Fibrosis is characterized by excessive deposition of the extracellular matrix and develops because of fibroblast differentiation during the process of inflammation. Various cytokines stimulate resident fibroblasts, which differentiate into myofibroblasts. Myofibroblasts actively synthesize an excessive amount of extracellular matrix, which indicates pathologic fibrosis. Although initial fibrosis is a physiologic response, the accumulated fibrous material causes failure of normal organ function. Cardiac fibrosis interferes with proper diastole, whereas pulmonary fibrosis results in chronic hypoxia; liver cirrhosis induces portal hypertension, and overgrowth of fibroblasts in the conjunctiva is a major cause of glaucoma surgical failure. Recently, several reports have clearly demonstrated the functional relevance of certain types of histone deacetylases (HDACs) in various kinds of fibrosis and the successful alleviation of the condition in animal models using HDAC inhibitors. In this review, we discuss the therapeutic potential of HDAC inhibitors in fibrosis-associated human diseases using results obtained from animal models.

Proteins dynamically contribute towards maintaining cellular homeostasis. Posttranslational modification regulates the function of target proteins through their immediate activation, sudden inhibition, or permanent degradation. Among numerous protein modifications, protein nitrosation and its functional relevance have emerged. Nitrosation generally initiates nitric oxide (NO) production in association with NO synthase. NO is conjugated to free thiol in the cysteine side chain (S-nitrosylation) and is propagated via the transnitrosylation mechanism. S-nitrosylation is a signaling pathway frequently involved in physiologic regulation. NO forms peroxynitrite in excessive oxidation conditions and induces tyrosine nitration, which is quite stable and is considered irreversible. Two main reducing systems are attributed to denitrosylation: glutathione and thioredoxin (TRX). Glutathione captures NO from S-nitrosylated protein and forms S-nitrosoglutathione (GSNO). The intracellular reducing system catalyzes GSNO into GSH again. TRX can remove NO-like glutathione and break down the disulfide bridge. Although NO is usually beneficial in the basal context, cumulative stress from chronic inflammation or oxidative insult produces a large amount of NO, which induces atypical protein nitrosation. Herein, we (1) provide a brief introduction to the nitrosation and denitrosylation processes, (2) discuss nitrosation-associated human diseases, and (3) discuss a possible denitrosylation strategy and its therapeutic applications.

Sung Hoon Kim, M.D., Eun Song Song, M.D., Somy Yoon, Ph.D., Gwang Hyeon Eom, Ph.D., Gaeun Kang, M.D., and Young Kuk Cho, M.D.. Ann Lab Med 2021;41:318-22. https://doi.org/10.3343/alm.2021.41.3.318

N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was recently reported as a biomarker for diagnosing Kawasaki disease (KD). The basal NT-proBNP level, however, gradually decreases with age. We investigated the usefulness of an age-stratified cutoff value of NT-proBNP for diagnosing KD. All the patients enrolled in this study visited Chonnam National University Hospital between December 2007 and March 2016. The KD groups consisted of 214 patients with complete KD and 129 patients with incomplete KD. The control group included 62 children with simple febrile illness but without heart disease. Laboratory data including NT-proBNP level were evaluated. Each group was divided into subgroups according to patient age (24 months), and different cutoff values of NT-proBNP were calculated. The cutoff values of NT-proBNP used to diagnose total KD and incomplete KD were 762 and 762 pg/mL (24 months), respectively. In conclusion, age-stratified NT-proBNP is a useful biomarker for the differential diagnosis of KD in patients with a simple febrile illness.

Background and aim: Severe fever with thrombocytopenia syndrome (SFTS) is a fatal tick-borne infectious disease lacking effective treatments or vaccines. Early identification of prognostic factors is essential for optimizing clinical management. This study investigated the predictors for mortality in SFTS patients. Methods: We conducted a retrospective multicenter cohort study of 413 SFTS patients hospitalized in South Korea from 2013 to 2024. Clinical and laboratory data were comprehensively analyzed to evaluate associations between in-hospital mortality and various inflammatory, immune, and nutritional biomarkers. Cox regression and time-dependent receiver operating characteristic (ROC) analyses were performed to identify risk factors. Results: 413 patients diagnosed with SFTS were included and In-hospital mortality was 17% (70/413). Multivariate Cox regression identified older age (HR: 1.042; 95% CI: 1.014–1.071), elevated PT(INR) (HR: 109.57; 95% CI: 19.79–606.57), and lower prognostic nutritional index (PNI) (HR: 0.937; 95% CI: 0.886–0.990) as early predictors of mortality. Time-dependent ROC analysis demonstrated predictive accuracy, with AUCs of 0.512 for age, 0.857 for PT(INR), and 0.694 for PNI at 30 days. Kaplan-Meier analysis revealed significant survival differences for patients stratified by PNI (< 40.75), PT(INR) (≥ 0.97), and age (≥ 59 years). Conclusions: PNI, PT(INR), and age were identified as key early predictors of mortality in SFTS. PNI, as a novel biomarker, was found to be a useful index for risk level and treatment strategies in SFTS patients. Clinical trial number: Not applicable.

Intensive research has focused on minimizing the infarct area and stimulating endogenous regeneration after myocardial infarction. Our group previously elucidated that apicidin, a histone deacetylase (HDAC) inhibitor, robustly accelerates the cardiac commitment of naïve mesenchymal stem cells (MSCs) through acute loss of YAP1. Here, we propose the novel regulation of YAP1 in MSCs. We found that acute loss of YAP1 after apicidin treatment resulted in the mixed effects of transcriptional arrest and proteasomal degradation. Subcellular fractionation revealed that YAP1 was primarily localized in the cytoplasm. YAP1 was acutely relocalized into the nucleus and underwent proteasomal degradation. Interestingly, phosphor-S127 YAP1 was shuttled into the nucleus, suggesting that a mechanism other than phosphorylation governed the subcellular localization of YAP1. Apicidin successfully induced acetylation and subsequent dissociation of YAP1 from 14-3-3, an essential molecule for cytoplasmic restriction. HDAC6 regulated both acetylation and subcellular localization of YAP1. An acetylation-dead mutant of YAP1 retarded nuclear redistribution upon apicidin treatment. We failed to acquire convincing evidence for polyubiquitination-dependent degradation of YAP1, suggesting that a polyubiquitination-independent regulator determined YAP1 fate. Nuclear PSME4, a subunit of the 26 S proteasome, recognized and degraded acetyl YAP1 in the nucleus. MSCs from PSME4-null mice were injected into infarcted heart, and aberrant sudden death was observed. Injection of immortalized human MSCs after knocking down PSME4 failed to improve either cardiac function or the fibrotic scar area. Our data suggest that acetylation-dependent proteasome subunit PSME4 clears acetyl-YAP1 in response to apicidin treatment in the nucleus of MSCs.