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The hallmark of multiple myeloma is myeloma related bone disease. Interactions between myeloma plasma cells (MPCs), stromal cells, and the bone marrow (BM) microenvironment play a critical role in the pathogenesis of MBD. Bone remodeling is severely dysregulated with the prevalence of osteoclast activity. We aimed to assess circulating levels of sRANKL, periostin, and osteopontin as osteoclast activators in NDMM patients at diagnosis and in the course of treatment, correlations with clinical and laboratory data, and to evaluate their potential as additional biomarkers for the assessment of MBD. The current study involved 74 subjects (41 NDMM patients, 33 controls). MBD was assessed by whole-body low-dose computed tomography. sRANKL, periostin, and osteopontin were assayed by commercial ELISA kits. At diagnosis, all tested parameters were significantly higher in NDMM patients compared to the controls (p < 0.0001), correlating with disease stage, MBD grade, and BM infiltration by MPCs. During therapy, the serum levels of all tested proteins decrease, most prominently after autologous stem cell transplantation (p < 0.0001). A significant reduction was established in patients achieving complete and very-good partial response compared to all others (p < 0.05). In conclusion, sRANKL, periostin, and osteopontin reflect MBD severity and could be promising markers for MBD monitoring and the effect of myeloma treatment.

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Endothelial dysfunction is one of the major factors in the pathogenesis of metabolic syndrome (MetS), and its molecular mechanisms are not completely understood. The present study aimed to examine the connection between nuclear factor2-related factor2 (Nrf2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), heme oxygenase 1 (HO-1), and plasma asymmetric dimethylarginine (ADMA) and malondialdehyde (MDA) in people with MetS. Participants in the study were as follows: with MetS (n = 30) and without MetS (Control) (n = 14). Expression of Nrf2, NF-kB, and HO-1 was measured in peripheral blood mononuclear cells (PBMCs). Plasma ADMA was determined using the ELISA technique and MDA via the thiobarbituric acid method. Our study showed that mRNA of NF-kB, Nrf2, and HO-1 levels in PBMCs in the MetS group were significantly higher than in the controls by 53%, 130%, and 185% (p < 0.05), respectively. Similarly, elevated levels of MDA (by 78%, p < 0.001) and ADMA (by 18.7%, p < 0.001) were established in the MetS group. Our findings show the importance of transcription factor Nrf2, playing an integral role in the protection of the endothelium, and of NF-κB, a transcription factor mediating the inflammatory response in MetS. Knowledge of complex cellular-molecular mechanisms would allow the use of biomarkers such as Nrf2, NF-kB, HO-1, and ADMA for the assessment of endothelial dysfunction in clinical practice.

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Dickkopf-1 (DKK-1) and sclerostin are essential Wnt/ß-catenin pathway inhibitors, playing an important role in multiple myeloma bone disease (MBD). We aimed to examine the serum DKK-1 and sclerostin variations in newly diagnosed multiple myeloma (NDMM) patients at diagnosis and in the course of therapy, including autologous stem cell transplantation (ASCT). This study included 41 NDMM-patients and 33 controls. MBD was assessed by whole-body low-dose computed tomography. DKK-1 and sclerostin were assayed by commercial ELISA kits. At diagnosis, NDMM-patients revealed significantly higher DKK-1 and sclerostin values (p < 0.0001), showing dependence on disease stage (lowest in ISS-I and highest in ISS-III: p < 0.0012 and p < 0.025, respectively, for both proteins). Bone lesions revealed significant positive correlation with both DKK-1 (p < 0.05) and sclerostin (p < 0.0001). In the course of therapy, significant reduction, more prominent after ASCT, was observed for both parameters in each treatment point compared to the baseline (p < 0.0001). Markedly lower sclerostin (p < 0.01) and DKK-1 (p < 0.05) values were observed in patients with complete and very good partial response compared to those with partial response, stable, or progressive disease. Sclerostin and DKK-1 in NDMM patients reflect the MBD severity and the effect of therapy. Both proteins could represent a novel tool for better disease monitoring and effectiveness of therapy.

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CONTEXT: Circulating uncarboxylated matrix Gla protein (ucMGP) is possibly related to coronary arterial calcification (CAC) in cardiovascular disease (CVD) patients. OBJECTIVE: We aimed to evaluate the relationships between circulating ucMGP, CVD pathology and CAC and its interplay with CVD risk factors. MATERIALS AND METHODS: ucMGP was measured in 99 CVD-patients. CAC score was determined by multislice computed tomography. Circulating ucMGP, uncarboxylated (ucOC) and carboxylated osteocalcin (cOC) were assayed by ELISA kits. Vitamin-K status was evaluated by ucOC/cOC ratio. RESULTS: A tendency for decreased ucMGP was observed for CAC ≥ 100 AU vs. CAC = 1-99 AU after exclusion of the patients on vitamin K-antagonist anticoagulants. Significant inverse correlations between ucMGP and vitamin-K status were indicated for the entire cohort and according to CAC score. Significant associations were found between ucMGP and risk factors for CVD. CONCLUSION: Circulating ucMGP may reflect certain stages of CVD and CAC. Future studies are needed to clarify its role as potential biomarker.

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BACKGROUND: The disturbed pleiotropic functions of vitamin D are related to numerous chronic non-skeletal diseases. The role of vitamin D insufficiency/deficiency in cardiovascular diseases (CVD) is controversial. Therefore, the aim was to study the vitamin D status in CVD patients and to reveal possible relationships with CVD risk factors. METHODS: This prospective study includes 93 individuals devided into two groups - patients with CVD (n = 49) and patients at risk for CVD (n = 44) served as controls. The CVD-patients were stratified into AF-group - with paroxysmal or persistent atrial fibrillation and HF-group - with heart failure with preserved ejection fraction, in sinus rhythm. Vitamin D status was assessed by measurement of serum 25-hydroxy-vitamin D (25OHD) using liquid chromatography with mass detection. Gene expression of the regulatory enzyme of vitamin D metabolism, 1-alfa-hydroxylase (CYP27B1), was evaluated by two-step real-time qPCR. Coronary artery calcium scans were performed and coronary artery calcium score (CACS) was calculated. Routine biochemical parameters were extracted from the medical documentation. Standard statistical methods (descriptive statistics, unpaired Student's t-test, one-way ANOVA, simple and multiple linear regression analyses) were applied. Statistical significance was considered at p < 0.05. RESULTS: Serum 25OHD levels of the controls were higher than those of the CVD-patients (37.36 ± 15.10 ng/mL vs. 27.70 ± 11.80 ng/mL, p = 0.008). The vitamin D status worsened with the severity of CVD pathology: significant decrease of 25OHD levels was found in the AF-group (29.56 ± 11.76 ng/mL, p = 0.044) and HF-group (24.47 ± 11.61 ng/mL, p = 0.003) vs. controls (37.36 ± 15.10 ng/mL). Significant reduction in circulating vitamin D levels with the increase of CACS (p = 0.007) was also observed. Linear regression analysis revealed significant negative association for serum 25OHD with CACS for both the entire studied group (p = 0.008) and for CVD patients (p = 0.049). The gene expression of CYP27B1 was down regulated with both the severity of CVD pathology (p = 0.05) and coronary calcium accumulation (p = 0.08). Moreover, we found a significant positive relationship (p = 0.041) between serum 25OHD levels and CYP27B1 gene expression. CONCLUSIONS: Vitamin D deficiency may be an independent cardiovascular risk factor associated with the severity of CVD pathology and increased coronary calcium deposition. The mechanism by which vitamin D itself can affect cardiovascular outcomes remains to be clarified.

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BACKGROUND: Inflammatory bowel disease (IBD) is a multifactorial immunologically mediated disorder characterized by repeated cycles of exacerbations and remissions. Diagnosis and monitoring of ulcerative colitis (UC) and Crohn's disease (CD) as common types of IBD require the usage of unpleasant invasive methods such as colonoscopy and cross-sectional imaging. Development of a non-invasive biomarker panel including different inflammatory parameters for evaluation of various aspects of gut inflammation and disease course is a priority task. In addition to the well-known inflammatory markers serum C-reactive protein (CRP) and fecal calprotectin (FC), adenosine deaminase (ADA) could be a promising candidate-biomarker. ADA has been shown to increase in several inflammatory conditions, but little is known about its significance in IBD. This preliminary research aims to study the serum levels of ADA in IBD patients and to evaluate its ability to adequately reflect the gut inflammatory process. METHODS: Fifty-four IBD patients (40 with UC and 14 with CD) and 50 controls were enrolled in the study. Routine laboratory parameters such as white blood cells (WBC) count, erythrocyte sedimentation rate (ESR), and CRP were used. The specific biomarker for intestinal inflammation FC was measured by sandwich immunoassay (BÜHLMANN) and ADA activity - by two-step enzyme method (BioSystems). RESULTS: The median [IQR: 25th - 75th percentile] ADA values in IBD patients were significantly higher than those in the controls (18.7 U/L [15.4 - 22.5] vs. 9.10 U/L [7.1 - 11.2] respectively; p < 0.0001). A significant difference was obtained when comparing median ADA values in patients with active disease (20.4 [17.8 - 25.3] U/L) with those in patients with mild form of the disease or in remission (15.3 [13.0 - 16.0]; p < 0.0001). A strong positive correlation between ADA and FC (r = 0.63; p < 0.0001) and moderate positive correlation between ADA and CRP (r = 0.46; p < 0.001) were observed. ROC-curve analysis revealed good ability of ADA to discriminate not only IBD patients from healthy individuals, but also patients with active disease and those in remission/mild form. CONCLUSIONS: The present study revealed that ADA levels were significantly increased in IBD patients. Together with FC and CRP, ADA could be used as an effective biomarker for assessment of intestinal inflammation and as a potential indicator for disease activity.

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BACKGROUND: The antiproliferative effect of the active form of vitamin D on cancer cells and its ability to induce cell differentiation and suppression of tumor-induced angiogenesis in the last decade has provoked enormous research for the elucidation of its role in the prevention of different types of cancer and in slowing down the malignancy progression. The aim of the present pilot study was to determine the circulating 25-hydroxy vitamin D (25OHD) levels in Bulgarian prostate cancer (PCa) patients and to investigate their relationship with various determinants associated with the severity and progression of the disease. METHODS: A total of 53 male patients (mean age 67.0 ± 7.1 years) with clinical suspicion for PCa were enrolled in the study. All patients were subjected to systemic transrectal ultrasound-guided tru-cut prostate biopsies (10 cores at least). Detected tumors were graded using the Gleason grading system. Prostate specific antigen (PSA) serum levels were measured immunochemically. The 25OHD assay was performed by a validated HPLC-UV method. Other covariates (BMI, age, family history of PCa) were collected by interview at the time of hospitalization. One-way ANOVA with Kruskal Wallis statistics was used for comparison of medians of different parameters. The level of significance was set at p < 0.05. RESULTS: Significantly lower 25OHD levels were detected in PCa patients compared to those with benign prostate hyperplasia (BPH) (p < 0.05). Patients with high grade tumors (Gleason score ≥ 7) showed significantly lower 25OHD levels, while those with low grade tumors (Gleason score < 7) revealed better 25OHD status (50.49 vs. 63.17 nmol/L, p < 0.05). A moderate negative correlation between 25OHD levels and the Gleason score was established (Spearman r = -0.46, p < 0.05). Significant seasonal variations in 25OHD levels, both for PCa and BPH patients, were detected (p < 0.01). CONCLUSIONS: This preliminary study shows an association between 25OHD status and classical markers characterizing the severity of PCa. The results might suggest a potential beneficial role of vitamin D for PCa patients. Further prospective studies are needed to strengthen the interrelationships between 25OHD levels and variables related with PCa and to test them for causality.

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AIMS: The present pilot study aimed to determine vitamin D status in Bulgarian patients with chronic HCV infection in respect to the severity of liver disease and response to interferon-ribavirin therapy. METHODS: The study encompassed 296 patients: 161 males (54.4%) aged 42.08 ± 14.87 years, 135 females (45.6%) aged 45.72 ± 14.34 years, 86.5% of them infected with HCV genotype 1. Total 25-hydroxyvitamin-D (25OHD) was determined by liquid chromatography/tandem-mass spectrometric detection. RESULTS: The median 25OHD level of the studied cohort was 50.40 nmol/L (range: 29.6-71.05). 25OHD deficient (< 25 nmol/L) were 16% of patients, 33% showed profound insufficiency (25-50 nmol/L), another 33% were in the range 50-80 nmol/L (mild insufficiency), the rest 18% were 25OHD sufficient. Significantly lower 25OHD levels were registered in cases with advanced fibrosis compared to those with mild or absent fibrosis (37.10 nmol/L vs. 53.00 nmol/L, respectively, p < 0.05). This association remained unchanged by seasonal variations in 25OHD levels. Inverse relationship was found between 25OHD and HCV-RNA (p < 0.01). Patients with sustained virological response to therapy had significantly higher 25OHD levels, compared to patients who failed to achieve viral eradication (56.90 nmol/L vs. 45.00 nmol/L, p = 0.012). CONCLUSION: More than 80% of HCV-infected patients were vitamin D-deficient and -insufficient. The inverse relationship between 25OHD levels and viral load, liver fibrosis and treatment outcomes supports the hypothesis that improvement of vitamin D status may have considerable potential to amend the host defense against HCV infection and response to therapy.

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The water phase antioxidant activity of extracts from 23 Bulgarian medicinal plants was studied in relation to their polyphenol content in comparison with mate, black tea, honeybush and rooibos foreign species. Antioxidant activity was measured by the ABTS (2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid)) cation radical decolorization assay, and the total polyphenol content was assayed according to the Folin-Ciocalteu method. Five Bulgarian plant extracts exhibited higher antioxidant activity than that of mate, which is 21.7% of all Bulgarian herbs included in this study. These were Alchemilla vulgaris L. (4.79 +/- 0.14 mm), Sambucus ebulus L. (4.03 +/- 0.07 mm), Mentha spicata L. (3.90 +/- 0.03 mm), Fragaria vesca L. (3.74 +/- 0.06 mm), Crataegus monogyna Jacq. (3.63 +/- 0.05 mm). Another eight Bulgarian medicinal plant extracts exhibited an intermediate antioxidant activity - lower than that of mate and higher than that of honeybush, which makes 34.8% of all Bulgarian herbs included in the study. More than half of the herbal extracts included in the present study exhibited antioxidant activity higher than or comparable to the reference foreign plants. A positive correlation (r = 0.92) between antioxidant activity and polyphenol content was found, suggesting that the antioxidant capacity of the aqueous plant extracts is due to a great extent to their polyphenols.

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