Hyperhomocysteinemia results from hepatic metabolism dysfunction and is characterized by a high plasma homocysteine level, which is also an independent risk factor for cardiovascular disease. ...Elevated levels of homocysteine in plasma lead to hepatic lesions and abnormal lipid metabolism. Therefore, lowering homocysteine levels might offer therapeutic benefits. Recently, we were able to lower plasma homocysteine levels in mice with moderate hyperhomocysteinemia using an adenoviral construct designed to restrict the expression of DYRK1A, a serine/threonine kinase involved in methionine metabolism (and therefore homocysteine production), to hepatocytes. Here, we aimed to extend our previous findings by analyzing the effect of hepatocyte-specific Dyrk1a gene transfer on intermediate hyperhomocysteinemia and its associated hepatic toxicity and liver dysfunction. Commensurate with decreased plasma homocysteine and alanine aminotransferase levels, targeted hepatic expression of DYRK1A in mice with intermediate hyperhomocysteinemia resulted in elevated plasma paraoxonase-1 and lecithin:cholesterol acyltransferase activities and apolipoprotein A–I levels. It also rescued hepatic apolipoprotein E, J, and D levels. Further, Akt/GSK3/cyclin D1 signaling pathways in the liver of treated mice were altered, which may help prevent homocysteine-induced cell cycle dysfunction. DYRK1A gene therapy could be useful in the treatment of hyperhomocysteinemia in populations, such as end-stage renal disease patients, who are unresponsive to B-complex vitamin therapy.
•Dyrk1a overexpression reduces plasma ALT levels in mice with intermediate hyperhomocysteinemia.•A negative correlation is found between plasma homocysteine levels and LCAT activity.•Dyrk1a overexpression rescues hepatic IkB levels in mice with intermediate hyperhomocysteinemia.
In vitro skin models are validated methods for screening cosmetics and pharmaceuticals, but still have limitations. The bilayer poly(ε‐caprolactone) scaffold/membrane model described here overcomes ...some of these deficits by integrating a solution electrospun (SES) membrane at the dermoepidermal interface and a melt electrowritten (MEW) scaffold that provides an optimal open‐pore environment for the dermis. To the knowledge, this scaffold/membrane model is the only one capable of creating a properly differentiated, full thickness skin model with neosynthesized extracellular matrix (ECM) in only 18 days. Both the wavy and straight fiber scaffold designs create a well‐organized dermis, but dermal collagen organization differs between designs. Adding cells and vitamin C to the scaffolds improves the mechanical properties to more closely mimic native human skin. These findings establish bicomponent scaffolds as a promising advancement for rapidly creating different skin models with varied properties. The versatility and adaptability of the described model can be used for studying how the biological and physical microenvironment impact skin, and testing dermo‐cosmetics and pharmaceutical treatments on different ages of skin. Furthermore, it can be an excellent new tool for studying wound healing and development into its use as a graft or wound dressing is ongoing.
An innovative skin model closely mimicking native human skin properties in only 18 days of culture is developed using a bilayer scaffold. This model is a valuable tool for studying skin responses to microenvironment variations, creating pathological skin models, and testing pharmaceutical treatments. Additionally, it shows promise for wound healing and skin graft applications.
Hyperhomocysteinemia due to cystathionine beta synthase deficiency confers diverse clinical manifestations. It is characterized by elevated plasma homocysteine levels, a common amino acid metabolized ...by remethylation to methionine or transsulfuration to cysteine. We recently found a relationship between hepatic Dyrk1A protein expression, a serine/threonine kinase involved in signal transduction in biological processes, hepatic S-adenosylhomocysteine activity, and plasma homocysteine levels. We aimed to study whether there is also a relationship between Dyrk1a and cystathionine beta synthase activity. We used different murine models carrying altered gene coy numbers for Dyrk1a, and found a decreased cystathionine beta synthase activity in the liver of mice under-expressing Dyrk1a, and an increased in liver of mice over-expressing Dyrk1a. For each model, a positive correlation was found between cystathionine beta synthase activity and Dyrk1a protein expression in the liver of mice, which was confirmed in a non-modified genetic context. The positive correlation found between liver Dyrk1a protein expression and CBS activity in modified and non-modified genetic context strengthens the role of this kinase in one carbon metabolism.
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