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1.
Disease association and therapeutic routes of aminoacyl-tRNA synthetases.
Yoon, I, Kim, U, Choi, J, Kim, S
Trends in molecular medicine. 2024;(1):89-105
Abstract
Aminoacyl-tRNA synthetases (ARSs) are enzymes that catalyze the ligation of amino acids to tRNAs for translation. Beyond their traditional role in translation, ARSs have acquired regulatory functions in various biological processes (epi-translational functions). With their dual-edged activities, aberrant expression, secretion, and mutations of ARSs are associated with human diseases, including cancer, autoimmune diseases, and neurological diseases. The increasing numbers of newly unveiled activities and disease associations of ARSs have spurred interest in novel drug development, targeting disease-related catalytic and noncatalytic activities of ARSs as well as harnessing ARSs as sources for biological therapeutics. This review speculates how the translational and epi-translational activities of ARSs can be related and describes how their activities can be linked to diseases and drug discovery.
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Intestinal stem cells: guardians of homeostasis in health and aging amid environmental challenges.
Choi, J, Augenlicht, LH
Experimental & molecular medicine. 2024;(3):495-500
Abstract
The intestinal epithelium is the first line of defense and acts as an interface between the vast microbial world within the gastrointestinal tract and the body's internal milieu. The intestinal epithelium not only facilitates nutrient absorption but also plays a key role in defending against pathogens and regulating the immune system. Central to maintaining a healthy epithelium are intestinal stem cells (ISCs), which are essential for replenishing the intestinal epithelium throughout an individual's lifespan. Recent research has unveiled the intricate interplay between ISCs and their niche, which includes various cell types, extracellular components, and signaling molecules. In this review, we delve into the most recent advances in ISC research, with a focus on the roles of ISCs in maintaining mucosal homeostasis and how ISC functionality is influenced by the niche environment. In this review, we explored the regulatory mechanisms that govern ISC behavior, emphasizing the dynamic adaptability of the intestinal epithelium in the face of various challenges. Understanding the intricate regulation of ISCs and the impact of aging and environmental factors is crucial for advancing our knowledge and developing translational approaches. Future studies should investigate the interactive effects of different risk factors on intestinal function and develop strategies for improving the regenerative capacity of the gut.
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Brain control of dual-task walking can be improved in aging and neurological disease.
Holtzer, R, Choi, J, Motl, RW, Foley, FW, Wagshul, ME, Hernandez, ME, Izzetoglu, M
GeroScience. 2024;(3):3169-3184
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Abstract
The peak prevalence of multiple sclerosis has shifted into older age groups, but co-occurring and possibly synergistic motoric and cognitive declines in this patient population are poorly understood. Dual-task-walking performance, subserved by the prefrontal cortex, and compromised in multiple sclerosis and aging, predicts health outcomes. Whether acute practice can improve dual-task walking performance and prefrontal cortex hemodynamic response efficiency in multiple sclerosis has not been reported. To address this gap in the literature, the current study examined task- and practice-related effects on dual-task-walking and associated brain activation in older adults with multiple sclerosis and controls. Multiple sclerosis (n = 94, mean age = 64.76 ± 4.19 years) and control (n = 104, mean age = 68.18 ± 7.01 years) participants were tested under three experimental conditions (dual-task-walk, single-task-walk, and single-task-alpha) administered over three repeated counterbalanced trials. Functional near-infrared-spectroscopy was used to evaluate task- and practice-related changes in prefrontal cortex oxygenated hemoglobin. Gait and cognitive performances declined, and prefrontal cortex oxygenated hemoglobin was higher in dual compared to both single task conditions in both groups. Gait and cognitive performances improved over trials in both groups. There were greater declines over trials in oxygenated hemoglobin in dual-task-walk compared to single-task-walk in both groups. Among controls, but not multiple sclerosis participants, declines over trials in oxygenated hemoglobin were greater in dual-task-walk compared to single-task-alpha. Dual-task walking and associated prefrontal cortex activation efficiency improved during a single session, but improvement in neural resource utilization, although significant, was attenuated in multiple sclerosis participants. These findings suggest encouraging brain adaptability in aging and neurological disease.
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Gut enterotype-dependent modulation of gut microbiota and their metabolism in response to xanthohumol supplementation in healthy adults.
Jamieson, PE, Smart, EB, Bouranis, JA, Choi, J, Danczak, RE, Wong, CP, Paraiso, IL, Maier, CS, Ho, E, Sharpton, TJ, et al
Gut microbes. 2024;(1):2315633
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Abstract
Xanthohumol (XN), a polyphenol found in the hop plant (Humulus lupulus), has antioxidant, anti-inflammatory, prebiotic, and anti-hyperlipidemic activity. Preclinical evidence suggests the gut microbiome is essential in mediating these bioactivities; however, relatively little is known about XN's impact on human gut microbiota in vivo. We conducted a randomized, triple-blinded, placebo-controlled clinical trial (ClinicalTrials.gov NCT03735420) to determine safety and tolerability of XN in healthy adults. Thirty healthy participants were randomized to 24 mg/day XN or placebo for 8 weeks. As secondary outcomes, quantification of bacterial metabolites and 16S rRNA gene sequencing were utilized to explore the relationships between XN supplementation, gut microbiota, and biomarkers of gut health. Although XN did not significantly change gut microbiota composition, it did re-shape individual taxa in an enterotype-dependent manner. High levels of inter-individual variation in metabolic profiles and bioavailability of XN metabolites were observed. Moreover, reductions in microbiota-derived bile acid metabolism were observed, which were specific to Prevotella and Ruminococcus enterotypes. These results suggest interactions between XN and gut microbiota in healthy adults are highly inter-individualized and potentially indicate that XN elicits effects on gut health in an enterotype-dependent manner.
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The addition of evolocumab to maximal tolerated statin therapy improves walking performance in patients with peripheral arterial disease and intermittent claudication (Evol-PAD study).
Clavijo, LC, Caro, J, Choi, J, Caro, JA, Tun, H, Rowe, V, Kumar, SR, Shavelle, DM, Matthews, RV
Cardiovascular revascularization medicine : including molecular interventions. 2023;:1-5
Abstract
OBJECTIVE To test the hypothesis that in patients with peripheral arterial disease (PAD) and claudication, treated with maximal tolerated statin therapy, the addition of a monthly subcutaneous injection of evolocumab for 6 months improves treadmill walking performance. BACKGROUND Lipid lowering therapy improves walking parameters in patients with PAD and claudication. Evolocumab decreases cardiac and limb adverse events in patients with PAD; however, the effect of evolocumab on walking performance is not known. METHODS We performed a double-blind, randomized, placebo-controlled study to compare maximal walking time (MWT) and pain free walking time (PFWT) in patients with PAD and claudication treated with monthly subcutaneous injections of evolocumab 420 mg (n = 35) or placebo (n = 35). We also performed measurements of lower limb perfusion, brachial flow mediated dilatation (FMD), carotid intima media thickness (IMT), and serum biomarkers of PAD disease severity. RESULTS After six-months of treatment with evolocumab MWT increased by 37.7 % (87.5 ± 24 s) compared to 1.4 % (-21.7 ± 22.9 s) in the placebo group, p = 0.01. PFWT increased by 55.3 % (67.3 ± 21.2 s) in the evolocumab group compared to 20.3 % (8.5 ± 20.3 s) in the placebo group, p = 0.051. There was no difference in lower extremity arterial perfusion measurements. FMD increased by 42.0 ± 73.9 % (1.01 ± 0.7 %) in the evolocumab group and decreased by 16.29 ± 20.06 % (0.99 ± 0.68 %) in the placebo group (p < 0.001). IMT decreased by 7.16 ± 4.6 % (0.06 ± 0.04 mm) in the evolocumab group and increased by 6.68 ± 4.9 % (0.05 ± 0.03 mm) in the placebo group, (p < 0.001). CONCLUSIONS The addition of evolocumab to maximal tolerated statin therapy improves maximal walking time in patients with PAD and claudication, increases FMD, and decreases IMT. CONDENSED ABSTRACT Peripheral arterial disease (PAD) impairs quality of life by causing lower extremity intermittent claudication, rest pain, or amputation. Evolocumab is a monthly injectable monoclonal antibody medication that reduces cholesterol. In this study, we randomly treated patients with PAD and claudication, and on background statin therapy, with evolocumab or placebo, and found that evolocumab improves walking performance on a treadmill test by increasing maximal walking time. We also found that evolocumab decreases plasma MRP-14 levels, a marker of PAD severity.
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Effect of a Wearable Device-Based Physical Activity Intervention in North Korean Refugees: Pilot Randomized Controlled Trial.
Kim, JY, Kim, KJ, Kim, KJ, Choi, J, Seo, J, Lee, JB, Bae, JH, Kim, NH, Kim, HY, Lee, SK, et al
Journal of medical Internet research. 2023;:e45975
Abstract
BACKGROUND Effective health interventions for North Korean refugees vulnerable to metabolic disorders are currently unelucidated. OBJECTIVE This study aimed to evaluate the effects of digital health interventions in North Korean refugees using a wearable activity tracker (Fitbit device). METHODS We conducted a prospective, randomized, open-label study on North Korean refugees aged 19-59 years between June 2020 and October 2021 with a 12-week follow-up period. The participants were randomly assigned to either an intervention group or a control group in a 1:1 ratio. The intervention group received individualized health counseling based on Fitbit data every 4 weeks, whereas the control group wore the Fitbit device but did not receive individualized counseling. The primary and secondary outcomes were the change in the mean daily step count and changes in the metabolic parameters, respectively. RESULTS The trial was completed by 52 North Korean refugees, of whom 27 and 25 were in the intervention and control groups, respectively. The mean age was 43 (SD 10) years, and 41 (78.8%) participants were women. Most participants (44/52, 95.7%) had a low socioeconomic status. After the intervention, the daily step count in the intervention group increased, whereas that in the control group decreased. However, there were no significant differences between the 2 groups (+83 and -521 steps in the intervention and control groups, respectively; P=.500). The effects of the intervention were more prominent in the participants with a lower-than-average daily step count at baseline (<11,667 steps/day). After the 12-week study period, 85.7% (12/14) and 46.7% (7/15) of the participants in the intervention and control groups, respectively, had an increased daily step count (P=.05). The intervention prevented the worsening of the metabolic parameters, including BMI, waist circumference, fasting blood glucose level, and glycated hemoglobin level, during the study period. CONCLUSIONS The wearable device-based physical activity intervention did not significantly increase the average daily step count in the North Korean refugees in this study. However, the intervention was effective among the North Korean refugees with a lower-than-average daily step count; therefore, a large-scale, long-term study of this intervention type in an underserved population is warranted. TRIAL REGISTRATION Clinical Research Information Service KCT0007999; https://cris.nih.go.kr/cris/search/detailSearch.do/23622.
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Genome-wide association study of lung adenocarcinoma in East Asia and comparison with a European population.
Shi, J, Shiraishi, K, Choi, J, Matsuo, K, Chen, TY, Dai, J, Hung, RJ, Chen, K, Shu, XO, Kim, YT, et al
Nature communications. 2023;(1):3043
Abstract
Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.
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Impact of probiotics on cognition and constipation in the elderly: A meta-analysis.
Recharla, N, Choi, J, Puligundla, P, Park, SJ, Lee, HJ
Heliyon. 2023;(7):e18306
Abstract
Cognitive decline and constipation are common complications in the elderly. Probiotics are potential therapeutic agents to ameliorate cognitive impairment through gut-brain axis. Several clinical studies have investigated the beneficial effects of probiotics on cognitive impairment and constipation in elderly. However, a quantitative meta-analysis is required to evaluate the efficacy of probiotics on cognitive function and constipation. Thirteen clinical studies were included in this meta-analysis. We examined the risk of bias assessment and heterogeneity of eight studies for cognition and five studies for constipation, followed by group and subgroup meta-analyses using a random-effects model to evaluate the potential of probiotic supplements on cognition function and constipation in aged people. The results of the pooled meta-analysis revealed that probiotic supplementation did not improve the cognitive rating scale assessment for all studies (estimate = 0.13; 95%CI [-0.18, 0.43]; p = 0.41; I2 = 83.51%). However, subgroup analysis of single strain supplementation showed improved cognitive function in elderly people (estimate = 0.35; 95%CI [0.02, 0.69]; p = 0.039; I2 = 19.19%) compared to multiple strains. Probiotics also enhanced defecation frequency in constipated patients (estimate = 0.27; 95%CI [0.05, 0.5]; p = 0.019; I2 = 67.37%). Furthermore, probiotic supplementation resulted in higher fecal Lactobacillus counts than placebo (estimate = 0.37; 95%CI [0.05, 0.69]; p = 0.026; I2 = 21.3%). Subgroup analysis indicated that a probiotic intervention period of ≥4 weeks was more effective (estimate = 0.35; 95%CI [0.01, 0.68]; p = 0.044; I2 = 0%) in reducing constipation symptoms than a short intervention duration. Based on these results, probiotic supplementation could be a potential intervention to reduce constipation symptoms in the elderly population. The heterogeneity between studies is high, and limited trials are available to evaluate the cognitive function of aged individuals using probiotics. Therefore, further studies are required to determine the effect of probiotics on cognition.
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Could Natural Products Help in the Control of Obesity? Current Insights and Future Perspectives.
Park, J, Nurkolis, F, Won, H, Yang, J, Oh, D, Jo, H, Choi, J, Chung, S, Kurniawan, R, Kim, B
Molecules (Basel, Switzerland). 2023;(18)
Abstract
Obesity is a global issue faced by many individuals worldwide. However, no drug has a pronounced effect with few side effects. Green tea, a well-known natural product, shows preventive effects against obesity by decreasing lipogenesis and increasing fat oxidation and antioxidant capacity. In contrast, other natural products are known to contribute to obesity. Relevant articles published on the therapeutic effect of natural products on obesity were retrieved from PubMed, Web of Science, and Scopus. The search was conducted by entering keywords such as "obesity", "natural product", and "clinical trial". The natural products were classified as single compounds, foods, teas, fruits, herbal medicines-single extract, herbal medicines-decoction, and herbal medicines-external preparation. Then, the mechanisms of these medicines were organized into lipid metabolism, anti-inflammation, antioxidation, appetite loss, and thermogenesis. This review aimed to assess the efficacy and mechanisms of effective natural products in managing obesity. Several clinical studies reported that natural products showed antiobesity effects, including Coffea arabica (coffee), Camellia sinensis (green tea), Caulerpa racemosa (green algae), Allium sativum (garlic), combined Ephedra intermedia Schrenk, Thea sinensis L., and Atractylodes lancea DC extract (known as Gambisan), Ephedra sinica Stapf, Angelica Gigantis Radix, Atractylodis Rhizoma Alba, Coicis semen, Cinnamomi cortex, Paeoniae radix alba, and Glycyrrhiza uralensis (known as Euiiyin-tang formula). Further studies are expected to refine the pharmacological effects of natural products for clinical use.
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A phase 1 study of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia or myelodysplastic syndrome.
DiNardo, CD, Hochhaus, A, Frattini, MG, Yee, K, Zander, T, Krämer, A, Chen, X, Ji, Y, Parikh, NS, Choi, J, et al
Journal of cancer research and clinical oncology. 2023;(3):1145-1158
Abstract
PURPOSE Isocitrate dehydrogenase enzyme 1 (IDH1) mutations at 132nd amino acid residue (R132*) result in the cellular accumulation of the oncometabolite, 2-hydroxyglutarate (2-HG). IDH305 is an orally bioavailable, brain-penetrant, mutant-selective allosteric IDH1 inhibitor demonstrating target engagement in preclinical models. This first-in human study was designed to identify the recommended dose for expansion/maximum tolerated dose of IDH305 in patients with IDH1R132-mutant acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). METHODS IDH305 was given at doses 75-750 mg twice daily in 41 patients with IDH1R132-mutant AML/MDS. Dose escalation was designed using Bayesian hierarchical model with overdose control principle and relationship with dose-limiting toxicity. RESULTS IDH305 exhibited rapid absorption with mean T1/2 approximately 4-10 h across doses. Interpatient variability was moderate and exposure increased with dose in a less than dose proportional manner. Most patients (35/41) demonstrated target engagement with reduction in 2-HG concentration at all doses. Complete remission (CR) or CR with incomplete count recovery occurred in 10/37 (27%) patients with AML and 1/ 4 patients with MDS. Adverse events (AEs) suspected to be related to study drug were reported in 53.7% of patients: increased blood bilirubin (14.6%), nausea (14.6%), increased alanine aminotransferase and aspartate aminotransferase (12.2%, each); most frequent grade 3 or 4 AEs were differentiation syndrome and tumor lysis syndrome (n = 3; 7.3%, each). Hepatotoxicity was manageable with dose modification. CONCLUSION Due to potentially narrow therapeutic window, the study was prematurely halted and recommended phase 2 dose could not be declared. TRIAL REGISTRATION Clinicaltrials.gov identifier: NCT02381886.