Changes in Dickkopf-1, but Not Sclerostin, in Gingival Crevicular Fluid Are Associated with Peroral Statin Treatment in Patients with Periodontitis.

Background and Objectives: Periodontitis is marked by the destruction of alveolar bone. Sclerostin (SOST) and dickkopf-1 (DKK-1) act as inhibitors of the Wingless-type (Wnt) signaling pathway, a key regulator of bone metabolism. Recent studies have suggested that statins play a role in bone resorption and formation by influencing Wnt signaling. The aim of this study was to determine the levels of SOST and DKK-1 in periodontal patients with and without peroral statins treatment in their therapy. Materials and Methods: A total of 79 patients with diagnosed periodontitis were divided into two groups: 39 patients on statin therapy (SP group) and 40 patients without statin therapy as a control group (P group). The periodontal clinical examination probing (pocket) depth (PD) and gingival recession (GR) were measured, and approximal plaque was detected, while vertical and horizontal bone resorption was measured using a panoramic radiograph image. Clinical attachment loss (CAL) values were calculated using PD and GR values. Gingival crevicular fluid (GCF) was collected and used for measuring SOST and DKK-1 levels. A questionnaire was used to assess lifestyle habits and statin intake. Patients' medical records were used to obtain biochemical parameters. Results: There was no significant difference in sclerostin concentration between the SP and P group. DKK-1 values were significantly higher in the SP group compared to the control group (p = 0.04). Also, PD (p = 0.001) and GR (p = 0.03) were significantly higher in the SP group. The level of DKK-1 had a positive relationship with the PD, the greater the PD, the higher the level of DKK-1 (Rho = 0.350), while there was no significant association with other parameters. Conclusions: Peroral statins in periodontal patients are associated with GCF levels of DKK-1 but not with sclerostin levels.

Preclinical Models and Promising Pharmacotherapeutic Strategies in Liver Fibrosis: An Update.

Liver fibrosis represents one of the greatest challenges in medicine. The fact that it develops with the progression of numerous diseases with high prevalence (NAFLD, viral hepatitis, etc.) makes liver fibrosis an even greater global health problem. Accordingly, it has received much attention from numerous researchers who have developed various in vitro and in vivo models to better understand the mechanisms underlying fibrosis development. All these efforts led to the discovery of numerous agents with antifibrotic properties, with hepatic stellate cells and the extracellular matrix at the center of these pharmacotherapeutic strategies. This review focuses on the current data on numerous in vivo and in vitro models of liver fibrosis and on various pharmacotherapeutic targets in the treatment of liver fibrosis.

Role of galectin-3 in diagnosis and severity assessment of epicardial artery lesions in patients with suspected coronary artery disease.

BACKGROUND: This study aimed to investigate the possible role of serum galectin-3 (Gal-3) levels in the diagnosis and assessment of significant epicardial artery lesions in patients with suspected coronary artery disease (CAD). METHODS: This was a single-center cross sectional cohort study including 168 subjects with suspected CAD and indications for coronary angiography divided into three groups: percutaneous coronary intervention (PCI) group (N 64), coronary artery bypass graft surgery (CABG) group (N 57), and group with no coronary stenosis (N 47). Gal-3 levels were measured and the syntax score (Ss) was calculated. RESULTS: The mean value of Gal-3 in the PCI and CABG group was 19.98 ng/ml, while in the control group, it was 9.51 ng/ml (p < 0.001). The highest value of Gal-3 was found in the group of subjects with three-vessel disease (p < 0.001). When subgroups were analyzed by Gal-3 levels (< 17.8 ng/ml low, 18.8-25.9 ng/ml intermediate, > 25 ng/ml high risk) there was a significant difference between at least two Gal-3 groups for the arithmetic mean of Syntax score (p < 0.001). The syntax I's arithmetic mean at low and intermediate-risk Gal-3 levels was significantly lower than at high-risk Gal-3 levels (p < 0.001). CONCLUSION: Gal-3 could be used as an additional tool for diagnosis and severity assessment of atherosclerotic disease in patients with suspected CAD. Furthermore, it could help identify high-risk subjects in patients with stable CAD.

The role of direct oral anticoagulants in the era of COVID-19: are antiviral therapy and pharmacogenetics limiting factors?

In patients with COVID-19, thromboinflammation is one of the main causes of morbidity and mortality, which makes anticoagulation an integral part of treatment. However, pharmacodynamic and pharmacokinetic properties of direct oral anticoagulants (DOACs) limit the use of this class of anticoagulants in COVID-19 patients due to a significant interference with antiviral agents. DOACs use in COVID-19 hospitalized patients is currently not recommended. Furthermore, patients already on oral anticoagulant drugs should be switched to heparin at hospital admission. Nevertheless, outpatients with a confirmed diagnosis of COVID-19 are recommended to continue prior DOAC therapy. More studies are required to clarify the pathogenesis of COVID-19-induced derangement of the coagulation system in order to recommend an appropriate anticoagulant treatment.

Pretreatment of Garlic Oil Extracts Hampers Epithelial Damage in Cell Culture Model of Peptic Ulcer Disease.

Background and Objectives: Peptic ulcer disease is a chronic disease affecting up to 10% of the world's population. Proton pump inhibitors, such as lansoprazole are the gold standard in the treatment of ulcer disease. However, various studies have shown the effectiveness of garlic oil extracts in the treatment of ulcer disease. A cellular model can be established in the human gastric cell line by sodium taurocholate. The aim of this study was to explore the effects of garlic oil extracts pretreatment and LPZ addition in the cell culture model of peptic ulcer disease by examining oxidative stress and F-actin distribution. Materials and Methods: Evaluation was performed by determination of glutathione and prostaglandin E2 concentrations by ELISA; human gastric cell line proliferation by cell counting; expression of ATP-binding cassette, sub-family G, member 2; nuclear factor kappa B subunit 2 by RT PCR; and F-actin cytoskeleton visualization by semi-quantification of Rhodamine Phalloidin stain. Results: Our results showed significant reduction of cell damage after sodium taurocholate incubation when the gastric cells were pretreated with lansoprazole (p < 0.001) and increasing concentrations of garlic oil extracts (p < 0.001). Pretreatment with lansoprazole and different concentrations of garlic oil extracts increased prostaglandin E2 and glutathione concentrations in the cell culture model of peptic ulcer disease (p < 0.001). Positive correlation of nuclear factor kappa B subunit 2 (p < 0.01) with lansoprazole and garlic oil extracts pretreatment was seen, while ATP-binding cassette, sub-family G, member 2 expression was not changed. Treatment with sodium taurocholate as oxidative stress on F actin structure was less pronounced, although the highest concentration of garlic oil extracts led to a statistically significant increase of total amount of F-actin (p < 0.001). Conclusions: Hence, pretreatment with garlic oil extracts had gastroprotective effect in the cell model of peptic ulcer disease. However, further experiments are needed to fully elucidate the mechanism of this protective role.

Renal Benefits of SGLT 2 Inhibitors and GLP-1 Receptor Agonists: Evidence Supporting a Paradigm Shift in the Medical Management of Type 2 Diabetes.

Diabetic nephropathy (DN) is one of the most perilous side effects of diabetes mellitus type 1 and type 2 (T1DM and T2DM).). It is known that sodium/glucose cotransporter 2 inhibitors (SGLT 2i) and glucagone like peptide-1 receptor agonists (GLP-1 RAs) have renoprotective effects, but the molecular mechanisms are still unknown. In clinical trials GLP-1 analogs exerted important impact on renal composite outcomes, primarily on macroalbuminuria, possibly through suppression of inflammation-related pathways, however enhancement of natriuresis and diuresis is also one of possible mechanisms of nephroprotection. Dapagliflozin, canagliflozin, and empagliflozin are SGLT2i drugs, useful in reducing hyperglycemia and in their potential renoprotective mechanisms, which include blood pressure control, body weight loss, intraglomerular pressure reduction, and a decrease in urinary proximal tubular injury biomarkers. In this review we have discussed the potential synergistic and/or additive effects of GLP 1 RA and SGLT2 inhibitors on the primary onset and progression of kidney disease, and the potential implications on current guidelines of diabetes type 2 management.

LIFESTYLE RISK FACTORS AND BONE MASS IN RECURRENT STONE-FORMING PATIENTS: A CROSS-SECTIONAL STUDY IN 144 SUBJECTS.

Patients with urolithiasis, particularly hypercalciuria, may have reduced bone mineral density (BMD). There are numerous risk factors contributing to reduction of BMD such as advanced age, sedentary lifestyle, smoking, low calcium intake, etc. The aim of our study was to investigate the association of lifestyle risk factors and daily intake of milk and dairy products with determinants of BMD in a group of recurrent calcium stone formers (RSF) compared with healthy subjects (HS). The study was carried out at the Department of Mineral Research, Faculty of Medicine in Osijek, Croatia. The study included 144 subjects, i.e. 56 RSF and 78 HS. BMD was assessed by dual-energy x-ray absorptiometry. A standard self-reported questionnaire was used to collect data on lifestyle risk factors. Current dietary intake was assessed by personal interview that included questions about milk and dairy product intake. Low BMD was observed in 44.64% of RSF and 35.90% of HS. RSF consumed significantly less milk and dairy products than HS. Calcium restriction in dietary recommendations might be unnecessary due to the impact on bone mineral loss in RSF and dual-energy x-ray absorptiometry should be included in the routine evaluation of RSF.

Heart failure biomarkers in revascularized patients with stable coronary heart disease as clinical outcome predictors.

Introduction: The aim of this study was to investigate serum levels of galectin-3 (Gal-3) and N-terminal pro-brain Natriuretic Peptide (NT-proBNP) in patients with stable obstructive coronary artery disease, as well as their potential to predict clinical outcomes. Methods: This was a single-center cross-sectional cohort study. 168 patients were divided into three groups: percutaneous coronary intervention (PCI) group (N 64), coronary artery bypass graft surgery (CABG) group (N 57), and group with no coronary stenosis (N 47). Gal-3 and NT-proBNP levels were measured and the Syntax score (Ss) was calculated. Results: The mean value of Gal-3 was 19.98 ng/ml and 9.51 ng/ml (p < 0.001) in the study group and control group, respectively. Highest value of Gal-3 was found in the group of subjects with three-vessel disease (p < 0.001). The mean value of NT-proBNP in the study group was 401.3 pg/ml, and in the control group 100.3 pg/ml (p = 0.159). The highest value of NT-proBNP was found in the group of subjects with three-vessel disease (p = 0.021). There was a statistically significant association between Gal-3, NT-proBNP and occurrence of adverse cardiovascular event (p = 0.0018; p = 0.0019). Conclusion: Gal-3 and NT-proBNP could be used as an additional tool for diagnosis and severity assessment of stable obstructive coronary artery disease. Furthermore, it could help identify high-risk patients who could experience major adverse cardiovascular events.

Biomarkers for Assessing Non-Alcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Mellitus on Sodium-Glucose Cotransporter 2 Inhibitor Therapy.

In the current modern era of unhealthy lifestyles, non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease and has become a serious global health problem. To date, there is no approved pharmacotherapy for the treatment of NAFLD, and necessary lifestyle changes such as weight loss, diet, and exercise are usually not sufficient to manage this disease. Patients with type 2 diabetes mellitus (T2DM) have a significantly higher risk of developing NAFLD and vice versa. Sodium-glucose cotransporter 2 (SGLT2) inhibitors are antidiabetic agents that have recently been approved for two other indications: chronic kidney disease and heart failure in diabetics and non-diabetics. They are also emerging as promising new agents for NAFLD treatment, as they have shown beneficial effects on hepatic inflammation, steatosis, and fibrosis. Studies in animals have reported favorable effects of SGLT2 inhibitors, and studies in patients also found positive effects on body mass index (BMI), insulin resistance, glucose levels, liver enzymes, apoptosis, and transcription factors. There are some theories regarding how SGLT2 inhibitors affect the liver, but the exact mechanism is not yet fully understood. Therefore, biomarkers to evaluate underlying mechanisms of action of SGLT2 inhibitors on the liver have now been scrutinized to assess their potential as a future in-label therapy for NAFLD. In addition, finding suitable non-invasive biomarkers could be helpful in clinical practice for the early detection of NAFLD in patients. This is crucial for a positive disease outcome. The aim of this review is to provide an overview of the most recent findings on the effects of SGLT2 inhibitors on NAFLD biomarkers and the potential of SGLT2 inhibitors to successfully treat NAFLD.

Impact of DAA Treatment on Cardiovascular Disease Risk in Chronic HCV Infection: An Update.

Hepatitis C virus (HCV) infection is a systemic disease associated with multiple significant extrahepatic manifestations. Emerging studies indicate association between the HCV infection and a higher incidence of major adverse cardiovascular events such as: coronary artery disease, heart failure, stroke and peripheral artery disease, when compared to general population. Atherosclerosis is a common pathophysiologic mechanism of cardiovascular disease (CVD) development which is the leading cause of mortality in the Western world. Proposed mechanisms of HCV-induced atherosclerosis includes systemic inflammation due to the chronic infection with increased levels of pro-atherogenic cytokines and chemokines. Furthermore, it has been demonstrated that HCV exists and replicates within atheroschlerotic plaques, supporting the theory of direct pro-atherogenic effect of the virus. Direct acting antiviral agents (DAAs) represent a safe and highly effective treatment of HCV infection. Beside the improvement in liver-related outcomes, DAAs exhibit a beneficial effect on extra-hepatic manifestations of chronic HCV infection. Recently, it has been shown that patients with chronic HCV infection treated with DAA-based therapeutic regimes had a 43% reduction of CVD events incidence risk. Moreover, eradication of HCV with DAAs results in a significant positive effect on risk factors for cardiovascular disease, despite a general worsening of the lipid profile. This positive effects is mainly due to an improvement of endothelial function and glucose metabolism. Although DAA treatment is associated with a beneficial impact on cardiovascular events, further studies are needed to fully elucidate the mechanisms responsible.

Sensorineural hearing loss in hemodialysis patients.

Chronic renal failure affects all organ systems. Senses are not exception and hearing impairment is common, particularly sensorineural hearing loss (SNHL). The term SNOS of unknown origin or uremic deafness is related to only a smaller part of the cases with unclear etiology of the impairment. The study searched for SNOS in 66 chronic hemodialysis (HD) patients, mean age 51.50 +/- 12.70 years. They were treated by HD for 69.70 +/- 53.80 months. The relation between the severity of the impairment and the patients' age, duration of HD treatment (months) and a set of laboratory parameters typical for chronic HD patients was examined. The aim of the study was to detect potential causes of the impairment. The increased hearing threshold (HT) of above 20 dB for all frequencies was found in 42 patients (mean HT 26 +/- 10.50 dB), for speaking area frequencies in 22 patients (mean HT 19.70 +/- 8.80 dB), and in 56 patients for high frequencies (mean HT 41.70 +/- 19.70 dB). The significant positive correlation of HT was found only with the patients' age (r = 0.49, p < 0.01). The patients older than 45 years had higher mean HT than those younger, and those older than 65 also had higher HT than the younger ones. Patients with pathological value of HT were significantly more common among the older subgroup of patients, when divided according to the age at both cutoff values of 45 and of 60 years. Mean HT did not differ significantly according to the duration of HD treatment (subgroups A- no longer than 60 months, B- from 61 to 120 months, and C- longer than 120 months). The patients with pathological HT did not differ significantly in frequency among those subgroups, and the subgroups were not different according to the mean age (A--50.30 +/- 13.20 years; B--51.40 +/- 12.75 years; C--55.80 +/- 10.55 years). In conclusion, our results along with other authors'published data report on SNHL as very frequent finding among chronic HD patients and suggest multifactorial etiology. Accurate proportion of those with SNHL of unknown origin is not possible to determine. Those cases are probably not caused by uremic polyneuropathy and/or preterm vascular aging only, although those factors are likely to play crucial roles.

Obesity Paradox in Chronic Liver Diseases: Product of Bias or a Real Thing?

In recent years, evidence supporting the theory of obesity paradox has increased, showing that obese/overweight people with prevalent chronic diseases experience lower mortality compared with patients of normal weight. So far, evidence is most comprehensive in cardiovascular and chronic renal diseases; however, published studies are prone to many biases, enabling us to reach a definite conclusion. Available data in chronic liver disease is scarce and ambiguous. Obesity is traditionally associated with nonalcoholic fatty liver disease and steatosis in viral hepatitis and as such one would not expect the obesity paradox to be a real possibility in liver disease. Yet, there seem to be new data indicating the opposite - the obesity paradox exists in severe and end-stage liver cirrhosis, which could be attributed to a better lean mass in patients with higher body mass index, meaning that sarcopenia, as one of the most important prognostic factors of survival, is less likely to be present. Nonetheless, the problem of various methodological problems addressing the association between body weight and mortality, which is present both in liver disease and other chronic diseases, are preventing us from attaining an unanimous conclusion. Still, we should be aware that the obesity paradox might be true, especially in severe and end-stage illness. This suggests focusing our efforts toward preserving or building up fat-free mass and decreasing inflammatory activity responsible for catabolism and sarcopenia, and implying that the underlaying cause should be treated.

Analysis of αSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing.

Fracture healing is a regenerative process that involves coordinated responses of many cell types, but characterization of the roles of specific cell populations in this process has been limited. We have identified alpha smooth muscle actin (αSMA) as a marker of a population of mesenchymal progenitor cells in the periosteum that contributes to osteochondral elements during fracture healing. Using a lineage tracing approach, we labeled αSMA-expressing cells, and characterized changes in the periosteal population during the early stages of fracture healing by histology, flow cytometry, and gene expression profiling. In response to fracture, the αSMA-labeled population expanded and began to differentiate toward the osteogenic and chondrogenic lineages. The frequency of mesenchymal progenitor cell markers such as Sca1 and PDGFRα increased after fracture. By 6 days after fracture, genes involved in matrix production and remodeling were elevated. In contrast, genes associated with muscle contraction and Notch signaling were downregulated after fracture. We confirmed that activating Notch signaling in αSMA-labeled cells inhibited differentiation into osteogenic and adipogenic lineages in vitro and ectopic bone formation in vivo. By characterizing changes in a selected αSMA-labeled progenitor cell population during fracture callus formation, we have shown that modulation of Notch signaling may determine osteogenic potential of αSMA-expressing progenitor cells during bone healing.