disease, have been observed. Moreover, the CANTOS study (NCT01327846) showed impressive results of immune-mediated inflammation as a new promising target of action for the fight against atherosclerotic endpoints. This review will reflect the putative role of B cells in AS in an attempt to connect observations from animal models with the small spectrum of the thus far available human data. We will also discuss the clinical therapeutic potency of B cell modulations on the process of AS.
Obesity and relative leucocyte telomere length (RTL) are both linked to accelerated aging and premature mortality. We examined if nuchal subcutaneous adipose tissue (SAT) thickness, a surrogate ...marker of central trunk-weighted obesity, is an independent predictor of RTL that provides information beyond BMI, metabolic and inflammatory markers. RTL and nuchal SAT thickness were determined in 362 participants of the STYJOBS/EDECTA study (STYrian Juvenile Obesity Study, Early DEteCTion of atherosclerosis), which included overweight individuals and matched eutrophic controls. Fasting plasma samples were used for the measurement of leptin, resistin, adiponectin, glucose, insulin, high-sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), liver enzymes, creatinine, cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, oxidized LDL, triglycerides, homocysteine and uric acid. Furthermore, all participants underwent carotid artery ultrasound. Obese individuals had markedly higher body mass index (BMI), nuchal SAT thickness, hip and waist circumferences and carotid intima media thickness (IMT) than eutrophic controls. In addition, they showed typical biochemical abnormalities related to energy metabolism, systemic inflammation and liver function. RTL was inversely correlated with nuchal SAT thickness, IMT, hs-CRP, alkaline phosphatase, insulin, resistin, and leptin. Positive correlations were seen with homocysteine and creatinine. Stepwise linear regression analyses identified nuchal SAT thickness and insulin as the only significant predictors of RTL. In conclusion, nuchal SAT thickness is a robust predictor of RTL that provides information beyond traditional obesity-related metabolic and inflammatory biomarkers. This suggests an important role of fat depots at the neck for accelerated telomere shortening.
Telomeres and Age-Related Diseases Gruber, Hans-Jürgen; Semeraro, Maria Donatella; Renner, Wilfried ...
Biomedicines,
09/2021, Letnik:
9, Številka:
10
Journal Article
Recenzirano
Odprti dostop
Telomeres are at the non-coding ends of linear chromosomes. Through a complex 3-dimensional structure, they protect the coding DNA and ensure appropriate separation of chromosomes. Aging is ...characterized by a progressive shortening of telomeres, which compromises their structure and function. Because of their protective function for genomic DNA, telomeres appear to play an important role in the development and progression of many age-related diseases, such as cardiovascular disease (CVD), malignancies, dementia, and osteoporosis. Despite substantial evidence that links telomere length with these conditions, the nature of these observations remains insufficiently understood. Therefore, future studies should address the question of causality. Furthermore, analytical methods should be further improved with the aim to provide informative and comparable results. This review summarize the actual knowledge of telomere biology and the possible implications of telomere dysfunction for the development and progression of age-related diseases. Furthermore, we provide an overview of analytical techniques for the measurement of telomere length and telomerase activity.
Prostate cancer is a common malignancy in men worldwide and it is known that oxidative stress is a risk factor for cancer development. A common functional haptoglobin (Hp) polymorphism, originating ...from a duplication of a gene segment spanning over two exons, results in three distinct phenotypes with different anti-oxidative capacities: Hp1-1, Hp1-2, and Hp2-2. The aim of the study was to investigate the relationship between this Hp polymorphism and prostate cancer mortality. The study was performed on 690 patients with histologically confirmed prostate cancer, recruited between January 2004 and January 2007. Hp genotypes were determined by a TaqMan fluorogenic 5'-exonuclease assay. Hp1-1 was present in 76 (11%), Hp1-2 in 314 (45.5%), and Hp2-2 in 300 (43.5%) patients. During a median follow-up of 149 months, 251 (35.3%) patients died. Hp genotypes were not significantly associated with higher overall mortality (HR 1.10; 95% CI 0.91-1.33; p = 0.34). This remained similar in a multivariate analysis including age at diagnosis, androgen deprivation therapy, and risk group based on PSA level, GS, and T stage (HR 1.11; 95% CI 0.91-1.34; p = 0.30). We conclude that the common Hp polymorphism does not seem to be associated with overall mortality in prostate cancer patients.
In order to assess SARS-CoV-2 real time quantitative polymerase chain reaction (RT-qPCR) results in a real-life setting, three independent laboratories in Graz (Austria) set up a continuous cross ...comparison schedule. The following test systems were used: The QIAGEN NeuMoDx SARS-CoV-2 Assay, the Allplex™ 2019-nCoV Assay (Seegene) on a MicroLab Nimbus (Hamilton) platform combined with RealStar SARS-CoV-2 RT-PCR Assay (Altona Diagnostics GmbH), and the cobas SARS-CoV-2 test on a fully automated cobas 6800 system (Roche). A total of 200 samples were analysed, 184 (92%) were found to be concordant with all testing platforms, 14 (7%) discordant. Two (1%) samples tested invalid on a single platform and were excluded from further analysis. Discordant results were distributed randomly across the assays. The Ct values from all assays correlated closely with each other. All discordant samples showed Ct values ≥ 26. SARS-CoV-2 RT-qPCR assays may show considerable variability, especially in samples with low viral RNA concentrations. Decision makers should thus balance the advantages and disadvantages of RT-qPCR for mass screening and adopt suitable strategies that ensure a rational management of positive samples with high Ct values.
Obesity and metabolic syndrome (MetS) are associated with hypoadiponectinemia. On the contrary, studies revealed correlations between the amount of subcutaneous adipose tissue (SAT) and higher serum ...adiponectin levels. Furthermore, independent association of intermuscular adipose tissue (IMAT) deposit in the thigh with cardiometabolic risk factors (including total blood cholesterol, low-density lipoprotein (LDL), and triglycerides), and decreased insulin sensitivity, as MetS components, are sufficiently described. The combined relationship of thigh IMAT and SAT with serum adiponectin, leptin levels, and cardiometabolic risk factors have not been investigated till date. Since both SAT and IMAT play a role in fat metabolism, we hypothesized that the distribution pattern of SAT and IMAT in the mid-thigh might be related to adiponectin, leptin levels, and serum lipid parameters. We performed adipose tissue quantification using magnetic resonance imaging (MRI) of the mid-thigh in 156 healthy volunteers (78 male/78 female). Laboratory measurements of lipid panel, serum adiponectin, and leptin levels were conducted. Total serum adiponectin level showed a significant correlation with the percentage of SAT of the total thigh adipose tissue (SAT/ (IMAT+SAT)) for the whole study population and in sex-specific analysis. Additionally, SAT/(IMAT+SAT) was negatively correlated with known cardiometabolic risk factors such as elevated total blood cholesterol, LDL, and triglycerides; but positively correlated with serum high-density lipoprotein. In multiple linear regression analysis, (SAT/(IMAT+SAT)) was the most strongly associated variable with adiponectin. Interestingly, leptin levels did not show a significant correlation with this ratio. Adipose tissue distribution in the mid-thigh is not only associated to serum adiponectin levels, independent of sex. This proposed quantitative parameter for adipose tissue distribution could be an indicator for individual factors of a person`s cardiometabolic risk and serve as additional non-invasive imaging marker to ensure the success of lifestyle interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Pancreatic ductal adenocarcinoma (PDAC) is devastating. Because of its silent nature, the disease is often only diagnosed once it has reached an advanced, frequently inoperable stage. To date, we ...have no biomarkers that facilitate earlier diagnosis, leaving sufficient time for curative therapy that effectively lowers the very high mortality rate of this cancer entity. Because of this, the life expectancy of patients with PDAC is low (i.e. ≤ 6% five-year survival rates). New data, including particular genetic signatures and features of the stromal architecture of PDAC tumors, may better explain their aggressiveness, their relatively long-lasting painless expansion, and why chemotherapy so frequently fails. The typical tumor-induced stromal desmoplasia is characterized by cancer-associated fibroblasts (CAFs), decreased immune surveillance, cancer-associated neural remodeling, and a very low vascular density. This stromal microenvironment generates hypoxia, nutrient deficiency, immune suppression, and chemoresistance. The combination of factors results in a vicious disease that begins with the long-lasting, asymptomatic development of a large tumor mass, followed by a delayed diagnosis with a high percentage of inoperable states, exhibiting a poor response to all conservative therapeutic options, including radiation, and which ends with metastasis resulting in a rapid fatal outcome.
In this article, we review coherences on genetic, cellular, immunological, Nano medical and stromal characteristics of PDAC tissue, and discuss metabolic abnormalities associated with and/or preceding the tumor progression rate.
A more comprehensive understanding of the underlying mechanisms can improve the diagnostic and therapeutic management of patients suffering from this devastating type of cancer.
Osteocalcin, in its non-carboxylated form, has a positive effect on glucose metabolism. Additionally, osteocalcin levels are related to body composition, especially muscle mass. The relation to the ...distribution of different adipose tissue types, such as subcutaneous, intermuscular, and visceral adipose tissue, is unclear. This study aimed to investigate associations between serum osteocalcin and the distribution of subcutaneous and intermuscular adipose tissue of the mid-thigh. Furthermore, the influence of different training methods on osteocalcin levels was investigated. We performed adipose tissue quantification of subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT) using MRI measurements of the mid-thigh in 128 volunteers (63 male/65 female). Laboratory analysis included blood lipid panel, serum insulin, adiponectin, and osteocalcin measurements. The main observation was a significant correlation of total serum osteocalcin (TOC) and the distribution of adipose tissue of the mid-thigh (SAT/(SAT + IMAT)) (cc = -0.29/
-value = 0.002), as well as the cross-sectional muscle area (MA), increasing with the weekly resistance training duration in males. Additionally, TOC (
-value = 0.01) and MA (
-value = 0.03) were negatively related to serum insulin. The significant relationship between TOC and SAT/(SAT + IMAT) is a new finding and confirms the negative influence of IMAT on glucose metabolism in a sex-specific approach. We could substantiate this by the negative relation of TOC with serum insulin.
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