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Abstract Background Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology. Results In this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca2+ mobilization and ERK phosphorylation, by enhancing β-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration. Conclusion Our study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.

Abstract Background Chronic kidney disease (CKD) is a significant health care burden, with a worldwide prevalence of approximately 11%. The general population spends over 50% of the awake time sedentary activities. However, to the best of our knowledge, no study has evaluated the association between sedentary time and CKD, with a focus on both kidney damage and kidney function, in the South Korean population. Accordingly, the present study aimed to address this gap in the knowledge. Method We used data from the 8th Korea National Health and Nutrition Examination Survey. The analysis included 9,534 participants, especially excluded those who had been diagnosed with kidney disease or who were currently undergoing treatment. Sedentary behavior was self-reported by the participants. An estimated glomerular filtration rate (eGFR) and/or albuminuria were used as measures for detection of CKD according to the guidelines of the Kidney Disease Improving Global Outcomes. We analyzed the data using multiple logistic regression. Results Among the women, the risk of CKD was significantly greater among those who sat for ≥ 12 h/d relative to those who sat for

Abstract Background Studies investigating the association between migraine and dementia have reported inconsistent findings. This study aimed to evaluate whether patients with migraine have an increased risk of dementia compared to individuals without migraine. Methods We obtained data from the 2002–2019 Korean National Health Insurance Health Screening Cohort. Non-migraine controls were selected using a 1:1 risk-set matching with a time-dependent propensity score. The main outcome was the development of all-cause dementia, and the secondary outcome was the development of each cause of dementia (Alzheimer’s, vascular, mixed or other specified, and unspecified dementia). The incidence rate of dementia was calculated using Poisson regression, and the association between migraine and dementia was evaluated using Cox proportional hazards regression. Results Among 88,390 participants, 66.1% were female, and the mean baseline age was 55.3 ± 9.4 years. During the study period, dementia cases were identified in 4,800 of the 44,195 patients with migraine and 3,757 of the 44,915 matched controls. The incidence rate of dementia was 139.6 (95% confidence interval [CI], 135.7–143.5) and 107.7 (95% CI, 104.3–111.1) cases per 10,000 person-years in patients with migraine and matched controls, respectively. Patients with migraine had a 1.30 (hazard ratio [HR], 1.30; 95% CI, 1.25–1.35), 1.29 (HR, 1.29; 95% CI, 1.23–1.35), 1.35 (HR, 1.35; 95% CI, 1.19–1.54), 1.36 (HR, 1.36; 95% CI, 1.00–1.83), and 1.30 (HR, 1.30; 95% CI, 1.17–1.45) times higher risk of developing all-cause dementia, Alzheimer’s dementia, vascular dementia, mixed or other specified dementias, and unspecified dementia than their matched controls, respectively. Conclusion Our results suggest that migraine is associated with an increased risk of subsequent dementia. Further research is warranted to confirm these findings and to reveal the underlying mechanisms.

Abstract Background C–C motif chemokine receptor 2 (CCR2), the main receptor for monocyte chemoattractant protein-1 (MCP-1), is expressed on immune cells, including monocytes, macrophages, and activated T cells, and mediates cell migration toward MCP-1 in inflammation-related diseases. The CCR2 gene encodes two isoforms: CCR2A and CCR2B. The CCR2B open reading frame is localized in a single exon, similar to other chemokine receptors, and CCR2A and CCR2B feature different amino acid sequences in their C-terminal intracellular loops due to alternative splicing. Most biochemical studies on CCR2-related cellular responses in the immune system have focused on CCR2B, with few reports focused on CCR2A. Understanding the functional properties of CCR2A in cellular responses may elucidate the roles played by MCP-1 and CCR2 in pathophysiological responses. Results CCR2 gene expression analysis in several cell types revealed that most adherent cells only expressed CCR2A, whereas CCR2B expression was dominant in monocytic cells. The C-terminal Helix 8 region of CCR2A contains few basic amino acids, which may be unfavorable for cell surface localization, as confirmed with the HiBiT assay. CCR2B contains many C-terminal Ser/Thr residues, similar to other chemokine receptors, which may be phosphorylated by G protein–coupled receptor kinases (GRKs) to promote β-arrestin recruitment and subsequent endocytosis. By contrast, CCR2A contains few C-terminal Ser/Thr residues, which are unlikely to be phosphorylated by GRKs. CCR2A localized on the cell surface is resistant to internalization, despite the interaction between Gβ and GRKs induced by ligand binding with CCR2A. CCR2A induced cellular responses at a relatively higher degree than CCR2B, although both receptors mediated signaling events through Gαq and Gαi. HeLa cells lacking CCR2A showed slowed growth compared with parent cells, regardless of MCP-1 stimulation, and their chemotactic activity toward MCP-1, in addition to basal motility, was significantly impaired. Conclusion MCP-1 and CCR2 may play pivotal roles in cancer progression by recruiting macrophages into cancer tissue. This study demonstrates that CCR2A but not CCR2B is expressed in solid cancer–derived cells. CCR2A is resistant to internalization by β-arrestin due to a distinct C-terminal region from CCR2B, which enhances MCP-1-stimulated responses, indicating that CCR2A may play essential roles in solid cancer progression.

Abstract Background Familial partial lipodystrophy (FPLD) is a rare disease characterized by selective loss of peripheral subcutaneous fat, associated with dyslipidemia and diabetes mellitus. Reductions in circulating levels of ANGPTL3 are associated with lower triglyceride and other atherogenic lipids, making it an attractive target for treatment of FPLD patients. This proof-of-concept study was conducted to assess the efficacy and safety of targeting ANGPTL3 with vupanorsen in patients with FPLD. Methods This was an open-label study. Four patients with FPLD (two with pathogenic variants in LMNA gene, and two with no causative genetic variant), diabetes (HbA1c ≥ 7.0 % and ≤ 12 %), hypertriglyceridemia (≥ 500 mg/dL), and hepatic steatosis (hepatic fat fraction, HFF ≥ 6.4 %) were included. Patients received vupanorsen subcutaneously at a dose of 20 mg weekly for 26 weeks. The primary endpoint was the percent change from baseline in fasting triglycerides at Week 27. Other endpoints analyzed at the same time point included changes in ANGPTL3, fasting lipids and lipoproteins, insulin secretion/sensitivity, postprandial lipids, and glycemic changes in response to a mixed meal test, HFF measured by MRI, and body composition measured by dual-energy absorptiometry (DEXA). Results Baseline mean ± SD fasting triglyceride level was 9.24 ± 4.9 mmol/L (817.8 ± 431.9 mg/dL). Treatment resulted in reduction in fasting levels of triglycerides by 59.9 %, ANGPTL3 by 54.7 %, and in several other lipoproteins/lipids, including very low-density lipoprotein cholesterol by 53.5 %, non-high-density lipoprotein cholesterol by 20.9 %, and free fatty acids (FFA) by 41.7 %. The area under the curve for postprandial triglycerides, FFA, and glucose was reduced by 60 %, 32 %, and 14 %, respectively. Treatment with vupanorsen also resulted in 55 % reduction in adipose tissue insulin resistance index, while other insulin sensitivity indices and HbA1c levels were not changed. Additional investigations into HFF and DEXA parameters suggested dynamic changes in fat partitioning during treatment. Adverse events observed were related to common serious complications associated with diabetes and FPLD. Vupanorsen was well tolerated, and there was no effect on platelet count. Conclusions Although limited, these results suggest that targeting ANGPTL3 with vupanorsen could address several metabolic abnormalities in patients with FPLD.

Abstract Background It is unclear whether visual and hearing acuity are independently or synergistically associated with muscle strength. We aimed to examine the associations of visual and self-reported hearing acuity with low handgrip strength and the additive interaction between visual and hearing acuity on low handgrip strength in people over 60 years. Method Data of 3,075 individuals aged over 60 years from the 2017 and 2018 Korea National Health and Nutrition Examination Survey were used for this cross-sectional study. Low handgrip strength was defined based on the 20th percentile of the study population (