Evaluation of oral tranexamic acid as a novel treatment for melasma with a high benefit-risk ratio.

BACKGROUND: Melasma is an acquired melanogenesis dysfunction resulting in chronic hyperpigmentation commonly affecting the face and other frequently sun-exposed areas of the body. Melasma typically presents in women of reproductive age and can significantly impact self-esteem, negatively affecting one's quality of life. In the United States, melasma is often treated with application of topical agents that interfere with melanin synthesis, lasers, or chemical peels; however, in some East Asian countries, oral tranexamic acid (TXA) is widely administered to alleviate hyperpigmentation during and after childbirth. TXA is currently only FDA-approved to treat hypermenorrhea and reduce blood loss in surgery but may offer women in the United States an additional therapeutic option to treat melasma. AIMS: The aim of this paper is to evaluate the safety and baseline efficacy of oral transmexic acid as a treatment for melasma. METHODS: We retrospectively surveyed 42 patients of Fitzpatrick skin types III-VI that were prescribed 650 mg of TXA ½ tablet to be taken twice daily by mouth. RESULTS: We found majority of patients saw noticeable improvement in their melasma. Of the 42 patients, only seven experienced side effects. The side effects noted were headaches, malaise and nausea, gastrointestinal upset, congestion, numbness in legs, hypomenorrhea, and hypermenorrhea. Patients who experienced unpleasant side effects discontinued taking oral TXA and were relieved of their symptoms. No long-term side effects were discovered, and the side effects experienced may be due to other confounding factors. CONCLUSION: From this data, we concluded oral TXA is a safe and effective treatment option for patients with persistent melasma.

Aging alters the metabolic flux signature of the ER-unfolded protein response in vivo in mice.

Age is a risk factor for numerous diseases, including neurodegenerative diseases, cancers, and diabetes. Loss of protein homeostasis is a central hallmark of aging. Activation of the endoplasmic reticulum unfolded protein response (UPRER ) includes changes in protein translation and membrane lipid synthesis. Using stable isotope labeling, a flux "signature" of the UPRER in vivo in mouse liver was developed by inducing ER stress with tunicamycin and measuring rates of both proteome-wide translation and de novo lipogenesis. Several changes in protein synthesis across ontologies were noted with age, including a more dramatic suppression of translation under ER stress in aged mice as compared with young mice. Binding immunoglobulin protein (BiP) synthesis rates and mRNA levels were increased more in aged than young mice. De novo lipogenesis rates decreased under ER stress conditions in aged mice, including both triglyceride and phospholipid fractions. In young mice, a significant reduction was seen only in the triglyceride fraction. These data indicate that aged mice have an exaggerated metabolic flux response to ER stress, which may indicate that aging renders the UPRER less effective in resolving proteotoxic stress.

ER Unfolded Protein Response in Liver In Vivo Is Characterized by Reduced, Not Increased, De Novo Lipogenesis and Cholesterol Synthesis Rates with Uptake of Fatty Acids from Adipose Tissue: Integrated Gene Expression, Translation Rates and Metabolic Fluxes.

The unfolded protein response in the endoplasmic reticulum (UPRER) is involved in a number of metabolic diseases. Here, we characterize UPRER-induced metabolic changes in mouse livers in vivo through metabolic labeling and mass spectrometric analysis of lipid and proteome-wide fluxes. We induced UPRER by tunicamycin administration and measured synthesis rates of proteins, fatty acids and cholesterol, as well as RNA-seq. Contrary to reports in isolated cells, hepatic de novo lipogenesis and cholesterogenesis were markedly reduced, as were mRNA levels and synthesis rates of lipogenic proteins. H&E staining showed enrichment with lipid droplets while electron microscopy revealed ER morphological changes. Interestingly, the pre-labeling of adipose tissue prior to UPRER induction resulted in the redistribution of labeled fatty acids from adipose tissue to the liver, with replacement by unlabeled glycerol in the liver acylglycerides, indicating that the liver uptake was of free fatty acids, not whole glycerolipids. The redistribution of adipose fatty acids to the liver was not explicable by altered plasma insulin, increased fatty acid levels (lipolysis) or by reduced food intake. Synthesis of most liver proteins was suppressed under UPRER conditions, with the exception of BiP, other chaperones, protein disulfide isomerases, and proteins of ribosomal biogenesis. Protein synthesis rates generally, but not always, paralleled changes in mRNA. In summary, this combined approach, linking static changes with fluxes, revealed an integrated reduction of lipid and cholesterol synthesis pathways, from gene expression to translation and metabolic flux rates, under UPRER conditions. The reduced lipogenesis does not parallel human fatty liver disease. This approach provides powerful tools to characterize metabolic processes underlying hepatic UPRER in vivo.