Overproduction Of Hyaluronic Acid Research Articles

What is “eczema”?

AbstractEczema is the most common category of inflammatory skin disorders as dermatologists see many patients with eczematous diseases in daily practice. It is characterized by the three major morphological features: multiple‐pinpoint condition, polymorphism, and itch. To describe polymorphism, “eczema triangle” has been used in German/Japanese dermatology. The multiple pinpoints correspond to numerous tiny foci from which individual papules/vesicles arise. The polymorphism betrays composition of erythema, papule, seropapule, vesicle, pustule, scale, and crust, which are seen in acute eczema. Meanwhile, chronic eczema is represented by lichenification and hyperpigmentation, and possibly by hypopigmentation. In acute eczema, spongiosis is associated with overproduction of hyaluronic acid, secretion of self‐protective galectin‐7, and decreased expression of E‐cadherin. In the upper dermis, Th1/Tc1 or Th2/Tc2, and additional Th17, Th22, and/or Tc22 infiltrate, depending on each eczematous disease. Innate lymphoid cells are also involved in the formation of eczema. In chronic eczema, periostin contributes to remodeling of inflammatory skin with dermal fibrosis, and epidermal melanogenesis and dermal pigment deposition result in hyperpigmentation. Finally, eczematous diseases are potentially associated with increased risk of comorbidities, including not only other allergic diseases but also coronary heart disease and mental problems such as depression. Although the original word for eczema is derived from old Greek “ekzein,” eczema remains a major target of modern science and novel therapies.

Convergent Approaches to Delineate the Metabolic Regulation of Tumor Invasion by Hyaluronic Acid Biosynthesis.

Metastasis is the leading cause of breast cancer-related deaths and is often driven by invasion and cancer-stem like cells (CSCs). Both the CSC phenotype and invasion are associated with increased hyaluronic acid (HA) production. How these independent observations are connected, and which role metabolism plays in this process, remains unclear due to the lack of convergent approaches integrating engineered model systems, computational tools, and cancer biology. Using microfluidic invasion models, metabolomics, computational flux balance analysis, and bioinformatic analysis of patient data, the functional links between the stem-like, invasive, and metabolic phenotype of breast cancer cells as a function of HA biosynthesis are investigated. These results suggest that CSCs are more invasive than non-CSCs and that broad metabolic changes caused by overproduction of HA play a role in this process. Accordingly, overexpression of hyaluronic acid synthases (HAS) 2 or 3 induces a metabolic phenotype that promotes cancer cell stemness and invasion in vitro and upregulates a transcriptomic signature predictive of increased invasion and worse patient survival. This study suggests that HA overproduction leads to metabolic adaptations to satisfy the energy demands for 3D invasion of breast CSCs highlighting the importance of engineered model systems and multidisciplinary approaches in cancer research.

MECHANISMS OF CYTOKINE STORM DEVELOPMENT IN COVID-19 AND NEW POTENTIAL TARGETS OF PHARMACOTHERAPY

The development of a "cytokine storm", characteristic of severe COVID-19 forms, can be defined as a state of uncontrolled release of a large number of inflammatory mediators.The attachment of SARS-CoV-2 S-glycoprotein to angiotensin-converting enzyme 2 is considered a process that triggers complex molecular interactions that lead to hyperinflammation. In its turn, it is realized through several systems: renin-angiotensin-aldosterone, kallikrein-kinin and a complement system. Knowledge of these mechanisms suggests potential therapeutic interventions that can be targeted by existing therapeutic agents to counter the cytokine storm and treat the acute respiratory distress syndrome associated with COVID-19.The aim of the review article is to summarize the currently known data on the molecular processes underlying the uncontrolled "cytokine storm" in the patients with severe COVID-19, and possible options for their pharmacological correction.Materials and methods. The data base was represented by such systems as Medline, Cochrane Central Register of Controlled Trials, Scopus, Web of Science Core Collection, Cochrane Library, ClinicalTrials.gov, Elibrary, Google-Academy. A search was carried out for the following keywords and combinations: COVID-19, renin-angiotensin-aldosterone system, bradykinin, complement system, hyaluronic acid, pharmacotherapy.Results. The development of a "cytokine storm" in COVID-19 is mediated by pathogenetic changes in the body in response to the penetration of SARS-CoV-2 into the cell. In the RAAS, suppression of ACE2 leads to a decrease in its ability to degrade ATII, which, on the one hand, leads to a decrease in the amount of AT1-7, and, on the other hand, to the effect of ATII on AT1R with the subsequent development of vasoconstriction and lung damage. The disturbances in the kallikrein-kinin system are associated, on the one hand, with the increased expression of kallikrein and an increase in the formation of bradykinin and its metabolite des-Arg 9-bradykinin. On the other hand, the disturbances are associated with the suppression of the expression of the C1-esterase inhibitor which prevents the formation of kallikrein, and impaired inactivation of des-Arg 9-bradykinin under the action of ACE 2. The nucleocapsid protein SARS-CoV-2 triggers the activation of the complement system through the lectin pathway. It leads to the production of anaphylatoxins C3a and C5a, which stimulate the synthesis of pro-inflammatory cytokines. Proinflammatory cytokines are potent inducers of the HAS 2 gene in the endothelium, which encodes the membrane enzymes of hyaluronate synthase. The sweating of the fluid into the alveoli caused by the "bradykinin storm" in combination with the overproduction of hyaluronic acid, which accumulates water 1000 times its own mass, can lead to the formation of a dense jelly-like substance that prevents gas exchange.Conclusion. Promising areas of pharmacotherapy for "cytokine storm" are associated with its impact on the dysfunction of the listed above systems. However, the efficacy and safety of most drugs for the treatment of COVID-19, is to be studied through carefully designed clinical trials.

GINGIVAL FOCAL MUCINOSIS: A CASE REPORT AND IMMUNOHISTOCHEMICAL ANALYSIS

Oral focal mucinosis (OFM) is a rare connective tissue disorder characterized by myxoid degeneration due to the overproduction of hyaluronic acid. Sometimes, other mesenchymal lesions with myxoid differentiation may create diagnostic difficulties when assessing OFM. Here, we report a case of gingival OFM. A 58-year-old woman presented in our service complaining of a painless gingival lesion 10 months ago. Intra-oral examination revealed a nodular, sessile and smooth surface lesion, located in the buccal gingiva, at level of the teeth #22 and #24. An excisional biopsy was performed, and microscopic analysis showed a well-defined, nonencapsulated area of myxomatous connective tissue surrounded by collagenous connective tissue. Alcian blue stain was positive. Immunohistochemical analysis revealed positivity only for vimentin and α-smooth muscle actin. The final diagnosis was OFM. The lesion did not present recurrence after 4 months’ of follow-up. OFM should be included in the differential diagnosis of gingival nodular lesions.

Oral Focal Mucinosis on the Palatal Mucosa: A Rare Case Report

Oral focal mucinosis (OFM) is a soft tissue lesion commonly characterized by swelling in the gingiva; its occurrence in the palatal mucosa is rare. Differential diagnosis of OFM includes mucocele, nerve sheath myxoma, and myxoma, and the histologic and immunohistochemical findings are important for diagnosis. A 62-year-old man presented with a nodular lesion on the hard palate; excisional biopsy was performed. The histopathologic examination revealed a loose, myxomatous connective tissue stroma, with ovoid, fusiform, or stellate-shaped fibroblasts. The stroma was positive for Alcian blue and negative for periodic acid–Schiff staining, indicating overproduction of hyaluronic acid. Immunohistochemical analysis demonstrated that spindle cells were negative for S-100, vimentin, and CD34. After surgical excision, the patient is under regular follow-up, and no recurrence has been observed. This case highlights the importance of immunohistochemical analysis to confirm the final diagnosis.

Hyaluronidase Injection in the Vocal Folds for Vocal Hemorrhage, Reinke Edema, and Hyaluronic Acid Overinjection: A Novel Application in the Larynx

Hyaluronidase (HAase) injection into the vocal folds is an off-label use of an enzyme for liquefaction of hyaluronic acid (HA). HAase injection was performed in 14 cases in 13 patients. Office and operative injections of HAase were performed. The indications were five cases of overinjection of HA, six cases of Reinke edema and polypoid corditis, and three cases of acute vocal hemorrhage with early fusiform polyp formation. All the patients tolerated the HAase without complications. Significant voice improvements were noted between pre- and postinjection procedures as evaluated by a self-rating of voice by the Voice Handicap Index-10. A marked decrement in the mass on the side of the injection of HAase was noted in all groups successfully injected upon viewing by videostroboscopy. HAase prevented an additional operative phonosurgery in 10 patients. In conclusion, HAase injection can be used in the vocal folds with good effect in patients. The indications are polypoid corditis with overproduction of HA, acute vocal hemorrhage, and correction of iatrogenic HA overinjection.

Oral focal mucinosis associated with surgically assisted rapid maxillary expansion

Oral focal mucinosis is a rare soft-tissue lesion that might result from the overproduction of hyaluronic acid by fibroblasts. The lesions are commonly found on the gingiva and palate; however, other sites, such as the tongue, have also been reported. The diagnosis of oral focal mucinosis is based on histologic analysis, and treatment involves surgical excision. Recurrences of lesions have not been reported. This article presents a patient with oral focal mucinosis that might be associated with surgically assisted rapid maxillary expansion.

Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation.

Unfettered hyaluronan (HA) production is a hallmark of rheumatoid arthritis. The discovery of three genes encoding hyaluronan synthases (HASs) allows for the investigation of the signaling pathways leading to the activation of these genes. Our objective is to further understanding of the regulation of these genes as well as to find ways to prevent undesired gene activation. Human fibroblast-like synoviocytes were used in these experiments. mRNA levels of HAS were monitored by reverse transcriptase-PCR. A series of specific kinase inhibitors were used to investigate intracellular pathways leading to the up-regulation of HAS1. Our experiments, testing a series of stimuli including tumor necrosis factor alpha (TNFalpha), demonstrate that TGF-beta is the most potent stimulus for HAS1 transcription. TGF-beta activates HAS1 in a dose-dependent manner with a maximum effect at a concentration of 0.5-1 ng/ml. TGF-beta-induced HAS1 mRNA can be detected within 60 min and reaches maximal levels at 6 h. Furthermore, TGF-beta treatment leads to an increase in synthase activity as determined by HA ELISA and by in vitro HA synthase assays. In contrast to the activatory effect on HAS1, TGF-beta dose-dependently suppresses HAS3 mRNA. As to the mode of action of TGF-beta-induced HAS1 mRNA activation, our experiments reveal that blocking p38 MAPK inhibited the TGF-beta effect by 90%, blocking the MEK pathway led to an inhibition by 40%, and blocking the JNK pathway had no effect. The presented data might contribute to a better understanding of the role of TGF-beta and of HA in the pathology of diseases.

Stimulation of prostaglandin E production in cultured human fibroblasts by poly(I)-poly(C) and human interferon.

PROSTAGLANDINS (PGs) have emerged as one of the principal mediators of the inflammatory process1–3. Elevation of tissue concentration of PGs was noted following inflammation3,4, or treatment with various hormones5,6, cyclic nucleotides (ref. 7 and U.Z., B. Strulovici and H.R.L., in preparation), serum8, drugs8,9 and antigen10. The beneficial effects of anti-inflammatory drugs have been correlated with their ability to suppress PG production either by curtailing precursor availability (glucocorticosteroids11,12) or by inhibiting PG synthetase activity (non-steroidal drugs1). Viral infections are associated with interferon production13 and with inflammation14. Little is known about the possible involvement of interferon in the inflammatory reaction, though it has been suggested that interferon may have anti-inflammatory properties15. It has been shown that an interferon inducer, double-stranded polyinosinate·polycytidylate [poly(I)·poly(C)], as well as human interferon, stimulate hyaluronic acid production by human synovial fibroblasts in culture16. Overproduction of hyaluronic acid is known to be associated with the inflammatory process16; the effect is prevented by cortisol or indomethacin16. We report here the stimulation by poly(I)·poly(C) and by human interferon of prostaglandin E (PGE) production by human synovial and foreskin fibroblasts in culture. Cortisol inhibited this effect.