Malondialdehyde, Antioxidant Defense System Components and Their Relationship with Anthropometric Measures and Lipid Metabolism Biomarkers in Apparently Healthy Women.

Cardiovascular diseases are the leading cause of mortality worldwide. Since atherosclerosis, an inflammatory, lipid-driven disease, is an underlying basis for the development of cardiovascular disease, it is important to understand its relationship with confounding factors, such as oxidative lipid degradation. In contrast, circulating antioxidants prevent oxidative lipid damage, and therefore, may be associated with reduced development of atherosclerosis. We aimed to assess oxidative lipid degradation biomarker malondialdehyde (MDA) and antioxidant defense system components, total antioxidant capacity (TAC) and superoxide dismutase (SOD) inhibition rate levels, in healthy women and evaluate their relationships with age, anthropometric measures, and lipid metabolism biomarkers. The study included 86 healthy middle-aged women. MDA in human serum samples was evaluated by HPLC, and the TAC and SOD inhibition rates were measured by photometric methods. MDA was found to be associated with age, total cholesterol, non-HDL cholesterol, apolipoprotein B and triacylglycerols. TAC was shown to be associated with age, BMI, and waist circumference, as well as lipid metabolism biomarkers apolipoprotein B and triacylglycerol, while SOD inhibition rate was only associated with total cholesterol, apolipoprotein B and triacylglycerols. In conclusion, the association of oxidative status indices, MDA, TAC and SOD, with cardiovascular risk factors suggests that they could be additional useful biomarkers in the research of aging, obesity, and atherosclerosis pathogenesis.

Clinical and immunological evaluation of peri-implant tissues around ultra-polished and conventionally-polished zirconia abutments. A 1-year follow-up randomized clinical trial.

PURPOSE: This is a randomized clinical trial to compare the clinical and immunological performance of ultrasmooth versus conventionally-smooth zirconia abutments placed subgingivally after a period of 1 year. MATERIALS AND METHODS: Sixty-two bone level platform-switched implants (NobelParallel CC) were placed epicrestally in the mandibular molar or premolar region in 62 patients. After osseointegration, implants were restored with auto polymerizing acrylic resin crowns and subsequently randomly allocated to two groups according to the type of screw-retained zirconia crown prescribed. The control group received custom zirconia restoration with the subgingival zirconia part conventionally polished, whereas the test group implants were restored with ultra-polished zirconia abutments. Periodontal parameters (PD, PI, and BOP) and marginal bone level changes (MBLC) were recorded for each implant 2 months after insertion (T0), 1 month after final delivery of the crown (T2), and at the 1-year follow-up (T3). Immunological mediators from gingival crevicular fluid (IL-1α, IL-1ra, and TNF-α) were inspected at 1 month after provisional (T1) and accordingly at T2 and T3. Data was analyzed statistically, and significance level was set to α = 0.05. RESULTS: After 1 year, there were no significant changes in PD control-2.18 ± 0.89 mm and test-2.5 ± 0.72 mm (p = 0.073). PD between T2 and T3 dropped significantly in the test group (p = 0.037) and remained stable in the control group. PI was not different in both groups at T0 (p = 0.518) and T2 (p = 0.817). At T3, the test group (0.9 ± 1.01) had a significantly lower PI than the control group (1.55 ± 1.23) (p = 0.035). There was no difference in BOP positive cases between groups after 1 year (control-61.3%, test-51.7%, and p = 0.455). The amount of IL-1ra decreased significantly in the test group (41.75 ± 57.58) (p = 0.001) but not in the control group (59.59 ± 70.43) (p = 0.177). MBLC for the control and test groups after 1 year were 0.68 ± 0.7 and 0.94 ± 0.65 mm (p = 0.061). CONCLUSIONS: PD dynamics, PI, BOP, and IL-1ra revealed better outcomes around ultra-polished zirconia abutments than around conventionally polished zirconia abutments.

Computational pharmacology: New avenues for COVID-19 therapeutics search and better preparedness for future pandemic crises.

The COVID-19 pandemic created an unprecedented global healthcare emergency prompting the exploration of new therapeutic avenues, including drug repurposing. A large number of ongoing studies revealed pervasive issues in clinical research, such as the lack of accessible and organised data. Moreover, current shortcomings in clinical studies highlighted the need for a multi-faceted approach to tackle this health crisis. Thus, we set out to explore and develop new strategies for drug repositioning by employing computational pharmacology, data mining, systems biology, and computational chemistry to advance shared efforts in identifying key targets, affected networks, and potential pharmaceutical intervention options. Our study revealed that formulating pharmacological strategies should rely on both therapeutic targets and their networks. We showed how data mining can reveal regulatory patterns, capture novel targets, alert about side-effects, and help identify new therapeutic avenues. We also highlighted the importance of the miRNA regulatory layer and how this information could be used to monitor disease progression or devise treatment strategies. Importantly, our work bridged the interactome with the chemical compound space to better understand the complex landscape of COVID-19 drugs. Machine and deep learning allowed us to showcase limitations in current chemical libraries for COVID-19 suggesting that both in silico and experimental analyses should be combined to retrieve therapeutically valuable compounds. Based on the gathered data, we strongly advocate for taking this opportunity to establish robust practices for treating today's and future infectious diseases by preparing solid analytical frameworks.

New associations of serum ß-carotene, lycopene, and zeaxanthin concentrations with NR1H3, APOB, RDH12, AND CYP genes.

Variation in carotenoid bioavailability at individual and population levels might depend on host-related factors where genetic variation has a part to play. It manifests itself through the proteins involved in carotenoid intestinal absorption and metabolism, blood lipoprotein transport, or tissue uptake. This study aims to identify novel SNPs which could be associated with carotenoid serum concentrations. A total of 265 self-reported healthy individuals of Lithuanian origin were genotyped (Illumina HumanOmniExpress-12v1.0 or v1.1 and Infinium OmniExpress-24v1.2 arrays) and fasting blood serum concentrations of ß- and α-carotene, ß-cryptoxanthin, lycopene, lutein, and zeaxanthin were measured (Shimadzu Prominence HPLC system). According to the individual carotenoid concentrations, the cohort was subdivided into quartiles. Q1 and Q4 were used for the following association analysis. The set of 2883 SNPs in 109 potential candidate genes (assumed for a direct or indirect role in carotenoid bioavailability) was analyzed. Liver X receptor alpha (NR1H3) "transport" polymorphisms rs2279238 (p = 2.129 × 10-5) and rs11039155 (p = 2.984 × 10-5), and apolipoprotein B (APOB) "transport" polymorphism rs550619 (p = 4.844 × 10-5) were associated with higher zeaxanthin concentration. Retinol dehydrogenase 12 (RDH12) "functional partner" polymorphism rs756473 (p = 7.422 × 10-5) was associated with higher lycopene concentration. Twenty-one cytochrome P450 (CYP2C9, CYP2C18, and CYP2C19) "metabolism" polymorphisms in locus 10q23.33 were significantly associated with higher ß-carotene concentration. To conclude, four novel genomic loci were found to be associated with carotenoid serum levels. Zeaxanthin, lycopene, and ß-carotene serum concentrations might depend on genetic variation in NR1H3, APOB, RDH12 and CYP2C9, CYP2C18, and CYP2C19 genes.

Hair Cortisol, Perceived Stress, and the Effect of Group Dynamics: A Longitudinal Study of Young Men during Compulsory Military Training in Lithuania.

Previous research shows a nonlinear dependency between hair cortisol concentrations and perceived stress levels. This may be due to stress being targeted at the individual level despite it also being a social phenomenon which is often affected by group dynamics. Therefore, the objective of this study was to determine the influence of perceived stress on the hair cortisol level, considering the impact of the variables of group dynamics (interpersonal, task, and norm cohesion). Information was collected on 11 groups of, in total, 112 young men in three phases of time during their compulsory military training (covering nine months in total). The classification and regression tree (C&RT) method was used to predict hair cortisol concentrations in groups. The results show that the variability of the hair cortisol level in young men groups can be explained by perceived stress only when the groups were in formation process (47.7% normalised importance in Model 1) and when the groups were working on their final tasks (37.80% normalised importance in Model 3); meanwhile, the importance of perceived stress in explaining hair cortisol concentrations is low when the group is in a routine period of a group life-span (28.9% normalised importance in Model 2). Interpersonal cohesion (normalised importance 100% in Model 1 and 80.0% in Model 3) and task cohesion (normalised importance 78.6% in Model 2) were the most important predictors in the study area. These results point to the importance of the elements of group dynamics when it comes to explaining the nature of hair cortisol as accumulated stress biomarkers in young men.

Perceived stress and hair cortisol levels amongst conscripts during basic military training: A repeated measures study.

The aim was to examine hair cortisol levels and self-reported stress amongst conscripts during their basic military training, and how they are related to four types of theory-derived determinants. The following prediction was made: lower levels of perceived stress and hair cortisol will be associated with: (1) higher levels of emotional stability (the individual nonmilitary aspect); (2) a lower degree of private life problems (the contextual nonmilitary aspect); (3) more positive attitudes toward the military, higher engagement in military service, and higher adaptability to military conditions (the individual-military aspect); and (4) stronger group cohesion and better leadership (the contextual-military aspect). The sample consisted of a total of 107 male Lithuanian conscripts. Assessments were made at the beginning of their basic military training, in the middle, and at the end. Established instruments were used on all self-reported scales. Hair cortisol levels were established through analyses of hair samples. Low to moderate levels of stress were found throughout the basic training period regarding perceived stress levels. Hair cortisol levels were mainly unrelated to the self-rating scales. Regarding perceived stress, the prediction was fully confirmed. The future value of the theoretical model is discussed.

The Association between Endogenous Hair Steroid Hormones and Social Environmental Factors in a Group of Conscripts during Basic Military Training.

This study aimed to analyse the association between endogenous hair steroid hormones as reliable biological indicators of an individual's stress level and the social environmental factors experienced during military training that are manifested at the beginning of compulsory military service. Hair steroid hormone concentrations-cortisol, cortisone, dehydroepiandrosterone (DHEA), and testosterone-in a group of 185 conscripts were measured using the ultra-high performance liquid chromatography-tandem mass spectrometry method. Six subjective social environmental factors in the military-attitude towards the military and military service, adaptation to the military environment, team, task, and norm cohesion, as well as psychological (un)safety in the group-were evaluated using military-specific research questionnaires. Weak but significant negative correlations were identified between cortisol and adaptation (r = -0.176, p < 0.05), attitude (r = -0.147, p < 0.05) as well as between testosterone and task cohesion (r = -0.230, p < 0.01) levels. Additionally, a multiple forward stepwise regression analysis highlighted that cortisone variation might be partially explained by task cohesion; the DHEA-determined by psychological (un)safety in the group, attitude towards the military and military service, and norm cohesion; and the testosterone-determined by task cohesion and adaptation to the new military environment. The results of this study suggest that subjective measures of social factors can be used to predict hair steroid hormone levels as objective measures of the chronic stress perceived by conscripts during their basic military training.

Association between hair cortisol concentration and metabolic syndrome.

Metabolic syndrome (MetS) is a highly prevalent disorder defined as a cluster of cardiometabolic risk factors including obesity, hyperglycemia, hypertension, and dyslipidemia. It is believed that excessive cortisol secretion due to psychosocial stress-induced hypothalamic-pituitary-adrenal axis activation might be involved in the pathogenesis of MetS. We sought to explore the association between MetS and psychosocial risk factors, as well as cortisol concentration measured in different biological specimens including saliva, blood serum, and hair samples. The study was conducted on a sample of 163 young and middle-aged men who were divided into groups according to the presence of MetS. Hair cortisol concentration (HCC) was determined using high performance liquid chromatography with UV detection, while blood serum and salivary cortisol levels were measured by enzyme-linked immunoassay. Lipid metabolism biomarkers were determined using routine laboratory methods. Anthropometric and lifestyle characteristics, as well as self-reported psychosocial indicators, were also examined. Significantly higher HCC and lower social support level among participants with MetS compared with individuals without MetS were found. However, no significant differences in blood serum and salivary cortisol levels were observed between men with and without MetS. In conclusion, chronically elevated cortisol concentration might be a potential contributing factor to the development of MetS.

In silico drug discovery for a complex immunotherapeutic target - human c-Rel protein.

Target evaluation and rational drug design rely on identifying and characterising small-molecule binding sites on therapeutically relevant target proteins. Immunotherapeutics development is especially challenging because of complex disease etiology and heterogenous nature of targets. c-Rel protein, a promising target in many human inflammatory and cancer pathologies, was selected as a case study for an effective in silico screening platform development since this transcription factor currently has no successful therapeutic inhibitors or modulators. This study introduces a novel in silico screening approach to probe binding sites using structural validation sets, molecular modelling and describes a method of a computer-aided drug design when a crystal structure is not available for the target of interest. In addition, we showed that binding sites can be analysed with the machine learning as well as molecular simulation approaches to help assess and systematically analyse how drug candidates can exert their mode of action. Finally, this cutting-edge approach was subjected to a high through-put virtual screen of selected 34 M drug-like compounds filtered from a library of 659 M compounds by identifying the most promising structures and proposing potential action mechanisms for the future development of highly selective human c-Rel inhibitors and/or modulators.

The influence of new immediate tissue level abutment on crestal bone stability of subcrestally placed implants: A 1-year randomized controlled clinical trial.

BACKGROUND: The relation between implant abutment disconnection (AD) and increased crestal bone loss is still debated. PURPOSE: To compare bone changes below implant-abutment junction of subcrestally placed implants between: (1) implant level restorations, that underwent four ADs and (2) implants with immediate tissue level abutment with no AD, 1 month (T2) and 1-year (T3) after final restoration delivery. MATERIALS AND METHODS: Sixty-four patients received 64 bone level implants with platform-switching and conical connection in edentulous sites of posterior mandible and maxilla. All implants were placed 1.5 mm subcrestally and distributed among: (1) control group, that received a regular healing abutment and (2) test group with immediate tissue level (ITL) abutment, which was torqued to implants during surgery, transforming bone level implant to tissue level type. After 2-3 months of healing and a 1-month temporization, final zirconia-based screw-retained crowns were delivered to both groups. Crestal bone levels were calculated after final crown delivery (T2); after 1-year follow-up (T3) and compared using Mann-Whitney U test (p ≤ .05). RESULTS: Early bone loss of the test and control groups was 0.14 ± 0.27 mm and 0.64 ± 0.64 mm, respectively; the 0.5 mm difference was statistically significant (p = .0001). Late bone loss was 0.06 ± 0.16 mm and 0.21 ± 0.56 mm for the test and control group, respectively; the 0.15 mm difference between the groups was no more statistically significant (p = .22). Both groups displayed bone gain, 0.08 and 0.43 mm, respectively, and the overall crestal bone loss was reduced. CONCLUSIONS: Immediate tissue level abutments can significantly reduce early bone loss when measured 1 month after final prosthesis delivery, however, after 1-year follow-up, difference between the groups was no more statistically significant.

Biophysics is reshaping our perception of the epigenome: from DNA-level to high-throughput studies.

Epigenetic research holds great promise to advance our understanding of biomarkers and regulatory processes in health and disease. An increasing number of new approaches, ranging from molecular to biophysical analyses, enable identifying epigenetic changes on the level of a single gene or the whole epigenome. The aim of this review is to highlight how the field is shifting from completely molecular-biology-driven solutions to multidisciplinary strategies including more reliance on biophysical analysis tools. Biophysics not only offers technical advancements in imaging or structure analysis but also helps to explore regulatory interactions. New computational methods are also being developed to meet the demand of growing data volumes and their processing. Therefore, it is important to capture these new directions in epigenetics from a biophysical perspective and discuss current challenges as well as multiple applications of biophysical methods and tools. Specifically, we gradually introduce different biophysical research methods by first considering the DNA-level information and eventually higher-order chromatin structures. Moreover, we aim to highlight that the incorporation of bioinformatics, machine learning, and artificial intelligence into biophysical analysis allows gaining new insights into complex epigenetic processes. The gained understanding has already proven useful in translational and clinical research providing better patient stratification options or new therapeutic insights. Together, this offers a better readiness to transform bench-top experiments into industrial high-throughput applications with a possibility to employ developed methods in clinical practice and diagnostics.

Association of Platelet Membrane Fatty Acid Composition with Markers of Oxidative Stress in Healthy Men.

BACKGROUND Platelet membranes are extremely susceptible to peroxidation, forming a variety of lipid peroxides, including malondialdehyde (MDA), which has been implicated in the etiology of cardiovascular diseases. Moreover, platelet-leukocyte aggregates (PLAs) are known to contribute to advanced endothelial injury and atherogenesis. MATERIAL AND METHODS Fatty acid (FA) methyl esters of the platelet membranes of 79 apparently healthy men without any acute clinical condition at the time of the study were identified by GC/MS. MDA was measured by HPLC in blood serum, and PLAs were analyzed by whole-blood flow cytometry. Individuals were divided into quartiles according to MDA concentration and percentage of PLAs formation. The composition of platelet membrane FAs was compared to MDA concentration and the percentage of PLAs formation in apparently healthy individuals. RESULTS In quartiles (Q) with higher MDA concentration, percentage of C 16: 1ω7 (Q1 vs. Q3, p=0.021), C 20: 1ω9 (Q2 vs. Q4, p=0.028) and C 20: 5ω3 (Q2 vs. Q4, p=0.046) was lower. However, C 22: 5ω3 (Q1 vs. Q4, p=0.038) and total ω3 (Q1 vs. Q2, p=0.024) were higher. CONCLUSIONS MDA and the formation of platelet-monocyte aggregates stimulate the incorporation of monounsaturated fatty acids and polyunsaturated fatty acids in platelet phospholipid membranes, which may be a hallmark for a changed level of biologically active compounds required for the activation of future platelets.

Association of Hair Cortisol Concentration with Prevalence of Major Cardiovascular Risk Factors and Allostatic Load.

BACKGROUND The high prevalence of cardiovascular diseases cannot be explained completely by conventional risk factors such as older age, smoking, diabetes mellitus, hypertension, obesity, and dyslipidemia. Results of recent studies indicate that chronic stress may be an independent risk factor for cardiovascular morbidity and mortality. Thus, the aim of our study was to investigate the associations between the hair cortisol concentration (HCC), which is considered as a potential biomarker of long-term psychosocial stress, and traditional cardiovascular risk factors, including smoking, dyslipidemia, hypertension, and obesity. MATERIAL AND METHODS Fasting blood samples and anthropometric and lifestyle data were collected from 163 apparently healthy men. HCC was determined using high-performance liquid chromatography. Allostatic load (AL) index, defined as an integrated score of multiple interacting systems involved in the adaptation to adverse physical or psychosocial situations, was also calculated. RESULTS We found that many prevalent cardiovascular risk factors, including hypertension, smoking, higher than recommended waist circumference (WC), and low-density lipoprotein cholesterol (LDL-C) median values, are associated with higher HCC. Hair cortisol level was also positively associated with the manifestation of individual cardiovascular risk factors such as higher-than-recommended total cholesterol, LDL-C, non-high-density lipoprotein cholesterol, body mass index, and WC median values. Moreover, a significant positive relationship between HCC and AL index was observed. CONCLUSIONS The results of this study suggest that increased prevalence of traditional cardiovascular risk factors is associated with higher HCC. Also, both HCC and AL index might be appropriate markers for the evaluation of chronic stress level.

Chronic and oxidative stress association with total count of endothelial microvesicles in healthy young male plasma.

BACKGROUND: Chronic and oxidative stress promotes injury to the endothelium. This happens early in the disease and novel biomarkers describing the rate of the damage may be important in early diagnostics and prevention. Microvesicles are shed from endothelial cells in response to oxidative stress, inflammation, coagulation, and angiogenesis. Their increased level in plasma could reflect the state of the endothelium. OBJECTIVES: The objective of this study was to test the association between oxidative and chronic stress markers, atherosclerosis risk factors and endothelial microvesicle (EMV) count in peripheral blood. MATERIAL AND METHODS: The study included 81 males, aged 25-55 years and apparently healthy. Venous blood samples were labeled with anti-CD144-FITC, anti-CD105-BV421, anti-CD42a-PerCP, anti-CD62e-PE, anti-CD31-APCy7, and anti-CD61-APC (BD Biosciences, San Jose, USA), and tested using a BD LSR Fortessa cytometer (BD Biosciences). Events were gated on forward and side-scattered light parameters. Malondialdehyde (MDA) and cortisol concentrations were measured using high-performance liquid chromatography (HPLC). RESULTS: Four populations of EMV expressing a combination of CD105+, CD31+, CD144+, and CD62e with CD42aor CD42a+ markers were examined. We found correlations between MDA concentration and hair cortisol and a total count of CD144+ microvesicles, and weak correlations with diastolic blood pressure (DBP) (p = 0.003, r = 0.324) and systolic blood pressure (SBP) (p = 0.016, r = 0.267), especially with the microvesicles carrying CD62e. There was a median difference of CD105+ microvesicle count between smoking (n = 13) and non-smoking (n = 68) individuals. A predictive model showed an association between CD144+ microvesicle counts with cortisol and MDA concentrations and waist circumference. CONCLUSIONS: In conclusion, our data and predictive model showed that the total counts of microvesicle populations were associated with stress-related parameters - cortisol and MDA concentrations; expression of CD62e in various populations of EMV and the ratio of CD144+ to CD105+/CD62e+ were associated with increased DBP and SBP, and also with total cholesterol concentration in healthy young male population.