Control of fibrosis with enhanced safety via asymmetric inhibition of prolyl-tRNA synthetase 1.

Prolyl-tRNA synthetase 1 (PARS1) has attracted much interest in controlling pathologic accumulation of collagen containing high amounts of proline in fibrotic diseases. However, there are concerns about its catalytic inhibition for potential adverse effects on global protein synthesis. We developed a novel compound, DWN12088, whose safety was validated by clinical phase 1 studies, and therapeutic efficacy was shown in idiopathic pulmonary fibrosis model. Structural and kinetic analyses revealed that DWN12088 binds to catalytic site of each protomer of PARS1 dimer in an asymmetric mode with different affinity, resulting in decreased responsiveness at higher doses, thereby expanding safety window. The mutations disrupting PARS1 homodimerization restored the sensitivity to DWN12088, validating negative communication between PARS1 promoters for the DWN12088 binding. Thus, this work suggests that DWN12088, an asymmetric catalytic inhibitor of PARS1 as a novel therapeutic agent against fibrosis with enhanced safety.

Nucleotide Excision Repair, XPA-1, and the Translesion Synthesis Complex, POLZ-1 and REV-1, Are Critical for Interstrand Cross-Link Repair in Caenorhabditis elegans Germ Cells.

Interstrand cross-links (ICLs) are adducts of covalently linked nucleotides in opposing DNA strands that obstruct replication and prime cells for malignant transformation or premature cell death. ICLs may be caused by alkylating agents or ultraviolet (UV) irradiation. These toxic lesions are removed by diverse repair mechanisms such as the Fanconi anemia (FA) pathway, nucleotide excision repair (NER), translesion synthesis (TLS), and homologous recombination (HR). In mammals, the xeroderma pigmentosum group F (XP-F) protein participates in both the FA pathway and NER, while DNA polymerase ζ (POLZ-1) and REV-1 mediate TLS. Nevertheless, little is known regarding the genetic determinants of these pathways in ICL repair and damage tolerance in germ cells. In this study, we examined the sensitivity of Caenorhabditis elegans germ cells to ICLs generated by trimethylpsoralen/ultraviolet A (TMP/UV-A) combination, and embryonic mortality was employed as a surrogate for DNA damage in germ cells. Our results show that XPA-1, POLZ-1, and REV-1 were more critical than FA pathway mediators in preserving genomic stability in C. elegans germ cells. Notably, mutant worms lacking both XPA-1 and POLZ-1 (or REV-1) were more sensitive to ICLs compared to either single mutant alone. Moreover, knockdown of XPA-1 and REV-1 leads to the retarded disappearance of RPA-1 and RAD-51 foci upon ICL damage. Since DNA repair mechanisms are broadly conserved, our findings may have ramifications for prospective therapeutic interventions in humans.

Association between Cigarette Smoking and Sarcopenia according to Obesity in the Middle-Aged and Elderly Korean Population: The Korea National Health and Nutrition Examination Survey (2008-2011).

BACKGROUND: The definition of sarcopenia focuses on muscle mass and function. Sarcopenic obesity is the relative excess of fat tissue with decreased muscle mass. We examined the association between cigarette smoking and sarcopenia according to obesity in middle-aged and elderly Koreans. METHODS: We conducted a cross-sectional study of 9,385 subjects (age ≥50 years) based on data from the fourth and fifth Korea National Health and Nutrition Examination Surveys (2008-2011). Smoking groups were categorized by smoking status and the number of cigarettes smoked daily. Sarcopenia was defined as weight-adjusted appendicular skeletal muscle mass of 2 standard deviations below the sex-specific mean for young adults. Obesity was defined as fat mass ≥30% for men and ≥40% for women. Subjects were categorized into three groups: sarcopenic obese (SO), sarcopenic non-obese (SNO), and normal. Multiple logistic regression analysis was performed to assess the association between smoking and SNO and SO. RESULTS: Among men, current smokers were more associated with SNO than never-smokers (adjusted odds ratio [OR], 3.34; 95% confidence interval [CI], 1.09-10.26). However, there was no significant association between smoking status and SNO in women or SO in either sex. Among current smokers, moderate smokers (11-20 cigarettes/d) were more likely to be SNO (adjusted OR, 5.81; 95% CI, 1.12-30.31) and heavy smokers (>20 cigarettes/d) were more likely to be SO (adjusted OR, 9.53; 95% CI, 1.65-55.01) than light smokers (<11 cigarettes/d). CONCLUSION: In men, smoking was positively associated with SNO, and heavy smokers were more likely to be SO than light smokers.

Relationship between Coffee Consumption and Metabolic Syndrome in Korean Adults: Data from the 2013-2014 Korea National Health and Nutrition Examination Survey.

BACKGROUND: The gradually increasing demand for coffee worldwide has prompted increased interest in the relationship between coffee and health issues as well as a need for research on metabolic syndrome in adults. METHODS: Data from 3,321 subjects (1,268 men and 2,053 women) enrolled in the 2013-2014 Korean National Health and Nutrition Examination Survey were analyzed. The subjects were divided into three groups according to their daily coffee consumption. The odds ratios (ORs) and 95% confidence intervals (95% CIs) for metabolic syndrome in the coffee-drinking groups were calculated using multiple logistic regression analysis by adjusting for confounding variables. RESULTS: The prevalence of metabolic syndrome was 15.5%, 10.7%, and 9.7% in men and 3.0%, 7.1%, and 6.5% in women according to their coffee consumption (less than one, one or two, or more than three cups of coffee per day), respectively. Compared with the non-coffee consumption group, the ORs (95% CIs) for metabolic syndrome in the group that consumed more than three cups of coffee was 0.638 (0.328-1.244) for men and 1.344 (0.627-2.881) for women after adjusting for age, body mass index, household income, education, smoking, alcohol, regular exercise, and daily caloric intake. CONCLUSION: The OR of metabolic syndrome was not statistically significant in both men and women.