Role of the RAAS in mediating the pathophysiology of COVID-19.

The renin-angiotensin-aldosterone system (RAAS) holds a position of paramount importance as enzymatic and endocrine homeostatic regulator concerning the water-electrolyte and acid-base balance. Nevertheless, its intricacy is influenced by the presence of various complementary angiotensins and their specific receptors, thereby modifying the primary RAAS actions. Angiotensin-converting enzyme 2 (ACE2) acts as a surface receptor for SARS-CoV-2, establishing an essential connection between RAAS and COVID-19 infection. Despite the recurring exploration of the RAAS impact on the trajectory of COVID-19 along with the successful resolution of many inquiries, its complete role in the genesis of delayed consequences encompassing long COVID and cardiovascular thrombotic outcomes during the post-COVID phase as well as post-vaccination, remains not fully comprehended. Particularly noteworthy is the involvement of the RAAS in the molecular mechanisms underpinning procoagulant processes throughout COVID-19. These processes significantly contribute to the pathogenesis of organ complications as well as determine clinical outcomes and are discussed in this manuscript.

Insulin and Metformin Administration: Unravelling the Multifaceted Association with Mortality across Various Clinical Settings Considering Type 2 Diabetes Mellitus and COVID-19.

Due to the molecular mechanisms of action of antidiabetic drugs, they are considered to be effective in the treatment of both COVID-19 and the post-COVID-19 syndromes. The aim of this study was to determine the effect of administering insulin and metformin on the mortality of patients with type 2 diabetes (T2DM) with symptomatic COVID-19 with the use of logistic regression models. The association between death and insulin and metformin was weak and could not be included in the multivariate model. However, the interaction of both drugs with other factors, including remdesivir and low-molecular-weight heparin (metformin), age and hsCRP (insulin), modulated the odds of death. These interactions hint at multifaceted (anti-/pro-) associations of both insulin and metformin with the odds of death, depending on the patient's characteristics. In the multivariate model, RDW-SD, adjusted with low-molecular-weight heparin treatment, age, sex and K+, was associated with mortality among patients with COVID-19 and T2DM. With a 15% increase in RDW-SD, the risk of death increased by 87.7%. This preliminary study provides the foundations for developing further, more personalized models to assess the risk of death in T2DM patients, as well as for identifying patients at an increased risk of death due to COVID-19.

Usefulness of the Veterans Health Administration COVID-19 (VACO) Index for Predicting Short-Term Mortality among Patients of the COLOS Study.

Advanced age is known to be a predictor with COVID-19 severity. Understanding of other disease progression factors may shorten the time from patient admission to applied treatment. The Veterans Health Administration COVID-19 (VACO index) was assumed to additionally anticipate clinical results of patients hospitalized with a proven infection caused by the SARS-CoV-2 virus. METHODS: The medical records of 2183 hospitalized patients were retrospectively analyzed. Patients were divided into four risk-of-death categories: low risk, medium risk, high-risk, and extreme risk depending on their VACO index calculation. RESULTS: Significant differences in the mortality at the hospital after three months of discharge and six months after discharge were noticed. For the patients in the extreme-risk group, mortality reached 37.42%, 62.81%, and 78.44% for in-hospital, three months of discharge, and six months of discharge, respectively. The mortality marked as high risk reached 20.38%, 37.19%, and 58.77%. Moreover, the secondary outcomes analysis acknowledged that patients classified as extreme risk were more likely to suffer from cardiogenic shock, myocardial infarction, myocardial injury, stroke, pneumonia, acute kidney injury, and acute liver dysfunction. Patients at moderate risk were more often admitted to ICU when compared to other patients. CONCLUSIONS: The usage of the VACO index, combined with an appropriate well-defined medical interview and past medical history, tends to be a helpful instrument in order to predict short-term mortality and disease progression based on previous medical records.

Dysnatremia in COVID-19 Patients-An Analysis of the COLOS Study.

BACKGROUND: Sodium imbalance is one of the most common electrolyte disturbances encountered in the medical practice, and it may present with either hyponatremia or hypernatremia. Both sodium abnormalities are related with unfavorable outcomes. OBJECTIVE: Elucidation of the prevalence of dysnatremia among COVID-19 patients and its impact on 30- and 90-day mortality and need for ICU admission was the goal. DESIGN AND PARTICIPANTS: A single-center, retrospective, observational study was conducted. A total of 2026 adult, SARS-CoV-2 positive patients, admitted to Wroclaw University Hospital between 02.2020 and 06.2021, were included. On admission, patients were divided into groups: normonatremic (N), hyponatremic (L), and hypernatremic (H). Acquired data was processed, and Cox hazards regression and logistic regression were implemented. KEY RESULTS: Hyponatremia on admission occurred in 17.47% (n = 354) of patients and hypernatremia occurred in 5.03% (n = 102). Dysnatremic patients presented with more comorbidities, used more drugs, and were statistically more often admitted to the ICU. Level of consciousness was the strongest predictor of ICU admission (OR = 1.21, CI: 1.16-1.27, p < 0.001). Thirty-day mortality was significantly higher in both the L and H groups (28.52%, p = 0.0001 and 47.95%, p < 0.0001, respectively), in comparison to 17.67% in the N group. Ninety-day mortality showed a similar trend in all study groups: 34.37% in the L group (p = 0.0001), 60.27% (p < 0.0001) in the H group, and 23.32% in the N group. In multivariable analyses, hypo- and hypernatremia were found to be independent predictors of 30- and 90-day mortality. CONCLUSIONS: Both hypo- and hypernatremia are strong predictors of mortality and disease severity in COVID-19 patients. Extraordinary care should be taken when dealing with hypernatremic, COVID-positive patients, as this group exhibits the highest mortality rates.

Cornelian Cherry (Cornus mas L.) Iridoid and Anthocyanin-Rich Extract Reduces Various Oxidation, Inflammation, and Adhesion Markers in a Cholesterol-Rich Diet Rabbit Model.

Atherogenesis leads to the development of atherosclerosis, a progressive chronic disease characterized by subendothelial lipoprotein retention and endothelial impairment in the arterial wall. It develops mainly as a result of inflammation and also many other complex processes, which arise from, among others, oxidation and adhesion. Cornelian cherry (Cornus mas L.) fruits are abundant in iridoids and anthocyanins-compounds with potent antioxidant and anti-inflammatory activity. This study aimed to determine the effect of two different doses (10 mg and 50 mg per kg of body weight, respectively) of iridoid and anthocyanin-rich resin-purified Cornelian cherry extract on the markers that are important in the progress of inflammation, cell proliferation and adhesion, immune system cell infiltration, and atherosclerotic lesion development in a cholesterol-rich diet rabbit model. We used biobank blood and liver samples that were collected during the previous original experiment. We assessed the mRNA expression of MMP-1, MMP-9, IL-6, NOX, and VCAM-1 in the aorta, and the serum levels of VCAM-1, ICAM-1, CRP, PON-1, MCP-1, and PCT. The application of the Cornelian cherry extract at a dose of 50 mg/kg bw resulted in a significant reduction in MMP-1, IL-6, and NOX mRNA expression in the aorta and a decrease in VCAM-1, ICAM-1, PON-1, and PCT serum levels. The administration of a 10 mg/kg bw dose caused a significant decrease in serum ICAM-1, PON-1, and MCP-1. The results indicate the potential usefulness of the Cornelian cherry extract in the prevention or treatment of atherogenesis-related cardiovascular diseases, such as atherosclerosis or metabolic syndrome.

The Usefulness of the COVID-GRAM Score in Predicting the Outcomes of Study Population with COVID-19.

BACKGROUND: The COVID-GRAM is a clinical risk rating score for predicting the prognosis of hospitalized COVID-19 infected patients. AIM: Our study aimed to evaluate the use of the COVID-GRAM score in patients with COVID-19 based on the data from the COronavirus in the LOwer Silesia (COLOS) registry. MATERIAL AND METHODS: The study group (834 patients of Caucasian patients) was retrospectively divided into three arms according to the risk achieved on the COVID-GRAM score calculated at the time of hospital admission (between February 2020 and July 2021): low, medium, and high risk. The Omnibus chi-square test, Fisher test, and Welch ANOVA were used in the statistical analysis. Post-hoc analysis for continuous variables was performed using Tukey's correction with the Games-Howell test. Additionally, the ROC analysis was performed over time using inverse probability of censorship (IPCW) estimation. The GRAM-COVID score was estimated from the time-dependent area under the curve (AUC). RESULTS: Most patients (65%) had a low risk of complications on the COVID-GRAM scale. There were 113 patients in the high-risk group (13%). In the medium- and high-risk groups, comorbidities occurred statistically significantly more often, e.g., hypertension, diabetes, atrial fibrillation and flutter, heart failure, valvular disease, chronic kidney disease, and obstructive pulmonary disease (COPD), compared to low-risk tier subjects. These individuals were also patients with a higher incidence of neurological and cardiac complications in the past. Low saturation of oxygen values on admission, changes in C-reactive protein, leukocytosis, hyperglycemia, and procalcitonin level were associated with an increased risk of death during hospitalization. The troponin level was an independent mortality factor. A change from low to medium category reduced the overall survival probability by more than 8 times and from low to high by 25 times. The factor with the strongest impact on survival was the absence of other diseases. The medium-risk patient group was more likely to require dialysis during hospitalization. The need for antibiotics was more significant in the high-risk group on the GRAM score. CONCLUSION: The COVID-GRAM score corresponds well with total mortality. The factor with the strongest impact on survival was the absence of other diseases. The worst prognosis was for patients who were unconscious during admission. Patients with higher COVID-GRAM score were significantly less likely to return to full health during follow-up. There is a continuing need to develop reliable, easy-to-adopt tools for stratifying the course of SARS-CoV-2 infection.

SARS-CoV-2 Infection and Pregnancy: Maternal and Neonatal Outcomes and Placental Pathology Correlations.

There is accumulating evidence on the perinatal aspects of COVID-19, but available data are still insufficient. The reports on perinatal aspects of COVID-19 have been published on a small group of patients. Vertical transmission has been noted. The SARS-CoV-2 genome can be detected in umbilical cord blood and at-term placenta, and the infants demonstrate elevated SARS-CoV-2-specific IgG and IgM antibody levels. In this work, the analysis of clinical characteristics of RT-PCR SARS-CoV-2-positive pregnant women and their infants, along with the placental pathology correlation results, including villous trophoblast immunoexpression status for SARS-CoV-2 antibody, is presented. RT-PCR SARS-CoV-2 amniotic fluid testing was performed. Neonatal surveillance of infection status comprised RT-PCR testing of a nasopharyngeal swab and the measuring of levels of anti-SARS-CoV-2 in blood serum. In the initial study group were 161 pregnant women with positive test results. From that group, women who delivered during the hospital stay were selected for further analysis. Clinical data, laboratory results, placental histomorphology results, and neonatal outcomes were compared in women with immunohistochemistry (IHC)-con SARS-CoV-2-positive and IHC SARS-CoV-2-negative placentas (26 cases). A positive placental immunoprofile was noted in 8% of cases (n = 2), whereas 92% of cases were negative (n = 24). Women with placental infection proven by IHC had significantly different pathological findings from those without. One infected neonate was noted (n = 1; 4%). Infection was confirmed in perinatal autopsy, as there was the intrauterine fetal demise. The potential course of the infection with the risk of vertical transmission and implications for fetal-neonatal condition is critical for proper clinical management, which will involve comprehensive, multidisciplinary perinatal care for SARS-CoV-2-positive patients.

Liver Function Tests in COVID-19: Assessment of the Actual Prognostic Value.

Deviations in laboratory tests assessing liver function in patients with COVID-19 are frequently observed. Their importance and pathogenesis are still debated. In our retrospective study, we analyzed liver-related parameters: aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), total bilirubin (TBIL), albumin, comorbidities and other selected potential risk factors in patients admitted with SARS-CoV-2 infection to assess their prognostic value for intensive care unit admission, mechanical ventilation necessity and mortality. We compared the prognostic effectiveness of these parameters separately and in pairs to the neutrophil-to-lymphocyte ratio (NLR) as an independent risk factor of in-hospital mortality, using the Akaike Information Criterion (AIC). Data were collected from 2109 included patients. We created models using a sample with complete laboratory tests n = 401 and then applied them to the whole studied group excluding patients with missing singular variables. We estimated that albumin may be a better predictor of the COVID-19-severity course compared to NLR, irrespective of comorbidities (p < 0.001). Additionally, we determined that hypoalbuminemia in combination with AST (OR 1.003, p = 0.008) or TBIL (OR 1.657, p = 0.001) creates excellent prediction models for in-hospital mortality. In conclusion, the early evaluation of albumin levels and liver-related parameters may be indispensable tools for the early assessment of the clinical course of patients with COVID-19.

The Usefulness of the C2HEST Risk Score in Predicting Clinical Outcomes among Hospitalized Subjects with COVID-19 and Coronary Artery Disease.

BACKGROUND: Even though coronary artery disease (CAD) is considered an independent risk factor of an unfavorable outcome of SARS-CoV-2-infection, the clinical course of COVID-19 in subjects with CAD is heterogeneous, ranging from clinically asymptomatic to fatal cases. Since the individual C2HEST components are similar to the COVID-19 risk factors, we evaluated its predictive value in CAD subjects. MATERIALS AND METHODS: In total, 2183 patients hospitalized due to confirmed COVID-19 were enrolled onto this study consecutively. Based on past medical history, subjects were assigned to one of two of the study arms (CAD vs. non-CAD) and allocated to different risk strata, based on the C2HEST score. RESULTS: The CAD cohort included 228 subjects, while the non-CAD cohort consisted of 1956 patients. In-hospital, 3-month and 6-month mortality was highest in the high-risk C2HEST stratum in the CAD cohort, reaching 43.06%, 56.25% and 65.89%, respectively, whereas in the non-CAD cohort in the high-risk stratum, it reached: 26.92%, 50.77% and 64.55%. Significant differences in mortality between the C2HEST stratum in the CAD arm were observed in post hoc analysis only for medium- vs. high-risk strata. The C2HEST score in the CAD cohort could predict hypovolemic shock, pneumonia and acute heart failure during hospitalization, whereas in the non-CAD cohort, it could predict cardiovascular events (myocardial injury, acute heart failure, myocardial infract, carcinogenic shock), pneumonia, acute liver dysfunction and renal injury as well as bleedings. CONCLUSIONS: The C2HEST score is a simple, easy-to-apply tool which might be useful in risk stratification, preferably in non-CAD subjects admitted to hospital due to COVID-19.

Usefulness of C2HEST Score in Predicting Clinical Outcomes of COVID-19 in Heart Failure and Non-Heart-Failure Cohorts.

Background: Patients with heart failure represent a vulnerable population for COVID-19 and are prone to having worse prognoses and higher fatality rates. Still, the clinical course of the infection is dynamic, and complication occurrence in particular in patients with heart failure is fairly unpredictable. Considering that individual components of the C2HEST (C2: Coronary Artery Diseases (CAD)/Chronic obstructive pulmonary disease (COPD); H: Hypertension; E: Elderly (Age ≥ 75); S: Systolic HF; T: Thyroid disease) are parallel to COVID-19 mortality risk factors, we evaluate the predictive value of C2HEST score in patients with heart failure (HF) Material and Methods: The retrospective medical data analysis of 2184 COVID-19 patients hospitalized in the University Hospital in Wroclaw between February 2020 and June 2021 was the basis of the study. The measured outcomes included: in-hospital mortality, 3-month and 6-month all-cause-mortality, non-fatal end of hospitalization, and adverse in-hospital clinical events. Results: The heart failure cohort consists of 255 patients, while 1929 patients were assigned to the non-HF cohort. The in-hospital, 3-month, and 6-month mortality rates were highest in the HF cohort high-risk C2HEST stratum, reaching 38.61%, 53.96%, and 65.36%, respectively. In the non-HF cohort, in-hospital, 3-month, and 6-month mortalities were also highest in the high-risk C2HEST stratum and came to 26.39%, 52.78%, and 65.0%, respectively. An additional point in the C2HEST score increased the total death intensity in 10% of HF subjects (HR 1.100, 95% CI 0.968−1.250 p = 0.143) while in the non-HF cohort, the same value increased by 62.3% (HR 1.623, 95% CI 1.518−1.734 p < 0.0001). Conclusions: The C2HEST score risk in the HF cohort failed to show discriminatory performance in terms of mortality and other clinical adverse outcomes during hospitalization. C2HEST score in the non-HF cohort showed significantly better performance in terms of predicting in-hospital and 6-month mortality and other non-fatal clinical outcomes such as cardiovascular events (myocardial injury, acute heart failure, myocardial infarction, cardiogenic shock), pneumonia, sepsis, and acute renal injury.

Factors That Influence the Use of Dietary Supplements among the Students of Wroclaw Medical University in Poland during the COVID-19 Pandemic.

BACKGROUND AND AIM: The use of dietary supplements (DS) and over-the-counter (OTC) drugs is increasing every year. The COVID-19 pandemic might additionally influence the use of such preparations. The study aimed to investigate factors influencing the use of dietary supplements (DS), including stress-relieving supplements, by the students. METHODS: In the cross-sectional study, 624 students of the Wroclaw Medical University in Poland, from the second to the last year of studies, completed the anonymous questionnaire, consisting of 22 items, about the use of DS/OTC drugs during the academic year 2020/2021. Obtained data were analyzed using Pearson's chi-square test, the U-Mann Whitney test, the Kruskal-Wallis test with the post-hoc analysis, and with logistic regression. RESULTS: About 70% of students declared the use of any DS, 33% used DS for stress, anxiety, depression, or sleeping problems, and 59% used other DS. The most important factors influencing the decision to take any kind of DS were Division (p = 0.0001, odds ratio [OR]: 0.35, and confidence interval [CI]: 0.21-0.59), a self-estimated level of stress (p = 0.014, OR: 1.13, CI: 1.03-1.25), and self-estimated level of knowledge about DS (p = 0.0000, OR: 1.31, CI: 1.19-1.36). In the case of students taking DS for stress, anxiety, depression, or sleeping problems, the level of stress and the declared knowledge had the greatest impact on the decision for such a use of DS (p = 0.0001, OD: 1.24, CI: 1.11-1.39 and p = 0.0000, OD: 1.35, CI: 1.22-1.5, respectively). The COVID-19 pandemic did not change the pattern of DS/OTC drug usage in about 33% of students. Those who started taking DS during the pandemic accounted for 19% of all students. CONCLUSIONS: The use of DS is common among Wroclaw Medical University students with some differences between subgroups of respondents. Additionally, despite declared good knowledge about DS, most students declare the need to learn more about them.

Platelet-Derived Drug Targets and Biomarkers of Ischemic Stroke-The First Dynamic Human LC-MS Proteomic Study.

(1) Objective: The aim of this dynamic LC-MS (liquid chromatography and mass spectrometry) human platelet proteomic study was to identify the potential proteins candidates for biomarkers of acute ischemic stroke (AIS), their changes during the acute phase of stroke and to define potential novel drug targets. (2) Methods: A total of 32 patients (18-80 years old) were investigated that presented symptoms of AIS lasting less than 24 h from the onset, confirmed by neurological examination and/or new cerebral ischemia visualized in the CT (computed-tomography) scans. The analysis of platelet proteome was performed using LC-MS at baseline, and then on the third and seventh day from the onset of symptoms. The control group was demographically matched without any clinical signs of acute brain injury. (3) Results: The differences between platelets, at 24 h after first symptoms of stroke subjects and the control group included: ß-amyloid A4 and amyloid-like protein 2, coactosin-like protein, thymidine phosphorylase 4 (TYMP-4), interferon regulatory factor 7 (IRF7), vitamin K-dependent protein S, histone proteins (H2A type 1 and 1-A, H2A types 2B and J, H2Av, -z, and -x), and platelet basic protein. The dynamic changes in the platelet protein concentration involved thrombospondin-1, thrombospondin-2, filamin A, B, and C. (4) Conclusions: This is the first human dynamic LC-MS proteomic study that differentiates platelet proteome in the acute phase of ischemic stroke in time series and compares the results with healthy controls. Identified proteins may be considered as future markers of ischemic stroke or therapeutic drug targets. Thymidine phosphorylase 4 (TYMP-4) holds promise as an interesting drug target in the management or prevention of ischemic stroke.

Sex-Dependent Differences in Predictive Value of the C2HEST Score in Subjects with COVID-19-A Secondary Analysis of the COLOS Study.

Background: Since the outbreak of the COVID-19 pandemic, a growing number of evidence suggests that COVID-19 presents sex-dependent differences in clinical course and outcomes. Nevertheless, there is still an unmet need to stratify the risk for poor outcome at the beginning of hospitalization. Since individual C2HEST components are similar COVID-19 mortality risk factors, we evaluated sex-related predictive value of the score. Material and Methods: A total of 2183 medical records of consecutive patients hospitalized due to confirmed SARS-CoV-2 infections were analyzed. Subjects were assigned to one of two of the study arms (male vs. female) and afterward allocated to different stratum based on the C2HEST score result. The measured outcomes included: in-hospital-mortality, three-month- and six-month-all-cause-mortality and in-hospital non-fatal adverse clinical events. Results: The C2HEST score predicted the mortality with better sensitivity in female population regarding the short- and mid-term. Among secondary outcomes, C2HEST-score revealed predictive value in both genders for pneumonia, myocardial injury, myocardial infarction, acute heart failure, cardiogenic shock, and acute kidney injury. Additionally in the male cohort, the C2HEST value predicted acute liver dysfunction and all-cause bleeding, whereas in the female arm-stroke/TIA and SIRS. Conclusion: In the present study, we demonstrated the better C2HEST-score predictive value for mortality in women and illustrated sex-dependent differences predicting non-fatal secondary outcomes.

Mortality Predictive Value of the C2HEST Score in Elderly Subjects with COVID-19-A Subanalysis of the COLOS Study.

Senility has been identified among the strongest risk predictors for unfavorable COVID-19-outcome. However, even in the elderly population, the clinical course of infection in individual patients remains unpredictable. Hence, there is an urgent need for developing a simple tool predicting adverse COVID-19-outcomes. We assumed that the C2HEST-score could predict unfavorable clinical outcomes in the elderly subjects with COVID-19-subjects. METHODS: We retrospectively analyzed 1047 medical records of patients at age > 65 years, hospitalized at the medical university center due to COVID-19. Subsequently, patients were divided into three categories depending on their C2HEST-score result. RESULTS: We noticed significant differences in the in-hospital and 3-month and 6-month mortality-which was the highest in high-risk-C2HEST-stratum reaching 35.7%, 54.4%, and 65.9%, respectively. The medium-risk-stratum mortalities reached 24.1% 43.4%, and 57.6% and for low-risk-stratum 14.4%, 25.8%, and 39.2% respectively. In the C2HEST-score model, a change from the low to the medium category increased the probability of death intensity approximately two-times. Subsequently, transfer from the low-risk to the high-risk-stratum raised all-cause-death-intensity 2.7-times. Analysis of the secondary outcomes revealed that the C2HEST-score has predictive value for acute kidney injury, acute heart failure, and cardiogenic shock. CONCLUSIONS: C2HEST-score analysis on admission to the hospital may predict the mortality, acute kidney injury, and acute heart failure in elderly subjects with COVID-19.

Usefulness of the C2HEST Score in Predicting the Clinical Outcomes of COVID-19 in Diabetic and Non-Diabetic Cohorts.

BACKGROUND: Diabetes mellitus is among the most frequent comorbidities worsening COVID-19 outcome. Nevertheless, there are no data regarding the optimal risk stratification of patients with diabetes and COVID-19. Since individual C2HEST components reflect the comorbidities, we assumed that the score could predict COVID-19 outcomes. MATERIAL AND METHODS: A total of 2184 medical records of patients hospitalized for COVID-19 at the medical university center were analyzed, including 473 diabetic patients and 1666 patients without any glucose or metabolic abnormalities. The variables of patients' baseline characteristics were retrieved to calculate the C2HEST score and subsequently the diabetic and non-diabetic subjects were assigned to the following categories: low-, medium- or high-risk. The measured outcomes included: in-hospital mortality; 3-month and 6-month all-cause mortality; non-fatal end of hospitalization (discharged home/sudden-deterioration/rehabilitation) and adverse in-hospital clinical events. RESULTS: A total of 194 deaths (41%) were reported in the diabetic cohort, including 115 in-hospital deaths (24.3%). The 3-month and 6-month in-hospital mortality was highest in the high-risk C2HEST stratum. The C2HEST score revealed to be more sensitive in non-diabetic-group. The estimated six-month survival probability for high-risk subjects reached 0.4 in both cohorts whereas for the low-risk group, the six-month survival probability was 0.7 in the diabetic vs. 0.85 in the non-diabetic group-levels which were maintained during whole observation period. In both cohorts, receiver operating characteristics revealed that C2HEST predicts the following: cardiogenic shock; acute heart failure; myocardial injury; and in-hospital acute kidney injury. CONCLUSIONS: We demonstrated the usefulness and performance of the C2HEST score in predicting the adverse COVID-19 outcomes in hospitalized diabetic subjects.

New Candidates for Biomarkers and Drug Targets of Ischemic Stroke-A First Dynamic LC-MS Human Serum Proteomic Study.

(1) Background: The aim of this dynamic-LC/MS-human-serum-proteomic-study was to identify potential proteins-candidates for biomarkers of acute ischemic stroke, their changes during acute phase of stroke and to define potential novel drug-targets. (2) Methods: A total of 32 patients (29-80 years) with acute ischemic stroke were enrolled to the study. The control group constituted 29 demographically-matched volunteers. Subjects with stroke presented clinical symptoms lasting no longer than 24 h, confirmed by neurological-examination and/or new cerebral ischemia visualized in the CT scans (computed tomography). The analysis of plasma proteome was performed using LC-MS (liquid chromatography-mass spectrometry). (3) Results: Ten proteins with significantly different serum concentrations between groups volunteers were: complement-factor-B, apolipoprotein-A-I, fibronectin, alpha-2-HS-glycoprotein, alpha-1B-glycoprotein, heat-shock-cognate-71kDa protein/heat-shock-related-70kDa-protein-2, thymidine phosphorylase-2, cytoplasmic-tryptophan-tRNA-ligase, ficolin-2, beta-Ala-His-dipeptidase. (4) Conclusions: This is the first dynamic LC-MS study performed on a clinical model which differentiates serum proteome of patients in acute phase of ischemic stroke in time series and compares to control group. Listed proteins should be considered as risk factors, markers of ischemic stroke or potential therapeutic targets. Further clinical validation might define their exact role in differential diagnostics, monitoring the course of the ischemic stroke or specifying them as novel drug targets.

Modulation of Prostanoids Profile and Counter-Regulation of SDF-1α/CXCR4 and VIP/VPAC2 Expression by Sitagliptin in Non-Diabetic Rat Model of Hepatic Ischemia-Reperfusion Injury.

Molecular mechanisms underlying the beneficial effect of sitagliptin repurposed for hepatic ischemia-reperfusion injury (IRI) are poorly understood. We aimed to evaluate the impact of IRI and sitagliptin on the hepatic profile of eicosanoids (LC-MS/MS) and expression/concentration (RTqPCR/ELISA) of GLP-1/GLP-1R, SDF-1α/CXCR4 and VIP/VPAC1, VPAC2, and PAC1 in 36 rats. Animals were divided into four groups and subjected to ischemia (60 min) and reperfusion (24 h) with or without pretreatment with sitagliptin (5 mg/kg) (IR and SIR) or sham-operated with or without sitagliptin pretreatment (controls and sitagliptin). PGI2, PGE2, and 13,14-dihydro-PGE1 were significantly upregulated in IR but not SIR, while sitagliptin upregulated PGD2 and 15-deoxy-12,14-PGJ2. IR and sitagliptin non-significantly upregulated GLP-1 while Glp1r expression was borderline detectable. VIP concentration and Vpac2 expression were downregulated in IR but not SIR, while Vpac1 was significantly downregulated solely in SIR. IRI upregulated both CXCR4 expression and concentration, and sitagliptin pretreatment abrogated receptor overexpression and downregulated Sdf1. In conclusion, hepatic IRI is accompanied by an elevation in proinflammatory prostanoids and overexpression of CXCR4, combined with downregulation of VIP/VPAC2. Beneficial effects of sitagliptin during hepatic IRI might be mediated by drug-induced normalization of proinflammatory prostanoids and upregulation of PGD2 and by concomitant downregulation of SDF-1α/CXCR4 and reinstating VIP/VCAP2 signaling.

Effect of the Renin-Angiotensin-Aldosterone System Reactivity on Endothelial Function and Modulative Role of Valsartan in Male Subjects with Essential Hypertension.

BACKGROUND: The aim of the study was to evaluate the relationship between renin-angiotensin-aldosterone (RAA) system activity and reactivity, and the endothelial function profile in normotensive subjects (N), and in essential hypertensives (H), followed by analysis of the modulatory role of an angiotensin receptor blocker (ARB): valsartan, administered in the management of hypertension. METHODS: A total of 101 male subjects were enrolled to the study: 31H and 70N. The nitric-oxide (NO) bioavailability (l-Arginine, asymmetric dimethylarginine (ADMA)), symmetric dimethylarginine (SDMA), endothelial vasodilative function (flow mediated dilation (FMD)), oxidative-stress markers (malonyldialdehyde (MDA), thiol index (GSH/GSSG), nitrotyrozine (N-Tyr)), and pro-inflammatory/angiogenic parameters (sICAM-1, sVCAM-1, PAI-1, sE-selectin, PAI-1, thromboxane -B2) were assessed at baseline, then after intravenous -l-arginine administration, which was repeated after the 4-day acetylsalicylic acid (ASA) administration (75 mg/24 h). In hypertensives, this whole protocol was repeated following 2 weeks of valsartan therapy. RESULTS: No effect of valsartan and ASA on the flow-mediated vasodilation (FMD) and the NO bioavailability in hypertensives was observed. Administration of valsartan increased plasma renin activity (PRA), but without a decrease in the aldosterone levels. ASA treatment minimized the pre-existing differences between the groups, and increased the PRA in the N-subgroup with the highest ARR values. The blood concentrations of proinflammatory sICAM-1, sE-selectin, sVCAM-1, and PAI-1 were higher, whereas the anti-inflammatory 6-keto-PGF1 alpha level was lower in hypertensive subjects. The levels of angiogenic VEGF did not differ between groups. CONCLUSIONS: Our study does not confirm the modulative effect of valsartan on endothelial function. Normotensive men showed an increase in FMD after l-arginine administration, possibly indicating baseline impairment of the NO synthesis.

Effect of a Low Dose of Carvedilol on Cyclophosphamide-Induced Urinary Toxicity in Rats-A Comparison with Mesna.

One of the major side effects of cyclophosphamide (CPX)-an alkylating anticancer drug that is still clinically used-is urotoxicity with hemorrhagic cystitis. The present study was designed to evaluate the ability of carvedilol to protect rats from cyclophosphamide-induced urotoxicity. Rats were injected intraperitoneally (i.p.) with CPX (200 mg/kg) and administered carvedilol (2 mg/kg) intragastrically a day before, at the day and a day after a single i.p. injection of CPX, with or without mesna (40, 80, and 80 mg/kg i.p. 20 min before, 4 h and 8 h after CPX administration, respectively). Pretreatment with carvedilol partly prevented the CPX-induced increase in urinary bladder and kidney index, and completely protects from CPX-evoked alterations in serum potassium and creatinine level, but did not prevent histological alterations in the urinary bladder and hematuria. However, carvedilol administration resulted in significant restoration of kidney glutathione (GSH) level and a decrease in kidney interleukin 1ß (IL-1ß) and plasma asymmetric dimethylarginine (ADMA) concentrations. Not only did mesna improve kidney function, but it also completely reversed histological abnormalities in bladders and prevented hematuria. In most cases, no significant interaction of carvedilol with mesna was observed, although the effect of both drugs together was better than mesna given alone regarding plasma ADMA level and kidney IL-1ß concentration. In conclusion, carvedilol did not counteract the injury caused in the urinary bladders but restored kidney function, presumably via its antioxidant and anti-inflammatory properties.

Cornelian Cherry (Cornus mas L.) Iridoid and Anthocyanin Extract Enhances PPAR-α, PPAR-γ Expression and Reduces I/M Ratio in Aorta, Increases LXR-α Expression and Alters Adipokines and Triglycerides Levels in Cholesterol-Rich Diet Rabbit Model.

Cornelian cherry (Cornus mas L.) fruits possess potential cardiovascular, lipid-lowering and hypoglycemic bioactivities. The aim of this study is to evaluate the influence of resin-purified cornelian cherry extract rich in iridoids and anthocyanins on several transcription factors, intima/media ratio in aorta and serum parameters, which determine or are valuable indicators of the adverse changes observed in the course of atherosclerosis, cardiovascular disease, and metabolic syndrome. For this purpose, male New Zealand rabbits were fed a diet enriched in 1% cholesterol for 60 days. Additionally, one group received 10 mg/kg b.w. of cornelian cherry extract and the second group 50 mg/kg b.w. of cornelian cherry extract. PPAR-α and PPAR-γ expression in the aorta, LXR-α expression in the liver; cholesterol, triglycerides, adipokines, apolipoproteins, glucose and insulin levels in serum; the intima and media diameter in the thoracic and abdominal aorta were determined. Administration of cornelian cherry extract resulted in an enhancement in the expression of all tested transcription factors, a decrease in triglycerides, leptin and resistin, and an increase in adiponectin levels. In addition, a significant reduction in the I/M ratio was observed for both the thoracic and abdominal aorta. The results we have obtained confirm the potential contribution of cornelian cherry extract to mitigation of the risk of developing and the intensity of symptoms of obesity-related cardiovascular diseases and metabolic disorders such as atherosclerosis or metabolic syndrome.