Host genetic variants associated with COVID-19 reconsidered in a Slovak cohort.

We present the results of an association study involving hospitalized coronavirus disease 2019 (COVID-19) patients with a clinical background during the 3rd pandemic wave of COVID-19 in Slovakia. Seventeen single nucleotide variants (SNVs) in the eleven most relevant genes, according to the COVID-19 Host Genetics Initiative, were investigated. Our study confirms the validity of the influence of LZTFL1 and 2'-5'-oligoadenylate synthetase (OAS)1/OAS3 genetic variants on the severity of COVID-19. For two LZTFL1 SNVs in complete linkage disequilibrium, rs17713054 and rs73064425, the odds ratios of baseline allelic associations and logistic regressions (LR) adjusted for age and sex ranged in the four tested designs from 2.04 to 2.41 and from 2.05 to 3.98, respectively. The OAS1/OAS3 haplotype 'gttg' carrying a functional allele G of splice-acceptor variant rs10774671 manifested its protective function in the Delta pandemic wave. Significant baseline allelic associations of two DPP9 variants in all tested designs and two IFNAR2 variants in the Omicron pandemic wave were not confirmed by adjusted LR. Nevertheless, adjusted LR showed significant associations of NOTCH4 rs3131294 and TYK2 rs2304256 variants with severity of COVID-19. Hospitalized patients' reported comorbidities were not correlated with genetic variants, except for obesity, smoking (IFNAR2), and hypertension (NOTCH4). The results of our study suggest that host genetic variations have an impact on the severity and duration of acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Considering the differences in allelic associations between pandemic waves, they support the hypothesis that every new SARS-CoV-2 variant may modify the host immune response by reconfiguring involved pathways.

Understanding Loss to Follow-Up in AMD Patients Receiving VEGF Inhibitor Therapy: Associated Factors and Underlying Reasons.

BACKGROUND: In patients with wet age-related macular degeneration (AMD), loss to follow-up (LTFU) leads to unplanned interruptions in therapy and the risk of visual loss. METHODS: This retrospective and prospective case-control cohort study compared AMD patients with (LTFU YES) and without (LTFU NO) LTFU during anti-VEGF treatment over 12 years. LTFU was defined as missing any treatment or monitoring visits, or not scheduling follow-ups for six months. RESULTS: Significant differences between LTFU NO (n = 298) and LTFU YES (n = 174) groups were age, treatment phase, baseline and final best-corrected visual acuity (BCVA), type of anti-VEGF drug, treatment switch, commuting distance, and escort during commuting. A multivariate logistic regression analysis identified the need for an escort during the commuting and treatment phase as the only significant difference. The four most common reasons for LTFU were general health worsening (21.8%), patient-missed appointments (16.7%), COVID-19-related issues (14.9%), and treatment dissatisfaction (8.6%). CONCLUSIONS: The factors associated with increased LTFU rates were older age, inactive treatment phase, lower baseline and final BCVA, bevacizumab treatment, monotherapy, longer travelling distance, and commuting with an escort. According to the multivariate logistic regression analysis, only the escort during the commuting and treatment phases was significant. These findings could direct research to explore social support in treatment adherence and highlight the importance of treatment phases in practice.

Angiotensin II constricts mouse iliac arteries: possible mechanism for aortic aneurysms.

Abdominal aortic aneurysms (AAA) result from maladaptive remodeling of the vascular wall and reduces structural integrity. Angiotensin II (AngII) infusion has become a standard laboratory model for studying AAA initiation and progression. We determined the different vasoactive responses of various mouse arteries to Ang II. Ex vivo isometric tension analysis was conducted on 18-week-old male C57BL/6 mice (n = 4) brachiocephalic arteries (BC), iliac arteries (IL), and abdominal (AA) and thoracic aorta (TA). Arterial rings were mounted between organ hooks, gently stretched and an AngII dose response was performed. Rings were placed in 4% paraformaldehyde for immunohistochemistry analysis to quantify peptide expression of angiotensin type 1 (AT1R) and 2 receptors (AT2R) in the endothelium, media, and adventitia. Results from this study demonstrated vasoconstriction responses in IL were significantly higher at all AngII doses when compared to BC, and TA and AA responses (maximum constriction-IL: 68.64 ± 5.47% vs. BC: 1.96 ± 1.00%; TA: 3.13 ± 0.16% and AA: 2.75 ± 1.77%, p < 0.0001). Expression of AT1R was highest in the endothelium of IL (p < 0.05) and in the media and (p < 0.05) adventitia (p < 0.05) of AA. In contrast, AT2R expression was highest in endothelium (p < 0.05), media (p < 0.01, p < 0.05) and adventitia of TA. These results suggest that mouse arteries display different vasoactive responses to AngII, and the exaggerated response in IL arteries may play a role during AAA development.

Heat shock proteins in cancer - Known but always being rediscovered: Their perspectives in cancer immunotherapy.

Heat shock proteins (HSPs) represent cellular chaperones that are classified into several families, including HSP27, HSP40, HSP60, HSP70, and HSP90. The role of HSPs in the cell includes the facilitation of protein folding and maintaining protein structure. Both processes play crucial roles during stress conditions in the cell such as heat shock, degradation, and hypoxia. Moreover, HSPs are important modulators of cellular proliferation and differentiation, and are strongly associated with the molecular orchestration of carcinogenesis. The expression and/or activity of HSPs in cancer cells is generally abnormally high and is associated with increased metastatic potential and activity of cancer stem cells, more pronounced angiogenesis, downregulated apoptosis, and the resistance to anticancer therapy in many patients. Based on the mentioned reasons, HSPs have strong potential as valid diagnostic, prognostic, and therapeutic biomarkers in clinical oncology. In addition, numerous papers describe the role of HSPs as chaperones in the regulation of immune responses inside and outside the cell. Importantly, highly expressed/activated HSPs may be inhibited via immunotherapeutic targets in various types of cancers. The aim of this work is to provide a comprehensive overview of the relationship between HSPs and the tumor cell with the intention of highlighting the potential use of HSPs in personalized cancer management.

Facing the Challenges in the COVID-19 Pandemic Era: From Standard Treatments to the Umbilical Cord-Derived Mesenchymal Stromal Cells as a New Therapeutic Strategy.

Coronavirus disease 2019 (COVID-19), the pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which counts more than 650 million cases and more than 6.6 million of deaths worldwide, affects the respiratory system with typical symptoms such as fever, cough, sore throat, acute respiratory distress syndrome (ARDS), and fatigue. Other nonpulmonary manifestations are related with abnormal inflammatory response, the "cytokine storm", that could lead to a multiorgan disease and to death. Evolution of effective vaccines against SARS-CoV-2 provided multiple options to prevent the infection, but the treatment of the severe forms remains difficult to manage. The cytokine storm is usually counteracted with standard medical care and anti-inflammatory drugs, but researchers moved forward their studies on new strategies based on cell therapy approaches. The perinatal tissues, such as placental membranes, amniotic fluid, and umbilical cord derivatives, are enriched in mesenchymal stromal cells (MSCs) that exert a well-known anti-inflammatory role, immune response modulation, and tissue repair. In this review, we focused on umbilical-cord-derived MSCs (UC-MSCs) used in in vitro and in vivo studies in order to evaluate the weakening of the severe symptoms, and on recent clinical trials from different databases, supporting the favorable potential of UC-MSCs as therapeutic strategy.

The performance and limitations of PCA3, TMPRSS2:ERG, HOXC6 and DLX1 urinary markers combined in the improvement of prostate cancer diagnostics.

BACKGROUND: Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. To date, the role of the combined application of long non-coding RNAs (PCA3, DLX1, HOXC6, TMPRSS2:ERG) for obtaining the most accurate method of detection of PCa has not yet been comprehensively investigated. METHODS: In total 240 persons were included in the retrospective study. Among them were 150 patients with confirmed PCa, 30 patients with benign prostatic hyperplasia, 30 patients with active chronic prostatitis and 30 healthy volunteers. In all patients, the urine samples were collected prior to biopsy or treatment. Polymerase chain reaction with reverse transcription was performed to detect the expression level of PCA3, HOXC6, DLX1 and the presence of the TMPRSS2:ERG transcript. RESULTS: PCA3 was detected in urine samples in all cases. Using a PCA3 score of 56 allowed the differentiation between PCa and all other cases with a sensitivity of 61% and specificity of 96% (p < 0.001) while a PCA3 score threshold value of 50 resulted in a differentiation between clinically significant PCa (ISUP grades 2-5) and all other cases with a sensitivity of 93% and specificity of 93% (p < 0.001). The TMPRSS2:ERG expression in urine was detected exclusively in the group of patients with PCa and only in 16% of all cases. CONCLUSIONS: PCA3 score detected in urine demonstrated moderate sensitivity and good specificity in differentiation between PCa and non-PCa and high sensitivity and specificity in differentiation between clinically significant PCa and non-PCa.

Cisplatin treatment reduces contraction to angiotensin II by altering expression of angiotensin II receptors: a pilot study.

The renin angiotensin system is a key regulator of blood pressure homeostasis. Angiotensin type 1 (AT1R) and 2 receptors (AT2R) have been investigated as targets for cisplatin-induced acute kidney injury; however, their therapeutic potential remains inconclusive. This pilot study aimed to determined the effect that acute cisplatin treatment had on angiotensin II (AngII)-induced contraction in blood vessels and expression profiles of AT1R and AT2R in mouse arteries and kidneys. Male C57BL/6 mice at 18 week of age (n = 8) were treated with vehicle or bolus dose of cisplatin (12.5 mg/kg). Thoracic aorta (TA), adnominal aorta (AA), brachiocephalic arteries (BC), iliac arteries (IL) and kidneys were collected for isometric tension and immunohistochemistry analysis. Cisplatin treatment reduced IL contraction to AngII at all doses (p < 0.01, p < 0.001, p < 0.0001); however, AngII did not induce contraction in TA, AA or BC in either treatment group. Following cisplatin treatment, AT1R expression was significantly upregulated in the media of TA (p < 0.0001) and AA (p < 0.0001), and in the endothelium (p < 0.05) media (p < 0.0001) and adventitia (p < 0.01) of IL. Cisplatin treatment significantly reduced AT2R expression in the endothelium (p < 0.05) and media (p < 0.05) of TA. In renal tubules, both AT1R (p < 0.01) and AT2R (p < 0.05) were increased following cisplatin treatment. Herein, we report that cisplatin reduces AngII-mediated contraction in IL and may be explained by an absence of normal counterregulatory expression of AT1R and AT2R, indicating other factors are involved.

Flavonoids attenuate cancer metabolism by modulating Lipid metabolism, amino acids, ketone bodies and redox state mediated by Nrf2.

Metabolic reprogramming of cancer cells is a common hallmark of malignant transformation. The preference for aerobic glycolysis over oxidative phosphorylation in tumors is a well-studied phenomenon known as the Warburg effect. Importantly, metabolic transformation of cancer cells also involves alterations in signaling cascades contributing to lipid metabolism, amino acid flux and synthesis, and utilization of ketone bodies. Also, redox regulation interacts with metabolic reprogramming during malignant transformation. Flavonoids, widely distributed phytochemicals in plants, exert various beneficial effects on human health through modulating molecular cascades altered in the pathological cancer phenotype. Recent evidence has identified numerous flavonoids as modulators of critical components of cancer metabolism and associated pathways interacting with metabolic cascades such as redox balance. Flavonoids affect lipid metabolism by regulating fatty acid synthase, redox balance by modulating nuclear factor-erythroid factor 2-related factor 2 (Nrf2) activity, or amino acid flux and synthesis by phosphoglycerate mutase 1. Here, we discuss recent preclinical evidence evaluating the impact of flavonoids on cancer metabolism, focusing on lipid and amino acid metabolic cascades, redox balance, and ketone bodies.

Procalcitonin kinetics following abdominal aortic surgery and its value for postoperative intestinal ischaemia detection.

OBJECTIVE: The purpose of our study was to describe perioperative kinetics of procalcitonin (PCT) in patients undergoing aortic surgery, to compare the kinetics in the open abdominal aortic aneurysm (AAA) repair and aortobifemoral bypass for aortoiliac occlusive disease (AIOD), and to evaluate the ability of PCT to detect intestinal ischaemia. METHODS: A prospective non-randomized observational cohort study in 80 patients (62 men and 18 women) undergoing elective aortic surgery was performed. Serum PCT was measured at baseline and defined intraoperative and postoperative timepoints up to postoperative day 7. MRI contrast-enhanced imaging was used to detect intestinal ischaemia. RESULTS: The comparison of the AAA and AIOD cohort did not show any significant difference in PCT levels. Patients with intestinal ischaemia had higher serum PCT at multiple timepoints postoperatively. The most accurate timepoints for early diagnosis were postoperative day 3, followed by 24 h after declamping of the vascular reconstruction, and postoperative day 7. The sensitivity and negative predictive values were 100% in all mentioned timepoints. However, event at the best timepoint the specificity was 89% and the positive predictive value 43%. CONCLUSIONS: Procalcitonin levels in the postoperative period at proper timepoints might help to detect postoperative intestinal ischaemia. The limitation of this marker is its low specificity for intestinal ischaemia and low positive predictive value. The highest value of this marker is that it can rule out this complication because normal PCT levels mean that intestinal ischaemia is very unlikely.

Additive prognostic value of high baseline coronary flow velocity to ejection fraction during resting echocardiography: 3-year prospective study.

BACKGROUND: There is a lack of information about the prognostic value of high velocity in coronary arteries during echocardiography. The present study was aimed at investigating the three-year prognostic value of coronary velocity assessment in all patients who were referred for echocardiography examination. METHODS: The prospective study comprises 747 consecutive patients. Death, myocardial infarction (MI), acute coronary syndrome (ACS), and/or revascularisation were defined as major adverse cardiac events (MACE). Routine echocardiography was added with coronary velocity assessment in the left main, anterior descending, or circumflex coronary arteries by the Doppler method. RESULTS: During a median follow-up of 36 months, 192 patients experienced MACE. Deaths occurred more frequently in patients with high local velocity in proximal left-sided segments vs. in middle left-sided segments vs. patients without high coronary velocity (9 vs. 3 vs. 1%, p < 0.0001). Death/MI/ACS occurred in 17 vs. 7 vs. 1%, p < 0.0001, respectively. Age (HR 1.04, 95% CI 1.00; 1.06; p < 0.04), a velocity more than 65 cm/s in any proximal segments of the arteries (HR 4.7, 95% CI 1.9; 11.9; p < 0.002), ejection fraction (HR 0.97, 95% CI 0.94; 0.99; p < 0.007) were strong independent prognostic predictors of death/MI/ACS. The maximal velocity of coronary flow velocity had a significant additive prognostic value to ejection fraction. CONCLUSIONS: The coronary velocity parameters give long-term prognostic information that can be used to identify persons with a high risk of MACE in consecutive non-selected patients.

Prognostic value of Doppler echocardiographic coronary flow velocity assessment at rest in elderly patients.

BACKGROUND: Atherosclerosis and coronary artery disease (CAD) are a common condition and cause of death in the elderly population. There are difficulties with risk assessment in the elderly as the objectification of their symptomatic status can be challenging due to neuromuscular weakness, physical deconditioning or neurological, orthopaedic, peripheral vascular, or respiratory limitations. Non-invasive coronary artery velocity assessment by Doppler method at rest could be helpful in the elderly population. To evaluate the prognostic role of coronary artery ultrasound assessment in a non-selected elderly population in everyday clinical practice. METHODS: One hundred forty-five patients, aged ≥75years (99 women; 80 ± 4 years), formed the study group. Left coronary artery flows were scanned in addition to conventional echocardiography. During a median follow-up of 26 months, 16 deaths and 2 non-fatal MI occurred. RESULTS: In multivariable analysis, maximal coronary velocity was the only independent predictor for mortality (heart rate [HR]: 1.02, 95%, CI: 1.01-1.04, p < .0005) and for mortality/MI (HR: 1.02, 95%, CI: 1.01-1.03, p < .0001). The value of 110 cm/s maximal coronary flow velocity (CFL) in the proximal segments of left arteries was the best predictor for death, sensitivity 50%, specificity 90%, p < .005. The annual mortality rate was 16.6% persons/year for patients with elevated CFL ≥110 cm/s. The value 81 cm/s was the best predictor for death/MI, sensitivity 61%, specificity 80%, p < .0005; annual mortality rate was 11.2% persons/year for patients with elevated CFL ≥81 cm/s (p < .0001). CONCLUSION: Doppler CFL scanning during routine echocardiography is a feasible and valuable tool for assessment of short-term prognosis in elderly patients.

Anti-SARS-CoV-2 Antibody Status at the Time of Hospital Admission and the Prognosis of Patients with COVID-19: A Prospective Observational Study.

The association between COVID-19 severity and antibody response has not been clearly determined. We aimed to assess the effects of antibody response to SARS-CoV-2 S protein at the time of hospital admission on in-hospital and longitudinal survival. Methods: A prospective observational study in naive hospitalised COVID-19 patients. The presence of anti-S SARS-CoV-2 IgM and IgG was evaluated using a lateral flow assay at the time of admission. The patients were followed up for 8-30 months to assess survival. We recruited 554 patients (330 men and 224 women). Overall, 63.0% of the patients had positive IgG or IgM anti-S SARS-CoV-2 antibodies at the time of hospital admission. In the univariate analysis, the patients with negative anti-S SARS-CoV-2 IgM and IgG antibodies were referred to the hospital sooner, had lower CRP and D-dimer concentrations, and were hospitalised longer. They were also more likely to be admitted to an intensive care unit and more often received baricitinib treatment. During their hospital stay, 8.5% of the antibody-positive and 22.3% of the antibody-negative patients died (p = 0.0001). The median duration of the follow-up was 21 months. During the follow-up after hospital discharge, 3.6% of antibody-positive and 9.1% of antibody-negative patients died (p = 0.027). In the multivariate analysis, the negative anti-S SARS-CoV-2 antibodies were associated with a higher risk of in-hospital death (OR 3.800; 95% CI 1.844-7.829; p = 0.0001) and with a higher risk of death during follow-up (OR 2.863; 95% CI 1.110-7.386; p = 0.030). These associations were independent of age, the time from symptom onset to hospital admission, CRP, D-Dimer, the number of comorbidities, disease severity at the time of hospital admission, and baricitinib therapy. Our study concludes that negative anti-S SARS-CoV-2 IgM and IgG at the time of admission are associated with higher in-hospital mortality and cause a higher risk of all-cause death during follow-up after discharge.

Flavonoids exert potential in the management of hypertensive disorders in pregnancy.

Hypertensive disorders in pregnancy represent severe complications of pregnancy, which, if not treated, can result in serious health consequences for the mother and the child. Flavonoids are bioactive secondary metabolites commonly found in fruits, vegetables, green tea, whole grains, and medicinal plants. Flavonoids exert potent protective efficacy in experimental models of hypertensive disorders in pregnancy, especially preeclampsia, demonstrated through their capacity to modulate inflammatory responses, oxidative stress, and vascular dysfunction. In addition to their potential as therapeutics, flavonoids or flavonoid-rich food could be helpful to decrease the risk of hypertensive disorders in pregnancy when included in the diet pattern before and during pregnancy. However, the clinical evaluation of the potential capacity of flavonoids in hypertensive disorders in pregnancy is insufficient. Due to promising results from experimental studies, we highlight the need for the evaluation of flavonoids also in an appropriate clinical setting, which can be, together with proper preventive strategies, helpful in the overall management of hypertensive disorders in pregnancy.

Should we routinely assess coronary artery Doppler in daily echocardiography practice?

A lot of people with coronary artery disease do not have specific symptoms, and myocardial infarction or death are the first manifestation of the disease. New accurate, non-invasive and safe screening methods are required that can assess the prognosis of patients during routine examinations performed on millions of people. The aim of this review was to discuss the current literature regarding the utility of non-invasive ultrasound imaging of the coronary artery in assessing a patient's prognosis in daily practice. Assessment of coronary artery flow during common stress echocardiography or echocardiography can provide additive incremental prognostic information without the burden of radiation. Exercise or pharmacologic stress echocardiography tests combined with coronary flow velocity reserve assessment has advantages over stress tests based only on regional wall motion abnormalities. Scanning of main coronary arteries as an addition to routine echocardiography can reveal patients at high risk of adverse cardiac events in the near future.

Dynamics of coronary artery velocity flow during exercise echocardiography.

PURPOSE: The aim of our study was to acquire non-invasive data from coronary flow velocity profiles during exercise in groups of healthy subjects and of patients with arterial hypertension. MATERIAL AND METHODS: We enrolled 83 patients into two groups: (1) 35 non-selected consecutive healthy subjects; (2) 25 consecutive patients with arterial hypertension. All the patients performed supine bicycle symptoms-limited tests. Throughout exercise the diastolic peaks of coronary flow velocity in LAD were recorded. Coronary flow velocity reserve (CFVR) was calculated off-line. Profiles of coronary artery velocity were acquired for all groups. The coronary artery flow parameters investigated were comparable in healthy and hypertensive patients at every stage. RESULTS: The average diastolic velocities were 54.8 ± 12.9 vs. 51.8 ± 12.2 cm/s, at 50 W; 69.2 ± 17.1 vs 64.4 ± 19.1 cm/s at 75 W; 70.7 ± 16.4 vs. 76.1 ± 19.0 cm/s at 100 W; 80.0 ± 16.0 vs. 72.9 ± 16.1 cm/s at 125 W; 83.7 ± 12.2 vs. 81.4 ± 17.0 at 150 W, p- non-significant, respectively. On average, the healthy group reached CFVR > 2.0 at a heart rate of 110-120 beats/min at 75 W. During supine bicycle exercise, healthy subjects and patients with arterial hypertension have a similar coronary artery flow velocity profile. CONCLUSION: The routine exercise echocardiography test can feasibly be supplemented with the additional measurement of coronary flow velocity during routine supine exercise stress tests, as the normal range of CFVR is reached before submaximal heart rate.

Kinetics of platelet adhesion to a fibrinogen-coated surface in whole blood under flow conditions.

AIM: To test a novel method of assessment of platelet adhesion to a fibrinogen-coated surface in whole blood under flow conditions. METHODS: We developed a fluidic device that mimics blood flow in vessels. The method of detection of platelet adhesion is based on recording of a scattered laser light signal from a fibrinogen-covered surface. Testing was performed in platelet-rich plasma (PRP) and whole blood of healthy volunteers. Control measurements were performed, followed by tests with inhibition of platelet GPIIa/IIIb and GPIb receptors. Then, the same testing sequence was performed in whole blood of persons with autoimmune thrombocytopenia and type 3 von Willebrand disease. RESULTS: The change in intensity of scattered light was 2.7 (2.4; 4.1) times higher in whole blood (0.2 ± 0.08V, n = 7) than in PRP (0.05 ± 0.02 V, n = 7), p < 0.01. The blocking of GP IIb/IIIa receptors decreased the intensity of scattered light to 8.5 (6.5;12)%; the blocking of GPIb receptors decreased it to 34 (23;58)%, p < 0.01. In the whole blood of a person with autoimmune thrombocytopenia, the inhibition of GPIb receptors decreased platelet adhesion, but no effect was observed in type 3 von Willebrand disease. Inhibition of platelet GPIIb/IIIa receptors alone or combined inhibition of GPIb and GPIIb/IIIa receptors resulted in almost total suppression of adhesion in both cases. CONCLUSION: Our system effectively registers platelet adhesion to a fibrinogen-coated surface under controlled-flow conditions and may successfully be applied to the investigation of platelet adhesion kinetics.

Flavonoids against the SARS-CoV-2 induced inflammatory storm.

The disease severity of COVID-19, especially in the elderly and patients with co-morbidities, is characterized by hypercytokinemia, an exaggerated immune response associated with an uncontrolled and excessive release of proinflammatory cytokine mediators (cytokine storm). Flavonoids, important secondary metabolites of plants, have long been studied as therapeutic interventions in inflammatory diseases due to their cytokine-modulatory effects. In this review, we discuss the potential role of flavonoids in the modulation of signaling pathways that are crucial for COVID-19 disease, particularly those related to inflammation and immunity. The immunomodulatory ability of flavonoids, carried out by the regulation of inflammatory mediators, the inhibition of endothelial activation, NLRP3 inflammasome, toll-like receptors (TLRs) or bromodomain containing protein 4 (BRD4), and the activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2), might be beneficial in regulating the cytokine storm during SARS-CoV-2 infection. Moreover, the ability of flavonoids to inhibit dipeptidyl peptidase 4 (DPP4), neutralize 3-chymotrypsin-like protease (3CLpro) or to affect gut microbiota to maintain immune response, and the dual action of angiotensin-converting enzyme 2 (ACE-2) may potentially also be applied to the exaggerated inflammatory responses induced by SARS-CoV-2. Based on the previously proven effects of flavonoids in other diseases or on the basis of newly published studies associated with COVID-19 (bioinformatics, molecular docking), it is reasonable to assume positive effects of flavonoids on inflammatory changes associated with COVID-19. This review highlights the current state of knowledge of the utility of flavonoids in the management of COVID-19 and also points to the multiple biological effects of flavonoids on signaling pathways associated with the inflammation processes that are deregulated in the pathology induced by SARS-CoV-2. The identification of agents, including naturally occurring substances such as flavonoids, represents great approach potentially utilizable in the management of COVID-19. Although not clinically investigated yet, the applicability of flavonoids against COVID-19 could be a promising strategy due to a broad spectrum of their biological activities.

Human Cytomegalovirus and Epstein-Barr virus specific immunity in patients with ulcerative colitis.

Human Cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) are endowed with the ability of establishing lifelong latency in human hosts and reactivating in immunocompromised subjects, including patients suffering from ulcerative colitis (UC). We, therefore, aimed to investigate virus-specific immunity in UC patients. A cohort of 24 UC patients (14 responders and 10 refractory to therapy) and 26 control subjects was prospectively enrolled to undergo virus-specific serology (by ELISA assay) and assessment of both CD4+ and CD8+ virus-specific T-cell response (by interferon-γ enzyme-linked immunospotanalysis). In parallel, mucosal viral load was determined by quantitative real-time PCR and the values were correlated with both clinical and endoscopic indexes of activity. For statistics, the t-test, Mann-Withney test, Fisher's exact test and Spearman rank correlation test were applied; p < 0.05 was considered significant. EBV-specific CD4+ and CD8+ T-cell responses were significantly lower in UC patients compared to controls (p < 0.0001 and p = 0.0006, respectively), whereas no difference was found for HCMV-specific T-cell response. When dividing the UC group according to response to therapy, both responders and refractory UC patients showed a deficient EBV-specific CD4+ T-cell response with respect to controls (p < 0.04 and p = 0.0003, respectively). Moreover, both EBV and HCMV mucosal loads were significantly higher in refractory UC than in responders and controls (p = 0.007 and 0.003; and p = 0.02 and 0.001, respectively), and correlated with activity indexes. Steroid therapy seemed the main risk factor for triggering EBV colitis. Finally, no cases of IgM positivity were found in the study population. An impaired EBV-specific immunity was clearly evident in UC patients, mostly in those refractory to therapy. The ELISPOT assay may serve as new tool for quantifying and monitoring virus-specific T-cell immunity in UC.

Health implication of vitamin D on the cardiovascular and the renal system.

Vitamin D regulates the calcium and phosphorus balance in the body. The activated form of vitamin D (1 α,25-dihydroxyvitamin D) binds to vitamin D receptor which regulates genes that control cell proliferation, differentiation and apoptosis. In the cardiovascular system, the vitamin D receptor is present in cardiomyocytes and the arterial wall. A clear correlation between vitamin D level and cardiovascular diseases is established. Vitamin D deficiency affects the renin-angiotensin system leading to ventricular hypertrophy and eventually to stroke. While clinical trials highlighted the positive effects of vitamin D supplements on cardiovascular disease these still need to be confirmed. This review outlines the association between vitamin D and cardiovascular and renal disease summarising the experimental data of selective cardiovascular disorders.

The role of plant-derived natural substances as immunomodulatory agents in carcinogenesis.

The role of immune system in carcinogenesis represents fundamental events associated with cancer eradication; however, tumor evolution is connected with various mechanisms of tumor evasion and progression of cancer. Based on recent evidence, phytochemicals are directly associated with immunomodulation of the innate and adaptive immunity via different mechanisms of action including stimulation and amplification of immune cells, humoral compartments, and associated molecules. This comprehensive study focuses on immunomodulating potential of phytochemicals (mixture in plants or separately such as individual phytochemical) and their impact on regulation of immune response during cancer development, immune tolerance, and immune escape. Clinical application of phytochemicals as modulators of host immunity against cancer may represent perspective approach in anticancer therapy.