The Role of Thiocyanate in Modulating Myeloperoxidase Activity during Disease.

Thiocyanate (SCN-) is a pseudohalide anion omnipresent across mammals and is particularly concentrated in secretions within the oral cavity, digestive tract and airway. Thiocyanate can outcompete chlorine anions and other halides (F-, Br-, I-) as substrates for myeloperoxidase by undergoing two-electron oxidation with hydrogen peroxide. This forms their respective hypohalous acids (HOX where X- = halides) and in the case of thiocyanate, hypothiocyanous acid (HOSCN), which is also a bactericidal oxidative species involved in the regulation of commensal and pathogenic microflora. Disease may dysregulate redox processes and cause imbalances in the oxidative profile, where typically favoured oxidative species, such as hypochlorous acid (HOCl), result in an overabundance of chlorinated protein residues. As such, the pharmacological capacity of thiocyanate has been recently investigated for its ability to modulate myeloperoxidase activity for HOSCN, a less potent species relative to HOCl, although outcomes vary significantly across different disease models. To date, most studies have focused on therapeutic effects in respiratory and cardiovascular animal models. However, we note other conditions such as rheumatic arthritis where SCN- administration may worsen patient outcomes. Here, we discuss the pathophysiological role of SCN- in diseases where MPO is implicated.

Are Janus Kinase Inhibitors Superior over Classic Biologic Agents in RA Patients?

The Janus Kinases (JAKs) are a family of intracellular tyrosine kinases that provide transmission signals from cytokine, interferons, and many hormones receptors to the nucleus resulting in synthesis of many biologically active compounds and changing cell metabolism and function. That was theoretical background to synthetize the JAK inhibitors (Jakinibs). In recent years a substantial battery of evidence has been collected indicating the potential role of Jakinibs to interact with the specific elements of the immune system, therefore changing the inflammatory response. JAK kinase blockade offers a unique opportunity to block most of the key cytokines enabling the deep interaction into immune system functioning. Following discovery first Jakinibs were intensively studied in various forms of autoimmune diseases, including rheumatoid arthritis, and finally two Jakinibs tofacitinib and Baricitinib have been approved for the treatment of rheumatoid arthritis. Some clinical data indicated that under special circumstances Jakinibs may be even superior to biologics in the treatment of RA; however this suggestion should be verified in large clinical and observational studies.

Phosphoinositide-3-kinases as the Novel Therapeutic Targets for the Inflammatory Diseases: Current and Future Perspectives.

OBJECTIVE: To review the role of PI3K/AKT/mTOR signalling pathway, and the current and future prospects of targeting PI3Ks for various diseases, like malignant, autoimmune, inflammatory, cardiovascular, neurological disorders etc., laying special emphasis on the inflammatory diseases and associated cellular responses. BACKGROUND: Recent findings have publicized phosphoinositide-3-kinases (PI3Ks) as novel therapeutic targets, which are also purported to be involved in the complex pathophysiology of inflammatory and various other diseases. They are recognized to participate in the inflammatory cellular responses by modulating the growth, development and proliferation of various immune cells and hence, affect the release of various cytokines and other inflammatory mediators involved in these manifestations. The recent literature relating this pathway with these diseases is highlighted, with a hope, which remains for the progression of PI3K inhibitors in the market as a treatment option. RESULT: With Idelalisib entering the market for cancer, PI3K/AKT signalling has also gained significance as an investigational target for various diseases, particularly for inflammation. Based on the pharmacological, genetic, and clinical data available, PI3K/AKT signalling can be designated as an outstanding target for their treatment. CONCLUSION: Further exploration of this pathway may also uncover its involvement in these disorders, which may further contribute to developing the new treatments and can turn out to be an innovative brainwave in the field of experimental and clinical pharmacology in future.

Peptidylarginine deiminases and the pathogenesis of rheumatoid arthritis: a reflection of the involvement of transglutaminase in coeliac disease.

Post-translational modifications are associated with certain autoimmune diseases. For example, in the initial steps of coeliac disease (CD), transglutaminase type 2 (TG2) catalyzes a post-translational deamidation of specific glutamine residues in dietary gluten, resulting in antibodies against both modified gliadin and against TG2. Anti-TG2 has become a specific biomarker for CD. In rheumatoid arthritis (RA), the presence of antibodies against citrullinated peptides (ACPA) characterizes a distinct subset of this inflammatory disorder. Moreover, antibodies against the enzyme that catalyzes the citrullination (peptidylarginine deiminase; PAD) are found in RA. Their relation to disease severity indicates a possible pathogenetic role. Thus, in two major autoimmune diseases (CD and RA), antibodies are present against a post-translationally modified substrate and against the calcium-dependent thiol-enzyme (TG2 and PAD, respectively) responsible for the modification. This review highlights the similarities between the TGs and the PADs and their putative pathogenetic roles in autoimmune diseases. Possible mechanisms of the effects of cigarette smoking and alcohol consumption on RA are discussed. By reflecting the progress in CD, the pathogenesis of ACPA-positive RA can be hypothesized where expression and regulation of PADs play significant roles. Indeed, autoimmune diseases should be studied collectively as well as individually. The new insight may lead towards innovative pharmacotherapeutic principles.

NADPH oxidase activity in the monocytes and neutrophils of patients with rheumatic fever.

The enzyme NADPH oxidase is involved in the production of oxygen free radicals. We measured its activity in neutrophils and monocytes obtained from patients with acute rheumatic fever, chronic rheumatic heart disease, acute streptococcal pharyngitis and normal controls. Follow up studies were made at 15 days, 3 months and 6 months. Streptococcal membrane antigen, carbohydrate antigens and latex were used to stimulate the oxidative activity in the neutrophils and monocytes. These three agents caused a significant increase in the enzyme activity of the phagocytes of patients with acute rheumatic fever and chronic rheumatic heart disease (p less than 0.001) but not in acute pharyngitis. Maximal NADPH oxidase enzyme activity was observed in patients with acute rheumatic fever. During the follow-up, there was a significant decline in the enzymatic activity in patients with acute rheumatic fever but not in those with chronic rheumatic heart disease. Enzymatic activity was greater when the phagocytic cells were triggered with membrane as compared to carbohydrate antigen and latex in all the groups and at all intervals. The enzymatic response of neutrophils and monocytes was similar although the magnitude of the NADPH oxidase activity was significantly higher in neutrophils than in monocytes.

[Changes in beta-glucuronidase activity in the blood cells and blood serum of patients with rheumatism in relation to clinical manifestations of the disease]. / Izmenenie aktivnosti beta-gliukuronidazy v kletkakh i syvorotke krovi bol'nykh revmatizmom v zavisimosti ot klinicheskikh proiavlenii bolezni.

The authors examined 22 patients with rheumatic fever in whose cells (neutrophils, mononuclear cells, thrombocytes) and in the blood serum they noted the activity of lysosomal enzyme of beta-glucuronidase (BGU) and the concentration of protein in the cells of the peripheral blood. The activity of the enzyme and concentration of protein in neutrophils of mononuclear cells was found to be decreased. Differences in determining the activity of BGU in the blood serum in relation to the clinical manifestations of the disease were also established. A significant rise in the activity of BGU in the blood serum as compared to the norm was observed in patients with a protracted course of rheumatic fever, with the I degree of the process activity, circulatory disorders and complicated cardiac failures. There was a clearly seen direct relationship between the activity of BGU in the blood serum and the level of circulating immune complexes, and an indirect relationship between the mentioned enzyme and alpha 2-globulin. A decrease in the activity of BGU in the cells was caused by degranulation of neutrophils and monocytes induced by immunological factors. A decrease in the level of BGU in the cells of patients with rheumatic fever apparently influences the processes of phagocytosis and aggravates immunological disorders, and, consequently, is connected with the disease pathogenesis. Determination of the BGU activity in the blood serum can be used for detection of the minimum activity of the inflammatory process in a chronic course of rheumatic fever.

[Genetic variants of acid erythrocytic phosphatase as a risk factor of rheumatic fever]. / Geneticheskie varianty kisloi éritrotsitarnoi fosfatazy kak faktor riska revmatizma.

A study was made of the genetic variants (isoenzymes, phenotypes) of acid erythrocytic phosphatase (AcP) in 120 patients with rheumatic fever. There were 78 women and 42 men aged 16 to 57 years. The population data concerned with distribution of the AcP variants among the population of Moscow were used as control. As compared with control, the patients suffering from rheumatic fever demonstrated the accumulation of the rarely occurring variants of AcP (AC, BC and CC, in particular). A significant direct correlation was established between the activity of isoenzymes and relative risk of rheumatic fever incidence. The definite regularities in the distribution of AcP variants were found to depend on the disease clinical patterns (the articular syndrome, the times of the formation of heart diseases, the character of recurrent rheumocarditis). The data obtained can used for distinguishing the rheumatic fever risk groups and forecasting the rheumatic process (to a certain degree of probability).

[Changes in lactate dehydrogenase levels in acute articular rheumatism, chorea minor and the Schönlein-Henoch syndrome in childhood]. / Variazioni del tasso della latticodeidrogenasi nel R.A.A., corea minor e sindrome di Schönlein-Henoch in età pediatrica.

Changes in serum LDH in AAR, Sydenham's chorea and purpura rheumatica and their significance were investigated in 103 cases observed at the 1st Paediatrics Clinic, University of Turin. A search was made for relation between such changes and the laboratory parameters in rheumatism. The data showed that blood LDH can be profitably determined in the diseases considered.

Raised serum transaminase levels in patients with rheumatic fever treated with salicylates.

Of 11 patients with acute rheumatic fever, 9 were treated with a total daily salicylate dosage of 3,6 g or less, 1 patient required a total daily dosage of 5,4 g and another required 9,0 g daily. Six of the 11 patients had elevated serum transaminase levels, and all were asymptomatic. The elevated transaminase levels appear to bear a direct relationship to the serum salicylate level, and a serum salicylate level of 19,2 mg/100 ml appears to be the critical point. In 5 out of the 6 patients with elevated transaminases, the serum salicylate level exceeded 19,2 mg/100 ml, while in the 5 patients with normal transaminases the serum salicylate level did not exceed 19,2 mg/100 ml. Also, in 10 of the 11 patients eosinophilia was noted, but this decreased despite continued or increased salicylate administration. A narrow margin thus appears to exist between therapeutic serum salicylate levels and hepatotoxic levels, and serial serum transaminase estimations are advocated in patients on long-term salicylate therapy.

Antihyaluronidase level in children with rheumatic fever and other streptococcal infection.

1) The serum ASO and AH assays were performed and compared in a series of 90 healthy children and 7 pediatric patients with rheumatic fever and other disorders related to hemolytic streptococcus infection. 2) The upper physiological limit of serum AH titer was estimated to be 256X for children. 3) In rheumatic fever, sometimes the serum AH level rises earlier than elevation of serum ASO and remains to be high over a long period even after the serum ASO has returned to normal level. 4) The results suggest importance of the serum AH determination in the serologic diagnosis of rheumatic fever and other conditions of hemolytic streptococcus infection.