Humoral Immune Response of Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Prime-Boost Vaccination against SARS-CoV-2 Variants in Korea.

The immunogenicity of a heterologous vaccination regimen consisting of ChAdOx1 nCoV-19 (a chimpanzee adenovirus-vectored vaccine) followed by mRNA-1273 (a lipid-nanoparticle-encapsulated mRNA-based vaccine) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the omicron variant (B.1.1.529), is poorly studied. The aim of this study was to evaluate the neutralizing antibody activity and immunogenicity of heterologous ChAdOx1 nCoV-19 and mRNA-1273 prime-boost vaccination against wild-type (BetaCoV/Korea/KCDC03/2020), alpha, beta, gamma, delta, and omicron variants of SARS-CoV-2 in Korea. A 50% neutralizing dilution (ND50) titer was determined in serum samples using the plaque reduction neutralization test. Antibody titer decreased significantly at 3 months compared with that at 2 weeks after the 2nd dose. On comparing the ND50 titers for the above-mentioned variants of concerns, it was observed that the ND50 titer for the omicron variant was the lowest. This study provides insights into cross-vaccination effects and can be useful for further vaccination strategies in Korea.

Skeletal Lipocalin-2 Is Associated with Iron-Related Oxidative Stress in ob/ob Mice with Sarcopenia.

Obesity and insulin resistance accelerate aging-related sarcopenia, which is associated with iron load and oxidative stress. Lipocalin-2 (LCN2) is an iron-binding protein that has been associated with skeletal muscle regeneration, but details regarding its role in obese sarcopenia remain unclear. Here, we report that elevated LCN2 levels in skeletal muscle are linked to muscle atrophy-related inflammation and oxidative stress in leptin-deficient ob/ob mice. RNA sequencing analyses indicated the LCN2 gene expression is enhanced in skeletal muscle of ob/ob mice with sarcopenia. In addition to muscular iron accumulation in ob/ob mice, expressions of iron homeostasis-related divalent metal transporter 1, ferritin, and hepcidin proteins were increased in ob/ob mice compared to lean littermates, whereas expressions of transferrin receptor and ferroportin were reduced. Collectively, these findings demonstrate that LCN2 functions as a potent proinflammatory factor in skeletal muscle in response to obesity-related sarcopenia and is thus a therapeutic candidate target for sarcopenia treatment.

PARP1 and PRC2 double deficiency promotes BRCA-proficient breast cancer growth by modification of the tumor microenvironment.

Poly (ADP-ribose) polymerase 1 (PARP1) and polycomb-repressive complex 2 (PRC2) are each known for their individual roles in cancer, but their cooperative roles have only been studied in the DNA damage repair process in the context of BRCA-mutant cancers. Here, we show that simultaneous inhibition of PARP1 and PRC2 in the MDA-MB-231 BRCA-proficient triple-negative breast cancer (TNBC) cell line leads to a synthetic viability independent of the mechanisms of DNA damage repair. Specifically, we find that either genetic depletion or pharmacological inhibition of both PARP1 and PRC2 can accelerate tumor growth rate. We attribute this to modifications in the tumor microenvironment (TME) that are induced by double-depleted breast cancer cells, such as promoting intratumoral angiogenesis and increasing the proportion of tumor-promoting type 2 (M2) macrophages. These changes subsequently inhibit cell death and promote proliferation. Mechanistically, we find that PARP1 and PRC2 double depletion induces not only a basal activation of the NF-κB pathway but also a maximal activation of NF-κB within the TME in response to external stimuli such as hypoxia and the presence of macrophages. In summary, our study reveals an unprecedented synthetic viable interaction between PARP1 and PRC2 in BRCA-proficient TNBC and identifies NF-κB as the downstream mediator. DATABASE: RNA-seq data are available in the GEO databases under the accession GSE142769.

The Role of SHIP1 on Apoptosis and Autophagy in the Adipose Tissue of Obese Mice.

Obesity-induced adipocyte apoptosis promotes inflammation and insulin resistance. Src homology domain-containing inositol 5'-phosphatase 1 (SHIP1) is a key factor of apoptosis and inflammation. However, the role of SHIP1 in obesity-induced adipocyte apoptosis and autophagy is unclear. We found that diet-induced obesity (DIO) mice have significantly greater crown-like structures and terminal deoxynucleotidyl transferase deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive cells than ob/ob or control mice. Using RNA sequencing (RNA-seq) analysis, we identified that the apoptosis- and inflammation-related gene Ship1 is upregulated in DIO and ob/ob mice compared with control mice. In particular, DIO mice had more SHIP1-positive macrophages and lysosomal-associated membrane protein 1 (LAMP1) as well as a higher B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 ratio compared with ob/ob or control mice. Furthermore, caloric restriction attenuated adipose tissue inflammation, apoptosis, and autophagy by reversing increases in SHIP1-associated macrophages, Bax/Bcl2-ratio, and autophagy in DIO and ob/ob mice. These results demonstrate that DIO, not ob/ob, aggravates adipocyte inflammation, apoptosis, and autophagy due to differential SHIP1 expression. The evidence of decreased SHIP1-mediated inflammation, apoptosis, and autophagy indicates new therapeutic approaches for obesity-induced chronic inflammatory diseases.

Caloric restriction reverses left ventricular hypertrophy through the regulation of cardiac iron homeostasis in impaired leptin signaling mice.

Leptin-deficient and leptin-resistant mice manifest obesity, insulin resistance, and left ventricular hypertrophy (LVH); however, LVH's mechanisms are not fully understood. Cardiac iron dysregulation has been recently implicated in cardiomyopathy. Here we investigated the protective effects of caloric restriction on cardiac remodeling in impaired leptin signaling obese mice. RNA-seq analysis was performed to assess the differential gene expressions in the heart of wild-type and ob/ob mice. In particular, to investigate the roles of caloric restriction on iron homeostasis-related gene expressions, 10-week-old ob/ob and db/db mice were assigned to ad libitum or calorie-restricted diets for 12 weeks. Male ob/ob mice exhibited LVH, cardiac inflammation, and oxidative stress. Using RNA-seq analysis, we identified that an iron uptake-associated gene, transferrin receptor, was upregulated in obese ob/ob mice with LVH. Caloric restriction attenuated myocyte hypertrophy, cardiac inflammation, fibrosis, and oxidative stress in ob/ob and db/db mice. Furthermore, we found that caloric restriction reversed iron homeostasis-related lipocalin 2, divalent metal transporter 1, transferrin receptor, ferritin, ferroportin, and hepcidin expressions in the heart of ob/ob and db/db mice. These findings demonstrate that the cardioprotective effects of caloric restriction result from the cellular regulation of iron homeostasis, thereby decreasing oxidative stress, inflammation, and cardiac remodeling. We suggest that decreasing iron-mediated oxidative stress and inflammation offers new therapeutic approaches for obesity-induced cardiomyopathy.

Hippocampal Lipocalin 2 Is Associated With Neuroinflammation and Iron-Related Oxidative Stress in ob/ob Mice.

Obesity causes brain injuries with inflammatory and structural changes, leading to neurodegeneration. Although increased circulating lipocalin 2 (LCN2) level has been implicated in neurodegenerative diseases, the precise mechanism of neurodegeneration in obesity is not clear. Here, we investigated whether LCN2-mediated signaling promotes neurodegeneration in the hippocampus of leptin-deficient ob/ob mice, which are characterized by obesity, insulin resistance, systemic inflammation, and neuroinflammation. In particular, there was significant upregulation of both LCN2 and matrix metalloproteinase 9 levels from serum and hippocampus in ob/ob mice. Using RNA-seq analysis, we found that neurodegeneration- sortilin-related receptor 1 (Sorl1) and brain-derived neurotrophic factor (Bdnf) genes were significantly reduced in the hippocampus of ob/ob mice. We additionally found that the endosome-related WD repeat and FYVE-domain-containing 1 (Wdfy1) gene were upregulated in ob/ob mice. In particular, iron overload-related mitochondrial ferritin and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) proteins were increased in the hippocampus of ob/ob. Thus, these findings indicate that iron-binding protein LCN2-mediated oxidative stress promotes neurodegeneration in ob/ob mice.

Association between Use of Nutritional Labeling and the Metabolic Syndrome and Its Components.

In this study, we looked into the association between the diagnosis of metabolic syndrome (MetS) and nutritional label awareness. This study used data from the Korea National Health and Nutritional Examination Survey (KNHANES) for the years 2007 to 2015. The study population consisted of a total of 41,667 Koreans of which 11,401 (27.4%) were diagnosed with metabolic syndrome and 30,266 (72.6%) were not. Groups not using nutritional labeling had a 24% increase in odds risk (OR: 1.24, 95% CI 1.14-1.35) of MetS compared to groups using nutritional labeling. Use of nutritional labeling was associated with all components of MetS. Central obesity showed the highest increase in odds risk (OR: 1.23, 95% CI 1.13-1.35) and high blood pressure showed the lowest increase in odds risk (OR: 1.11, 95% CI 1.02-1.20). Subgroup analysis revealed that statistically significant factors were smoking status, drinking status and stress status. Groups that smoke, groups that do not drink and groups with high stress were more vulnerable to MetS when not using nutritional labeling. People not using food labels tends to develop metabolic syndromes more than people using foods labels. In the subgroup analysis, drinking status, smoking status and stress status were significant factors.