Can Adipokine FAM19A5 Be a Biomarker of Metabolic Disorders?

Aim: One of the most critical functions of adipose tissue is the production of adipokines, ie, numerous active substances that regulate metabolism. One is the newly discovered FAM19A5, whose older name is TAFA-5. Purpose: The study aimed to review the literature on the FAM19A5 protein. Methods: The review was conducted in December 2023 using the PubMed (Medline) search engine. Sixty-four papers were included in the review. Results: This protein exhibits the characteristics of an adipokine with positive features for maintaining homeostasis. The results showed that FAM19A5 was highly expressed in adipose tissue, with mild to moderate expression in the brain and ovary. FAM19A5 may also inhibit vascular smooth muscle cell proliferation and migration through the perivascular adipose tissue paracrine pathway. Serum levels of FAM19A5 were decreased in obese children compared with healthy controls. There are negative correlations between FAM19A5, body mass index, and fasting insulin. Serum FAM19A5 level is correlated with type 2 diabetes, waist circumference, waist-to-hip ratio, glutamic pyruvic transferase, fasting plasma glucose, HbA1c, and mean shoulder pulse wave velocity. FAM19A5 expression was reduced in mice with obesity. However, the data available needs to be clarified or contradictory. Conclusion: Considering today's knowledge about FAM19A5, we cannot consider this protein as a biomarker of the metabolic syndrome. According to current knowledge, FAM19A5 cannot be considered a marker of metabolic disorders because the results of studies conducted in this area are unclear.

Automated Peritoneal Dialysis With Remote Patient Monitoring: Clinical Effects and Economic Consequences for Poland.

OBJECTIVES: Remote patient monitoring (RPM) of patients treated with automated peritoneal dialysis (APD) at home allows clinicians to supervise and adjust the dialysis process remotely. This study aimed to review recent scientific studies on the use of RPM in patients treated with APD and based on extracted relevant data assess possible clinical implications and potential economic value of introducing such a system into practice in Poland. METHODS: A systematic literature review was performed in the MEDLINE, EMBASE, and Cochrane databases. The model of clinical effects and costs associated with APD was built as a cost-effectiveness analysis with a 10-year time horizon from the Polish National Health Fund perspective. Cost-effectiveness analysis compared 2 strategies: APD with RPM versus APD without RPM. RESULTS: Thirteen publications assessing the clinical value of RPM among patients with APD were found. The statistical significance of APD with RPM compared with APD without RPM was identified for the main clinical outcomes: frequency and length of hospitalizations, APD technique failure, and death. An incremental cost-effectiveness ratio was equal to €27 387 per quality-adjusted life-year. The obtained incremental cost-effectiveness ratio is below the willingness-to-pay threshold for the use of medical technologies in Poland (€36 510 per quality-adjusted life-year), which means that APD with RPM was a cost-effective technology. CONCLUSIONS: RPM in patients starting APD is a clinical option that is worth considering in Polish practice because it has the potential to decrease the frequency of APD technique failure and shorten the length of hospitalization.

The myeloperoxidase product, hypochlorous acid, reduces thrombus formation under flow and attenuates clot retraction and fibrinolysis in human blood.

Hypochlorite (HOCl), a strong oxidant and antimicrobial agent, has been proposed to be associated with hemostatic abnormalities during inflammatory response. However, its complex impact on hemostasis is not completely understood. In this report we studied the effect of clinically relevant (micromolar) HOCl concentrations on thrombus formation under flow, kinetics of platelet-fibrin clot formation, its architecture, retraction, and lysis. We found that HOCl (up to 500 µM) did not affect kinetics of coagulation measured in whole blood. HOCl (500-1000 µM) markedly diminished thrombus formation under flow. Clot retraction rate was reduced by HOCl dose-dependently (50-500 µM). HOCl (125-500 µM) inhibited fibrinolysis in whole blood and in platelet-depleted plasma, dose-dependently. Activity of plasmin was reduced by HOCl at concentrations started from 500 µM. HOCl (up to 500 µM) did not reduce plasminogen binding to fibrin under flow. HOCl (125-500 µM) modulated architecture of fibrin- and platelet-fibrin clots towards structures made of thin and densely packed fibers. Exposure of pure fibrinogen to HOCl (10-1000 µM) resulted in formation of dityrosine and was associated with altered fibrin structure derived from such modified fibrinogen. HOCl-altered fibrin net structure was not related with modulation of platelet procoagulant response, thrombin generation, and factor XIII activity. We conclude that, in human blood, clinically relevant HOCl concentrations may inhibit thrombus formation under flow, clot retraction and fibrinolysis. Fibrinolysis and clot retraction seem to be the most sensitive to HOCl-evoked inhibition. HOCl-modified fibrinogen and altered clot structure associated with it are likely to be primary sources of attenuated fibrinolysis.

Effect of quinolinic acid - A uremic toxin from tryptophan metabolism - On hemostatic profile in rat and mouse thrombosis models.

PURPOSE: We aimed to determine the effect of quinolinic acid (QA) on hemostasis in rat and mouse models of thrombosis. MATERIAL AND METHODS: Wistar rats (male, n = 72) received QA dissolved in drinking water in doses of 3, 10, 30 mg/kg or pure drinking water (vehicle control group -VEH) for 14 days. On the 14th day of the experiment the effect of QA on hemostasis was evaluated using electrically induced arterial thrombosis model. The following parameters were measured: thrombus weight, hematology, thromboelastometric (ROTEM) parameters, TXA2 and 6-keto-PGF1α concentration, coagulation and fibrinolytic markers activity and concentration. GFP mice (male, n = 30) were assigned to the group receiving QA (30 mg/kg) or VEH for 14 days and to the group receiving: single intravenous dose of QA (30 mg/kg) or VEH or the same dose of QA and anti-CD31 (platelet endothelial cell adhesion molecule-1, PECAM-1) antibody conjugated with Alexa Fluor 647. The effect of QA on hemostasis was evaluated in the model of laser-induced injury of mesentery vein using intravital confocal microscopy. RESULTS: Administering QA for 14 days resulted in a divergent, depending on dose, increase in concentration of active form of tPA and PAI-1 and concentration of total PAI-1 and PAP complexes in rats' plasma. In turn, administering QA for 14 days in mice revealed its prothrombotic activity, while single-dose IV administration revealed its antithrombotic activity, through the up-regulation of PECAM-1 expression. CONCLUSIONS: We demonstrated the first evidence for the opposite biological effects of QA on hemostasis in rat and mouse thrombosis models.

Surface Modification of Cellulose Nanocrystals with Succinic Anhydride.

The surface modification of cellulose nanocrystals (CNC) is a key intermediate step in the development of new functionalities and the tailoring of nanomaterial properties for specific applications. In the area of polymeric nanocomposites, apart from good interfacial adhesion, the high thermal stability of cellulose nanomaterial is vitally required for the stable processing and improvement of material properties. In this respect, the heterogeneous esterification of CNC with succinic anhydride was investigated in this work in order to obtain CNC with optimised surface and thermal properties. The influence of reaction parameters, such as time, temperature, and molar ratio of reagents, on the structure, morphology and thermal properties, were systematically studied over a wide range of values by DLS, FTIR, XPS, WAXD, SEM and TGA methods. It was found that the degree of surface substitution of CNC increased with the molar ratio of succinic anhydride to cellulose hydroxyl groups (SA:OH), as well as the reaction time, whilst the temperature of reaction showed a moderate effect on the degree of esterification in the range of 70-110 °C. The studies on the thermal stability of modified nanoparticles indicated that there is a critical extent of surface esterification below which only a slight decrease of the initial temperature of degradation was observed in pyrolytic and oxidative atmospheres. A significant reduction of CNC thermal stability was observed only for the longest reaction time (240 min) and the highest molar ratio of SA:OH. This illustrates the possibility of manufacturing thermally stable, succinylated, CNC by controlling the reaction conditions and the degree of esterification.

Decomposition of Piloty's acid derivatives - Toward the understanding of factors controlling HNO release.

The recent interest in the clinical applications of Piloty's acid derivatives as HNO donors for the treatment of cardiovascular system dysfunction has led us to the examination of factors controlling HNO release from selected ortho-substituted N-hydroxysulfonamides. Here we present the kinetic and quantum mechanical studies on the mechanism of HNO release from selected ortho-substituted N-hydroxysulfonamides and in vivo examination of the antiaggregatory properties of N-hydroxy-(2-bromobenzene)sulfonamide complex with sodium salt of ß-cyclodextrin sulfobutyl ethers-ethyl ethers as compared with Angeli's salt.

Preparation of Musk-Smelling Macrocyclic Lactones from Biomass: Looking for the Optimal Substrate Combination.

Macrocyclic musk belongs to a well-known and valued class of the fragrance family. Originally, natural musks were obtained from rectal musk glands which often led to the death of the animals. Recently, a lot of effort was invested to obtain such macrocycles in a synthetic way. This research presents a study on the preparation of macrocyclic lactones with the musk scent by ring-closing metathesis (RCM) using biomass-derived starting materials: oleic and 9-decenoic acid. An experimental rule correlating the C-C double bond substitution pattern in the starting diene and the yield for the RCM macrocyclization was proposed.

Antithrombotic Potential of Tormentil Extract in Animal Models.

Potentilla species that have been investigated so far display pharmacological activity mainly due to the presence of polyphenols. Recently, it was shown that polyphenol-rich extract from rhizome of Potentilla erecta (tormentil extract) affects the metabolism of arachidonic acid and exerts both anti-inflammatory and anti-oxidant activities, suggesting a possible effect on thrombosis. Accordingly, the aim of the study was to evaluate the effect of tormentil extract on haemostasis in a rat model of thrombosis. Lyophilized water-methanol extract from P. erecta rhizome was administrated per os for 14 days in doses of 100, 200, and 400 mg/kg in a volume of 2 mL/kg in a 5% water solution of gummi arabici (VEH). In the in vivo experiment an electrically induced carotid artery thrombosis model with blood flow monitoring was used in Wistar rats. Collected blood samples were analyzed ex vivo functionally and biochemically for changes in haemostasis. Tormentil extract (400 mg/kg) significantly decreased thrombus weight and prolonged the time to carotid artery occlusion and bleeding time without changes in the blood pressure. In the ex vivo experiment tormentil extract (400 mg/kg) reduced thromboxane production and decreased t-PA activity, while total t-PA concentration, as well as total PAI-1 concentration and PAI-1 activity remained unchanged. Furthermore, tormentil extract (400 mg/kg) decreased bradykinin concentration and shortened the time to reach maximal optical density during fibrin generation. Prothrombin time, activated partial thromboplastin time, QUICK index, fibrinogen level, and collagen-induced aggregation remained unchanged. To investigate the involvement of platelets in the antithrombotic effect of tormentil, the extract was administrated per os for 2 days to mice and irreversible platelets activation after ferric chloride induced thrombosis was evaluated under intravital conditions using confocal microscopy system. In this model tormentil extract (400 mg/kg) significantly reduced platelet activation at the same extent as acetylsalicylic acid. Taken together, we have shown for the first time that tormentil extract inhibits arterial thrombosis in platelet- and endothelial-dependent mechanisms without hemodynamic changes. Further studies on the detailed mechanism of action of tormentil extract toward fibrinolysis and the kinin system should be carried out.

Risk factors for seroma evacuation in breast cancer patients treated with intraoperative radiotherapy.

BACKGROUND: Novel techniques in oncology provide new treatment opportunities but also introduce different patterns of side effects. Intraoperative radiotherapy (IORT) allows a shortened overall treatment time for early breast cancer either combined with whole breast radiotherapy (WBRT), or alone. Although the early side effects of IORT are well known, data on clinically important late side effects, which require medical intervention, are scarce. AIM: In this study, we analyze risk factors for seroma evacuation more than 6 months after IORT. MATERIALS AND METHODS: We evaluated 120 patients with a mean follow-up of 27.8 months (range: 7-52 months). Fifty-one patients received IORT only and 69 were additionally treated with WBRT. RESULTS: Seroma evacuation was performed 6-38 months after IORT. Two (3.9%) events were observed in the IORT group and 14 (20%) in the IORT + WBRT group. Univariate (Kaplan-Meier) analysis showed that addition of WBRT to IORT increased the risk of seroma evacuation [hazard ratio = 5.5, 95% confidence interval: 2.0-14.7, P = 0.011]. In a multivariate analysis (Cox proportional hazards regression), WBRT and axillary lymph node dissection were significant risk factors for seroma evacuation (model P value = 0.0025). CONCLUSIONS: WBRT applied after IORT is associated with increased risk of seroma evacuation, which might be considered as a late side effect.

Pharmacological modulation of fibrinolytic response - In vivo and in vitro studies.

Fibrinolysis is an action of converting plasminogen by its activators, like tissue- or urokinase-type plasminogen activators (t-PA, u-PA), to plasmin, which in turn cleaves fibrin, thereby causing clot dissolution and restoration of blood flow. Endothelial cells release t-PA, prostacyclin (PGI2) and nitric oxide (NO), the potent factors playing a crucial role in regulation of the fibrinolytic system. Since blood platelets can release not only prothrombotic, but also antifibrinolytic factors, like plasminogen activator inhibitor type-1 (PAI-1), they are involved in fibrynolysis regulation. Therefore agents enhancing fibrinolysis can be preferred pharmacologicals in many cardiovascular diseases. This review describes mechanisms by which major cardiovascular drugs (renin-angiotensin-aldosterone system inhibitors, statins, adrenergic receptors and calcium channel blockers, aspirin and 1-methylnicotinamide) influence fibrinolysis. The presented data indicate, that the influence of these drugs on endothelium-blood platelets interactions via NO/PGI2 pathway is fundamental for its antithrombotic and profibrinolytic action. We also described new approaches for intravital confocal real-time imaging as a tool useful to investigate mechanisms of thrombus formation and the effects of drugs affecting haemostasis and mechanisms of their action in the circulation.

Plasma biomarkers of pulmonary hypertension identified by Fourier transform infrared spectroscopy and principal component analysis.

The main goal of this study was to find specific plasma spectral markers associated with pulmonary arterial hypertension (PAH) induced by monocrotaline injection in rats. FTIR was used to monitor biochemical changes in plasma caused by PAH as compared with the systemic hypertension induced by partial ligation on the left artery and with the control group. Both pathologies, systemic and pulmonary hypertension, induced a unique response in the biochemical content of plasma, mainly related to the composition and secondary structure of plasma proteins. For PAH, ß-pleated sheet components of plasma proteins were identified whereas the protein composition in systemic hypertension was dominated by unordered structures. In addition, a higher concentration of tyrosine-rich proteins was found in plasma in PAH than in systemic hypertension. The differences between both pathologies were identified also in terms of lipid composition/metabolism as well as in the content of RNA and glucose, suggesting that lipid peroxidation appears upon pulmonary hypertension development. In summary, this work demonstrates that FTIR spectroscopy supported by principal component analysis (PCA) has the potential to become a fast and non-destructive method for biochemical characterization of plasma that consequently could have a diagnostic significance in pulmonary hypertension.

Antithrombotic effects of pyridinium compounds formed from trigonelline upon coffee roasting.

Coffee may exert a preventive effect on arterial thrombosis. Trigonelline is one of the most abundant compounds in coffee that undergoes pyrolysis upon roasting of coffee beans. The aim of the present study was to identify pyridinium compounds formed upon trigonelline pyrolysis and coffee roasting and to investigate the effect of three of them, i.e., 1-methylpyridine and 1,3- and 1,4-dimethylpyridine, on experimentally induced arterial thrombosis in rats. 1,3- and 1,4-dimethylpyridine but not 1-methylpyridine inhibited arterial thrombus formation. 1,3-Dimethylpyridine inhibited platelet aggregation and reduced fibrin formation in platelet-rich plasma, whereas 1,4-dimethylpyridine increased the plasma level of 6-keto-PGF1α. 1,4-Dimethylpyridine slightly increased rat tissue plasminogen activator plasma activity. In summary, we demonstrated that pyridinium compounds display mild antithrombotic properties due to stimulation by prostacyclin release (1,4-dimethylpyridine) and inhibition of platelet aggregation (1,3-dimethylpyridine). Those pyridinium compounds may, to some extent, be responsible for the beneficial effects of coffee drinking.

Aliskiren inhibits experimental venous thrombosis in two-kidney one- clip hypertensive rats.

A substantial amount of evidence links the renin-angiotensin system with thrombosis. For example, ACE inhibitors and angiotensin receptor blockers possess independent of the hemodynamic changes, antithrombotic activity. Aliskiren direct renin inhibitor belongs to a new very promising antihypertensive drug that effectively inhibits the renin-angiotensin system. The aim of study was to determine the influence of aliskiren on stasis-induced venous thrombosis in renovascular hypertensive and normotensive rats. The involvement of nitric oxide and prostacyclin in the potential antithrombotic action was also elucidated. Six weeks after clipping of the left renal artery rats developed hypertension which was confirmed by the "tail cuff" method. Hypertensive and normotensive rats were treated with aliskiren (10, 30 and 100mg/kg/day) per os for 10days. Venous thrombosis was induced by stasis of vena cava inferior. Aliskiren at the highest dose induced a significant decrease in systolic blood pressure in hypertensive, but did not change this parameter in normotensive rats. Oral administration of aliskiren resulted in dose-dependent decrease of venous thrombus weight in hypertensive and normotensive rats. The antithrombotic activity of aliskiren was abolished both by NO synthase inhibitor and prostacyclin synthesis inhibitor. Aliskiren decreased collagen-induced platelet aggregation, increased plasma level of tissue plasminogen activator activity whereas no changes in plasminogen activator inhibitor activity and coagulation parameters were found. We showed that aliskiren prevents the development of venous thrombosis by enhanced fibrinolysis and the blood platelet inhibition via nitric oxide and/or prostacyclin-dependent mechanism.

Antithrombotic properties of water-soluble carbon monoxide-releasing molecules.

OBJECTIVE: We compared the antithrombotic effects in vivo of 2 chemically different carbon monoxide-releasing molecules (CORM-A1 and CORM-3) on arterial and venous thrombus formation and on hemostatic parameters such as platelet activation, coagulation, and fibrinolysis. The hypotensive response to CORMs and their effects on whole blood gas analysis and blood cell count were also examined. METHODS AND RESULTS: CORM-A1 (10-30 µmol/kg, i.v.), in a dose-dependent fashion, significantly decreased weight of electrically induced thrombus in rats, whereas CORM-3 inhibited thrombosis only at the highest dose used (30 µmol/kg). CORM-A1 showed a direct and stronger inhibition of platelet aggregation than CORM-3 in healthy rats, both in vitro and in vivo. The antiaggregatory effect of CORM-A1, but not CORM-3, correlated positively with weight of the thrombus. Concentration of active plasminogen activator inhibitor-1 in plasma also decreased in response to CORM-A1, but not to CORM-3. Neither CORM-A1 nor CORM-3 had an effect on plasma concentration of active tissue plasminogen activator. CORM-3, but not CORM-A1, decreased the concentration of fibrinogen, fibrin generation, and prolonged prothrombin time. Similarly, laser-induced venous thrombosis observed intravitally via confocal system in green fluorescent protein mice was significantly decreased by CORMs. Although both CORM-A1 and CORM-3 (30 µmol/kg) decreased platelets accumulation in thrombus, only CORM-A1 (3-30 µmol/kg) inhibited platelet activation to phosphatidylserine on their surface. CONCLUSIONS: CORM-3 and CORM-A1 inhibited thrombosis in vivo, however CORM-A1, which slowly releases carbon monoxide, and displayed a relatively weak hypotensive effect had a more pronounced antithrombotic effect associated with a stronger inhibition of platelet aggregation associated with a decrease in active plasminogen activator inhibitor-1 concentration. In contrast, the fast CO releaser CORM-3 that displayed a more pronounced hypotensive effect inhibited thrombosis primarily through a decrease in fibrin generation, but had no direct influence on platelet aggregation and fibrynolysis.