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Chronic obstructive pulmonary disease (COPD) is a complex pulmonary condition characterized by bronchitis, emphysema, and mucus stasis. Due to the variability in symptoms among patients, traditional approaches to treating COPD as a singular disease are limited. This led us to focus on phenotype/endotype classifications. In this study, we explore the potential therapeutic role of thyroid hormone (T3) by using mouse models: emphysema-dominant elastase-induced COPD and airway-dominant C57BL/6-βENaC-Tg to represent different types of the disease. Here, we showed that intratracheal T3 treatment (40, 80 μg/kg, i.t., every other day) resulted in significant improvements regarding emphysema and the enhancement of respiratory function in the elastase-induced COPD model. T3-dependent improvement is likely linked to the up-regulation of Ppargc1a, a master regulator of mitochondrial biogenesis, and Gclm, a factor associated with oxidative stress. Conversely, neither short- nor long-term T3 treatments improved COPD pathology in the C57BL/6-βENaC-Tg mice. Because the up-regulation of extrathyroidal T3-producing enzyme Dio2, which is also considered a marker of T3 requirement, was specifically observed in elastase-induced COPD lungs, these results demonstrate that exogenous T3 supplementation may have therapeutic potential for acute but not chronic COPD exacerbation. Moreover, this study highlights the relevance of considering not only COPD phenotypes but also COPD endotypes (expression levels of Ppargc1a and/or Dio2) in the research and development of better treatment approaches for COPD. [ABSTRACT FROM AUTHOR]

Transthyretin (TTR) is a homo-tetrameric serum protein associated with sporadic and hereditary systemic amyloidosis. TTR amyloid formation proceeds by the dissociation of the TTR tetramer and the subsequent partial unfolding of the TTR monomer into an aggregation-prone conformation. Although TTR kinetic stabilizers suppress tetramer dissociation, a strategy for stabilizing monomers has not yet been developed. Here, we show that an N-terminal C10S mutation increases the thermodynamic stability of the TTR monomer by forming new hydrogen bond networks through the side chain hydroxyl group of Ser10. Nuclear magnetic resonance spectrometry and molecular dynamics simulation revealed that the Ser10 hydroxyl group forms hydrogen bonds with the main chain amide group of either Gly57 or Thr59 on the DE loop. These hydrogen bonds prevent the dissociation of edge strands in the DAGH and CBEF β-sheets during the unfolding of the TTR monomer by stabilizing the interaction between β-strands A and D and the quasi-helical structure in the DE loop. We propose that introducing hydrogen bonds to connect the N-terminal region to the DE loop reduces the amyloidogenic potential of TTR by stabilizing the monomer. [ABSTRACT FROM AUTHOR]

Alport syndrome (AS) is a hereditary glomerular nephritis caused by mutation in one of the type IV collagen genes α3/α4/α5 that encode the heterotrimer COL4A3/4/5. Failure to form a heterotrimer due to mutation leads to the dysfunction of the glomerular basement membrane, and end-stage renal disease. Previous reports have suggested the involvement of the receptor tyrosine kinase discoidin domain receptor (DDR) 1 in the progression of AS pathology. However, due to the similarity between DDR1 and DDR2, the role of DDR2 in AS pathology is unclear. Here, we investigated the involvement of DDR2 in AS using the X-linked AS mouse model. Mice were treated subcutaneously with saline or antisense oligonucleotide (ASO; 5 mg/kg or 15 mg/kg per week) for 8 weeks. Renal function parameters and renal histology were analyzed, and the gene expressions of inflammatory cytokines were determined in renal tissues. The expression level of DDR2 was highly elevated in kidney tissues of AS mice. Knockdown of Ddr2 using Ddr2-specific ASO decreased the Ddr2 expression. However, the DDR2 ASO treatment did not improve the proteinuria or decrease the BUN level. DDR2 ASO also did not significantly ameliorate the renal injury, inflammation and fibrosis in AS mice. These results showed that Ddr2 knockdown by ASO had no notable effect on the progression of AS indicating that DDR2 may not be critically involved in AS pathology. This finding may provide useful information and further understanding of the role of DDRs in AS. [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is a complex pulmonary condition characterized by bronchitis, emphysema, and mucus stasis. Due to the variability in symptoms among patients, traditional approaches to treating COPD as a singular disease are limited. This led us to focus on phenotype/endotype classifications. In this study, we explore the potential therapeutic role of thyroid hormone (T 3 ) by using mouse models: emphysema-dominant elastase-induced COPD and airway-dominant C57BL/6-βENaC-Tg to represent different types of the disease. Here, we showed that intratracheal T 3 treatment (40, 80 μg/kg, i.t. , every other day) resulted in significant improvements regarding emphysema and the enhancement of respiratory function in the elastase-induced COPD model. T 3 -dependent improvement is likely linked to the up-regulation of Ppargc1a , a master regulator of mitochondrial biogenesis, and Gclm , a factor associated with oxidative stress. Conversely, neither short- nor long-term T 3 treatments improved COPD pathology in the C57BL/6-βENaC-Tg mice. Because the up-regulation of extrathyroidal T 3 -producing enzyme Dio2 , which is also considered a marker of T 3 requirement, was specifically observed in elastase-induced COPD lungs, these results demonstrate that exogenous T 3 supplementation may have therapeutic potential for acute but not chronic COPD exacerbation. Moreover, this study highlights the relevance of considering not only COPD phenotypes but also COPD endotypes (expression levels of Ppargc1a and/or Dio2 ) in the research and development of better treatment approaches for COPD.

Background: Bardoxolone methyl activates nuclear factor erythroid 2-related factor 2 (Nrf2) via covalent binding and irreversible inhibition of Kelch-like ECH-associated protein 1 (Keap1), the negative regulator of Nrf2. Ongoing clinical trials of bardoxolone methyl show promising effects for patients with CKD. However, the direct inhibition of Keap1-Nrf2 protein-protein interaction (PPI) as an approach to activate Nrf2 is less explored., Methods: We developed a noncovalent Nrf2 activator UBE-1099, which highly selectively inhibits Keap1-Nrf2 PPI, and evaluated its efficacy on the progressive phenotype in an Alport syndrome mouse model ( Col4a5 -G5X)., Results: Similar to bardoxolone methyl, UBE-1099 transiently increased proteinuria and reduced plasma creatinine in Alport mice. Importantly, UBE-1099 improved the glomerulosclerosis, renal inflammation, and fibrosis, and prolonged the life span of Alport mice. UBE-1099 ameliorated the dysfunction of Nrf2 signaling in the renal tissue of Alport mice. Moreover, transcriptome analysis in the glomerulus showed that UBE-1099 induced the expression of genes associated with the cell cycle and cytoskeleton, which may explain its unique mechanism of improvement such as glomerular morphologic change., Conclusions: UBE-1099 significantly ameliorates the progressive phenotype in Alport mice. Our results revealed the efficacy of Keap1-Nrf2 PPI inhibitor for glomerulosclerosis and present a potential therapeutic drug for CKD., Competing Interests: H. Kai received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. S. Kaseda received research funding from the Japan Society for the Promotion of Science. T. Shuto reports received research funding from Grants-in-Aid for Scientific Research from the Ministry of Education, Sciences, Sports, and Culture (MEXT) of Japan. All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)