Low Vitamin K Status in Patients with Psoriasis Vulgaris: A Pilot Study.

Psoriasis vulgaris (PV) is a disease characterized by skin manifestations and systemic inflammation. There are no published studies to date on vitamin K status assessed by extrahepatic vitamin K-dependent proteins [e.g., osteocalcin (OC) and matrix Gla protein (MGP)] in patients with PV, even if vitamin K was found to promote wound contraction and decrease the healing time of the skin. Metabolic syndrome (MS), a comorbidity of PV, was found to influence vitamin K status, and vitamin D was found to be involved in the pathogenesis of PV. Therefore, our aim was to assess the status of vitamins K and D in subjects with PV. We enrolled 44 patients with PV and 44 age- and sex-matched subjects as a control group (CG), of which individuals with MS were designated the CG with MS subgroup. Furthermore, the PV patients were stratified into two subgroups: those with MS (n = 20) and those without MS (n = 24). In addition to the quantification of vitamin D and MGP in all subjects, the uncarboxylated OC/carboxylated OC (ucOC/cOC) ratio was also assessed as an inversely proportional marker of vitamin K status. We found an increased ucOC/cOC ratio in the PV group compared to CG but also a greater ucOC/cOC ratio in the PV with MS subgroup than in the CG with MS subgroup. MGP was decreased in the PV with MS subgroup compared to CG with MS subgroup. There was no difference in the vitamin D concentration between the groups. This is the first study to report decreased vitamin K status in patients with PV, independent of the presence of MS.

Targeted EGFR Nanotherapy in Non-Small Cell Lung Cancer.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Despite advances in treatment, the prognosis remains poor, highlighting the need for novel therapeutic strategies. The present review explores the potential of targeted epidermal growth factor receptor (EGFR) nanotherapy as an alternative treatment for NSCLC, showing that EGFR-targeted nanoparticles are efficiently taken up by NSCLC cells, leading to a significant reduction in tumor growth in mouse models. Consequently, we suggest that targeted EGFR nanotherapy could be an innovative treatment strategy for NSCLC; however, further studies are needed to optimize the nanoparticles and evaluate their safety and efficacy in clinical settings and human trials.

First Comparative Evaluation of Short-Chain Fatty Acids and Vitamin-K-Dependent Proteins Levels in Mother-Newborn Pairs at Birth.

BACKGROUND: The interplay between vitamin K (vitK) (as carboxylation cofactor, partially produced by the gut microbiota) and short-chain fatty acids (SCFAs), the end-product of fiber fermentation in the gut, has never been assessed in mother-newborn pairs, although newborns are considered vitK deficient and with sterile gut. METHODS: We collected venous blood from 45 healthy mothers with uncomplicated term pregnancies and umbilical cord blood from their newborns at birth. The concentrations of total SCFAs and hepatic/extra-hepatic vitK-dependent proteins (VKDPs), as proxies of vitK status were assayed: undercarboxylated and total matrix Gla protein (ucMGP and tMGP), undercarboxylated osteocalcin (ucOC), undercarboxylated Gla-rich protein (ucGRP), and protein induced by vitK absence II (PIVKA-II). RESULTS: We found significantly higher ucOC (18.6-fold), ucMGP (9.2-fold), and PIVKA-II (5.6-fold) levels in newborns, while tMGP (5.1-fold) and SCFAs (2.4-fold) were higher in mothers, and ucGRP was insignificantly modified. In mother-newborn pairs, only ucGRP (r = 0.746, p < 0.01) and SCFAs (r = 0.428, p = 0.01) levels were correlated. Conclusions: We report for the first time the presence of SCFAs in humans at birth, probably transferred through the placenta to the fetus. The increased circulating undercarboxylated VKDPSs in newborns revealed a higher vitamin K deficiency at the extrahepatic level compared to liver VKDPs.

Diet-Related Changes of Short-Chain Fatty Acids in Blood and Feces in Obesity and Metabolic Syndrome.

Obesity-related illnesses are one of the leading causes of death worldwide. Metabolic syndrome has been associated with numerous health issues. Short-chain fatty acids (SCFAs) have been shown to have multiple effects throughout the body, both directly as well as through specific G protein-coupled receptors. The main SCFAs produced by the gut microbiota are acetate, propionate, and butyrate, which are absorbed in varying degrees from the large intestine, with some acting mainly locally and others systemically. Diet has the potential to influence the gut microbial composition, as well as the type and amount of SCFAs produced. High fiber-containing foods and supplements increase the production of SCFAs and SCFA-producing bacteria in the gut and have been shown to have bodyweight-lowering effects. Dietary supplements, which increase SCFA production, could open the way for novel approaches to weight loss interventions. The aim of this review is to analyze the variations of fecal and blood SCFAs in obesity and metabolic syndrome through a systematic search and analysis of existing literature.

The Active Isoforms of MGP Are Expressed in Healthy and Varicose Veins without Calcification.

Matrix Gla protein (MGP), a local inhibitor of tissue mineralization, is associated with vascular calcification. Depending on the carboxylation and phosphorylation status, MGP has active conformations, e.g., carboxylated MGP (cMGP) and phosphorylated MGP (pMGP), but also inactive conformations, e.g., uncarboxylated MGP (ucMGP) and dephosphorylated MGP (dpMGP). Our purpose was to assess the presence of all MGP conformations in healthy veins (HV) and varicose veins (VV), concurrently with the analysis of circulating total MGP (tMGP) before and after the surgical stripping of VV. We collected samples from the great saphenous vein, considered as control group, and tissue from VV, designated as VV group. Plasma levels of tMGP were significantly decreased after the surgical removal of the VV (before 59.5 ± 17.2 vs. after 38.1 ± 11.3, p < 0.001). By using immunohistochemistry staining, we identified local cMGP and pMGP in the control and VV groups, both without calcification, while ucMGP and dpMGP were absent. cMGP was observed in the nucleus and cytoplasm and pMGP in the nucleus of cells belonging to the tunica media, tunica intima and vasa vasorum. Therefore, the active conformations of MGP (cMGP and pMGP) are prevalent in HV and VV without calcification, affirming their anti-calcifying role in veins.

Sirtuin 3 (SIRT3) Pathways in Age-Related Cardiovascular and Neurodegenerative Diseases.

Age-associated cardiovascular and neurodegenerative diseases lead to high morbidity and mortality around the world. Sirtuins are vital enzymes for metabolic adaptation and provide protective effects against a wide spectrum of pathologies. Among sirtuins, mitochondrial sirtuin 3 (SIRT3) is an essential player in preserving the habitual metabolic profile. SIRT3 activity declines as a result of aging-induced changes in cellular metabolism, leading to increased susceptibility to endothelial dysfunction, hypertension, heart failure and neurodegenerative diseases. Stimulating SIRT3 activity via lifestyle, pharmacological or genetic interventions could protect against a plethora of pathologies and could improve health and lifespan. Thus, understanding how SIRT3 operates and how its protective effects could be amplified, will aid in treating age-associated diseases and ultimately, in enhancing the quality of life in elders.

Calciprotein Particles and Serum Calcification Propensity: Hallmarks of Vascular Calcifications in Patients with Chronic Kidney Disease.

Cardiovascular complications are one of the leading causes of mortality worldwide and are strongly associated with atherosclerosis and vascular calcification (VC). Patients with chronic kidney disease (CKD) have a higher prevalence of VC as renal function declines, which will result in increased mortality. Serum calciprotein particles (CPPs) are colloidal nanoparticles that have a prominent role in the initiation and progression of VC. The T50 test is a novel test that measures the conversion of primary to secondary calciprotein particles indicating the tendency of serum to calcify. Therefore, we accomplished a comprehensive review as the first integrated approach to clarify fundamental aspects that influence serum CPP levels and T50, and to explore the effects of CPP and calcification propensity on various chronic disease outcomes. In addition, new topics were raised regarding possible clinical uses of T50 in the assessment of VC, particularly in patients with CKD, including possible opportunities in VC management. The relationships between serum calcification propensity and cardiovascular and all-cause mortality were also addressed. The review is the outcome of a comprehensive search on available literature and could open new directions to control VC.

Vitamin K Dependent Proteins in Kidney Disease.

Patients with chronic kidney disease (CKD) have an increased risk of developing vascular calcifications, as well as bone dynamics impairment, leading to a poor quality of life and increased mortality. Certain vitamin K dependent proteins (VKDPs) act mainly as calcification inhibitors, but their involvement in the onset and progression of CKD are not completely elucidated. This review is an update of the current state of knowledge about the relationship between CKD and four extrahepatic VKDPs: matrix Gla protein, osteocalcin, growth-arrest specific protein 6 and Gla-rich protein. Based on published literature in the last ten years, the purpose of this review is to address fundamental aspects about the link between CKD and circulating VKDPs levels as well as to raise new topics about how the interplay between molecular weight and charge could influence the modifications of circulating VKDPs at the glomerular level, or whether distinct renal etiologies have effect on VKDPs. This review is the output of a systematic literature search and may open future research avenues in this niche domain.

Serum total matrix Gla protein: Reference interval in healthy adults and variations in patients with vascular and osteoarticular diseases.

BACKGROUND: Matrix Gla protein (MGP) species are inhibitors of ectopic calcification in vascular diseases (VD) and osteoarticular diseases (OD). Among the MGP assays, we aimed to establish the reference interval for serum total MGP (tMGP) in healthy adults, the variation in patients with VD and OD and the associations with common cardiovascular risk factors. METHODS: We enrolled n = 124 healthy subjects and n = 95 patients with VD and OD in a small cross-sectional study. Serum high sensitivity C-reactive protein (hs-CRP), tMGP, glucose and lipid profile was measured. RESULTS: We established the reference interval for tMGP as 6-108 µg/L in healthy adults, the population under 40 having higher tMGP levels than those over 40 (61 ±â€¯28, 51 ±â€¯22 µg/L, p < 0.05). In healthy participants, tMGP was associated with smoking (ß = 0.303, p = 0.001), age under 40 (ß = -0.201, p = 0.032) and marginally with hs-CRP (ß = -0.165, p = 0.08). In multivariate regression models, the association between smoking and tMGP was preserved even after adjusting for age under 40 and hs-CRP (ß = 0.267, p = 0.005). The healthy population over 40 had lower tMGP levels than patients with OD and VD (51 ±â€¯22, 90 ±â€¯26, 106 ±â€¯30 µg/L, p < 0.001). CONCLUSIONS: Higher tMGP levels could identify patients with VD and OD, being also associated with smoking in healthy adults.

BONE MARKERS IN ARTHROPATHIES.

Bone endures a lifelong course of construction and destruction, with bone marker (BM) molecules released during this cycle. The field of measuring BM levels in synovial fluid and peripheral blood is a cardinal part of bone research within modern clinical medicine and has developed extensively in the last years. The purpose of our work was to convey an up-to-date overview on synovial fluid and serum BMs in the most common arthropathies.

Elevated Serum Levels of Sclerostin are Associated with High Disease Activity and Functional Impairment in Patients with Axial Spondyloarthritis.

BACKGROUND: Recent research suggests that biomarkers may be useful in assessing disease activity, structural damage, and response to therapy in axial spondyloarthritis (axSpA). Our study aims at evaluating the relationship between inflammation and bone remodeling markers and variables assessing disease activity and functional disability in patients with axSpA. METHODS: Serum levels of sclerostin, matrix metalloproteinase-3 (MMP-3), interleukin-17 (IL-17), and IL-23 were measured in 60 patients with axSpA and 20 healthy controls. Disease activity was evaluated using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Functional status was assessed by Bath Ankylosing Spondylitis Function Index (BASFI) and measures of spinal mobility. RESULTS: Sclerostin levels were more elevated in axSpA patients with high disease activity than in those with low disease activity and in controls. They were significantly correlated with BASFI values (r = 0.29, p = 0.03) and measures of spinal mobility, but not with the classical markers of disease activity (BASDAI, ASDAS, CRP, and ESR). Although both MMP-3 and IL-17 levels were elevated in patients with active disease, they were not correlated with markers of disease activity or with functional disability. The levels of sclerostin, MMP-3, IL-17, and IL-23 were similar in axSpA patients and healthy controls. CONCLUSIONS: Elevated levels of sclerostin, MMP-3, and IL-17 were observed in axSpA patients with active disease, suggesting their potential role in assessing disease activity. In axSpA patients, sclerostin levels might be equally influenced by inflammation and level of physical activity. Further studies are required to confirm our findings in order to understand their clinical value.

Nitro-oxidative stress, VEGF and MMP-9 in patients with cirrhotic and non-cirrhotic portal hypertension.

BACKGROUND AND AIMS: Nitro-oxidative stress may have pathophysiological consequences. The study aimed to assess the nitro-oxidative stress, the vascular growth factor, and metalloproteinase-9 levels in patients with noncirrohic and cirrhotic portal hypertension. METHODS: Patients with noncirrhotic portal hypertension (n=50) and cirrhotic portal hypertension (n=50) from the 3rd Medical Clinic in Cluj-Napoca Romania were prospectively enrolled between October 2004 and October 2006. A control group of healthy volunteers (n=50) was also evaluated. Nitro-oxidative stress was assessed by measuring serum concentration of nitrites and nitrate, 3-nitrotyrosine, total oxidative status, total antioxidant reactivity, and oxidative stress index. Serum vascular growth factor and matrix metalloproteinase-9 were also determined. RESULTS: Serum nitrites and nitrate levels significantly increased in both noncirrhotic (p<0.001) and cirrhotic portal hypertension (p=0.057). 3-nitrotyrosine also increased in noncirrhotic (p=0.001) and cirrhotic portal hypertension patients (p=0.014). Total oxidative status showed a significant increase in noncirrhotic (p<0.001) and in cirrhotic portal hypertension (p<0.001), but total antioxidant reactivity did not change significantly. The oxidative stress index increased in both noncirrhotic (p <0.001) and cirrhotic portal hypertension (p<0.001), as well as the serum vascular growth factor (p=0.005 and p=0.01, respectively). In NCPHT patients serum MMP-9 was significantly lower than in the healthy controls (p=0.03) and CPHT patients (p=0.05). CONCLUSION: In patients with noncirrhotic and cirrhotic portal hypertension a significant systemic nitro-oxidative stress was found, correlated with an increase of VEGF. MMP-9 decreased in noncirrhotic portal hypertension.

Circulating osteoprotegerin and asymptomatic carotid atherosclerosis in postmenopausal non diabetic women.

PURPOSE: Osteoprotegerin (OPG) is a bone metabolism regulator but it is also involved in vascular calcification. Its role in the development of atherosclerosis is still a subject of debate. Postmenopausal women seem to have an increased risk for cardiovascular disease. The aim of the study is to evaluate the relationship between serum OPG and asymptomatic carotid atherosclerosis in postmenopausal non-diabetic women. MATERIAL/METHODS: Carotid artery examination was performed in 100 postmenopausal women without diabetes mellitus and overt cardiovascular disease, using B-mode ultrasonography to determine the carotid intima-media thickness (CIMT) and the presence of plaques. Serum OPG was measured in all study participants and its relationship with clinical, biochemical and vascular parameters was evaluated. RESULTS: CIMT correlated with age (r=0.45, p<0.001), years since menopause (r=0.30, p=0.003), abdominal circumference (r=0.25, p=0.01) and OPG (r=0.23, p=0.02). Carotid plaques correlated with age (p<0.001), obesity (p=0.03), abdominal circumference (p=0.03) and CIMT (p<0.001), but not with serum OPG (p=0.86). In regression analyses the independent predictors for CIMT were age (ß=0.717, p<0.001), OPG (ß=0.214, p=0.02), and years since menopause (ß=-0.334, p=0.04) and for the presence of carotid plaques were obesity (p=0.04, OR=3.90), CIMT (p<0.001, OR=6408.86) and smoking (p=0.02, OR=687.93). CONCLUSION: OPG is associated with cardiovascular risk factors, CIMT, but not with the presence of asymptomatic carotid plaques in non diabetic postmenopausal women. OPG may be a marker of cardiovascular risk.

Apolipoprotein E genotype may influence urinary gammacarboxyglutamate (Gla) concentrations in young individuals.

Upon degradation of vitamin K-dependent proteins (known as Gla-proteins) the free aminoacid Gla cannot be re-utilized and is excreted in the urine, where it can be used as an overall marker for vitamin K status. We report the urinary Gla excretion values in first morning void urine for healthy young Romanian subjects from birth, childhood and young adulthood. In these subjects we have evaluated age, gender and apo E genotype as potential confounders. The urinary free Gla/creat ratio (Gla/creat, mg/g) was highest in newborns (34.8 ± 19.5; p < 0.001), than fell in the group 4 to 48 months old (13.1 ± 11.1) to levels that were not significantly different from the young adult group (18.3 ± 5.5). No gender-related differences were observed in Gla/creat in newborns and young children, but Gla excretion in women was higher than in men (28.6%; p < 0.029). Remarkably, Gla excretion in subjects bearing the apo ε2+ allele was significantly lower (11.9 ± 4.2) than in those bearing combinations of the ε3+ and ε4+ alleles (20.3 ± 4.1). The novelty of this study resides in the evaluation of urinary Gla excretion in relation with apo E genotype, suggesting that apo ε2 allele is a risk factor for developing vitamin K insufficiency.

Circulating matrix Gla protein: a potential tool to identify minor carotid stenosis with calcification in a risk population.

BACKGROUND: Carotid calcification is an independent marker for future ischemic events, which are more frequently encountered in postmenopausal women as the prevalence of type 2 diabetes mellitus (T2DM) and hypertension (HT) increases. Matrix Gla protein (MGP) is a major inhibitor of vascular calcification. Here, we report on the prospect of serum MGP to become an identifying tool for minor carotid stenosis (minCAS) with calcification in a risk population. METHODS: Based on carotid ultrasound examination, out of 72 enrolled postmenopausal women, 33 had minCAS with carotid calcification (minCAS group) and 39 were without minCAS and carotid calcification (non-minCAS group). Serum total MGP, high-sensitivity C-reactive protein (hs-CRP), bone mineral density (BMD) and carotid intima-media thickness (CIMT) were determined. RESULTS: We found significantly elevated serum MGP levels in the minCAS compared to the non-minCAS group (p < 0.05). MGP was independently associated with hs-CRP (unstandardized ß -regression coefficient = 2.6; 95 % CI 0.007 ­ 5.3; p = 0.049) and CIMT ( ß = ­ 611.3; 95 % CI ­ 1172.6 ­ ­ 49.9; p = 0.034) within the minCAS group, but not with BMD. Furthermore, significantly higher MGP levels were determined in two minCAS subgroups (one with HT or T2DM and second with both diseases) compared to a non-minCAS subgroup with HT or T2DM (p < 0.05 and p < 0.01, respectively). A threshold of 87.9 µ g/L serum MGP (area under the receiver operating characteristic = 0.72 } 0.06; 95 % CI 0.60 ­ 0.84; p = 0.001) may identify minCAS with calcification in postmenopausal women with 63 % precision. CONCLUSIONS: Higher circulating MGP levels could help identify minCAS with calcification in a relatively homogenous risk population (i.e., postmenopausal women), regardless of underlying cardiovascular risk factors.

Synovial and serum levels of uncarboxylated matrix Gla-protein (ucMGP) in patients with arthritis.

BACKGROUND: Matrix Gla-protein (MGP) is a calcification inhibitor produced by cartilage and vessel walls. Arthritis is defined by inflammation, cartilage and bone destruction/formation and articular calcifications. Our objectives were to evaluate ucMGP levels in synovial fluid (SF) in arthritis patients and to investigate the relationship between local and circulating ucMGP and their association with age and inflammation. METHODS: Arthritis patients (n=26) with knee joint effusion and controls (n=30) underwent an ultrasonographic knee examination for articular calcifications assessment. Patients were divided into inflammatory and non-inflammatory groups. ucMGP levels were determined in serum and SF using a competitive ELISA assay. RESULTS: Within the arthritis patients, the inflammatory group had the lowest ucMGP serum levels, and the highest levels of synovial ucMGP. Furthermore, the inflammatory group had significantly (p<0.05) higher RucMGP (synovial ucMGP/serum ucMGP*100) than the non-inflammatory group [36 (17-69) vs. 24 (5-55)], and this parameter positively correlated (r=0.4; p<0.05) with the erythrocyte sedimentation rate (ESR). No correlation was found between age and local or circulating ucMGP in patients and controls. CONCLUSIONS: The ucMGP assay can be used for determination of MGP in SF, and combined assessment of ucMGP in serum and SF could potentially serve as a joint inflammatory marker in arthritis patients.

Biochemical markers of bone turnover as tools in the evaluation of skeletal involvement in patients with type 1 Gaucher disease.

Gaucher disease is caused by the inherited deficiency of glucocerebrosidase, a lysosomal enzyme responsible for the cleavage of glucosylceramide. In addition to organomegaly and hematological abnormalities, type 1 (nonneuronopathic) disease is characterized by insidiously progressive and often severe skeletal involvement. We investigated the applications of biochemical markers of bone turnover in the evaluation of skeletal lesions in type 1 Gaucher disease patients. Serum osteocalcin, a marker of osteoblastic bone formation, and type I collagen C-terminal telopeptide, a marker of osteoclastic bone resorption, were measured in 16 type 1 Gaucher disease patients and in 29 age-matched controls. Our results indicate a significant decrease of both osteocalcin (11.13 +/- 2.27 ng/ml) and type I collagen C-terminal telopeptide (3617.62 +/- 536.69 ng/ml) values in patients with Gaucher disease, compared to the unaffected controls (38.67+/-6.24 ng/ml and 6808.57 ng/ml +/- 865.66, respectively). These low values were observed in all patients, irrespective of their age, indicating a marked failure of both osteoblastic and osteoclastic functions in Gaucher disease. Significant differences in the mean serum values of biochemical bone turnover markers were found in different evolutional stages of bone involvement. We conclude that measurement of serum biochemical markers of bone turnover can be used as an auxiliary tool in the diagnosis, staging, and monitoring the skeletal lesions in Gaucher disease, in conjunction with imaging methods and bone densitometry measurements.