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  • 1
    Online Resource
    Online Resource
    Identification of New Non-BBB Permeable Tryptophan Hydroxylase Inhibitors for Treating Obesity and Fatty Liver Disease
    MDPI AG ; 2022
    In:  Molecules Vol. 27, No. 11 ( 2022-05-25), p. 3417-
    Details
    In: Molecules, MDPI AG, Vol. 27, No. 11 ( 2022-05-25), p. 3417-
    Abstract: Serotonin (5-hydroxytryptophan) is a hormone that regulates emotions in the central nervous system. However, serotonin in the peripheral system is associated with obesity and fatty liver disease. Because serotonin cannot cross the blood-brain barrier (BBB), we focused on identifying new tryptophan hydroxylase type I (TPH1) inhibitors that act only in peripheral tissues for treating obesity and fatty liver disease without affecting the central nervous system. Structural optimization inspired by para-chlorophenylalanine (pCPA) resulted in the identification of a series of oxyphenylalanine and heterocyclic phenylalanine derivatives as TPH1 inhibitors. Among these compounds, compound 18i with an IC50 value of 37 nM was the most active in vitro. Additionally, compound 18i showed good liver microsomal stability and did not significantly inhibit CYP and Herg. Furthermore, this TPH1 inhibitor was able to actively interact with the peripheral system without penetrating the BBB. Compound 18i and its prodrug reduced body weight gain in mammals and decreased in vivo fat accumulation.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules27113417
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2008644-1
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  • 2
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    Sleep-Enhancing Effect of Water Extract from Jujube (Zizyphus jujuba Mill.) Seeds Fermented by Lactobacillus brevis L32
    MDPI AG ; 2023
    In:  Foods Vol. 12, No. 15 ( 2023-07-27), p. 2864-
    Details
    In: Foods, MDPI AG, Vol. 12, No. 15 ( 2023-07-27), p. 2864-
    Abstract: Although Ziziphus jujuba Mill (jujube) is used in folk medicine for hypnotic sedative, anxiolytic, and many other purposes, to date, only a few studies have revealed its sleep-promoting effects and related mechanisms. Currently, drugs used for the treatment of sleep disorders have various side effects, so it is essential to develop safe natural materials. Therefore, we evaluated the sleep-enhancing activity and mechanism of action of an aqueous extract of jujube seeds (ZW) fermented with Lactobacillus brevis L-32 in rodent models. The starch contained in ZW was removed by enzymatic degradation and fermented with L. brevis to obtain a fermented product (ZW-FM) with a high γ-aminobutyric acid (GABA) content. To evaluate the sleep-promoting effect of ZW-FM, pentobarbital-induced sleep tests were performed on ICR mice, and electroencephalography analysis was undertaken in Sprague Dawley rats. Additionally, the awakening relief effects of ZW-FM were confirmed in a caffeine-induced insomnia model. Finally, the mechanism of sleep enhancement by ZW-FM was analyzed using GABA receptor type A (GABAA) antagonists. The ZW-FM-treated groups (100 and 150 mg/kg) showed increased sleep time, especially the δ-wave time during non-rapid eye movement (NREM) sleep. In addition, the 150 mg/kg ZW-FM treatment group showed decreased sleep latency and increased sleep time in the insomnia model. In particular, NREM sleep time was increased and REM sleep time, which was increased by caffeine treatment, was decreased by ZW-FM treatment. ZW-FM-induced sleep increase was inhibited by the GABAA receptor antagonists picrotoxin, bicuculline, and flumazenil, confirming that the increase was the result of a GABAergic mechanism. These results strongly suggest that the increased GABA in water extract from jujube seeds fermented by L. brevis acts as a sleep-promoting compound and that the sleep-promoting activity is related to GABAA receptor binding.
    Type of Medium: Online Resource
    ISSN: 2304-8158
    URL: Article
    DOI: 10.3390/foods12152864
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2704223-6
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  • 3
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    Online Resource
    Underweight and Weight Change Increases End-Stage Renal Disease Risk in Patients with Diabetes: A Nationwide Population-Based Cohort Study
    MDPI AG ; 2021
    In:  Nutrients Vol. 14, No. 1 ( 2021-12-29), p. 154-
    Details
    In: Nutrients, MDPI AG, Vol. 14, No. 1 ( 2021-12-29), p. 154-
    Abstract: Weight variability has known as a risk factor for cardiovascular events and mortality. However, its effect on end-stage renal disease (ESRD) development remains controversial. We investigated the relationship between weight change and ESRD risk. Overall, 97,029 patients with DM aged 〉 20 years were selected from the Korean National Health Screening Program 2009–2012. Weight change was defined as differences in body weight from the index year to 2 years later. Newly diagnosed ESRD was observed until 2017 end. Over a 5.1-year median follow-up period, ESRD was newly diagnosed in 7932 (4.81%) DM patients. BMI 〈 18.5 kg/m2 and waist circumferences 〈 85/80 and 〉 100/95 cm were ESRD risk factors. ESRD risk increased with increasing weight change; ≥10% weight loss (hazard ratio [HR], 1.247) followed by ≥10% weight gain (1.247) was associated with a higher HR than ≤5% weight change after adjusting for several confounding factors. The association between weight change and ESRD risk in a subgroup analysis was significantly stronger in patients aged 〈 65 years, without proteinuria, with BMI ≥ 25, with DM duration 〈 5 years, and prescribed less than 3 classes of DM medication. Underweight patients showed higher ESRD risks than overweight patients. Weight loss 〉 10% was associated with the fastest decline in renal function.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu14010154
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2518386-2
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  • 4
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    Online Resource
    Bone Mineral Density and All-Cause Mortality in Patients with Nondialysis Chronic Kidney Disease: Results from KNOW-CKD Study
    MDPI AG ; 2023
    In:  Journal of Clinical Medicine Vol. 12, No. 5 ( 2023-02-25), p. 1850-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 12, No. 5 ( 2023-02-25), p. 1850-
    Abstract: Despite the clear association between low BMD and all-cause mortality in the general population, the association has not been validated in patients with nondialysis CKD. To investigate the association of low BMD with all-cause mortality in this population, a total of 2089 patients with nondialysis CKD at stages 1 to predialysis 5 were categorized into normal BMD (T-score ≥ −1.0), osteopenia (−2.5 〈 T-score 〈 −1.0), and osteoporosis (T-score ≤ − 2.5) by the BMD at femoral neck. The study outcome was all-cause mortality. Kaplan–Meier curve depicted a significantly increased number of all-cause death events in the subjects with osteopenia or osteoporosis during the follow-up period compared with subjects with normal BMD. Cox regression models demonstrated that osteoporosis, but not osteopenia, was significantly associated with an increased risk of all-cause mortality (adjusted hazard ratio 2.963, 95% confidence interval 1.655 to 5.307). Smoothing curve fitting model visualized a clear inverse correlation between BMD T-score and the risk of all-cause mortality. Even after recategorizing the subjects by BMD T-scores at total hip or lumbar spine, the result was similar to the primary analyses. Subgroup analyses revealed that the association was not significantly modified by clinical contexts, such as age, gender, body mass index, estimated glomerular filtration rate, and albuminuria. In conclusion, low BMD is associated with an increased risk of all-cause mortality in patients with nondialysis CKD. This emphasizes that the routine measurement of BMD by DXA may confer an additional benefit beyond the prediction of fracture risk in this population.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm12051850
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2662592-1
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  • 5
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    Online Resource
    Urinary Angiotensinogen and Progression of Chronic Kidney Disease: Results from KNOW-CKD Study
    MDPI AG ; 2022
    In:  Biomolecules Vol. 12, No. 9 ( 2022-09-10), p. 1280-
    Details
    In: Biomolecules, MDPI AG, Vol. 12, No. 9 ( 2022-09-10), p. 1280-
    Abstract: The prognostic value of urinary angiotensinogen (UAGT) in patients with chronic kidney disease (CKD) has not been completely evaluated, although the association of UAGT with renal outcomes has been suggested in specific subsets of CKD. In the present study, to investigate the association of UAGT with renal outcomes in patients with non-dialysis CKD irrespective of the primary cause, a total of 1688 subjects from the Korean Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD) were prospectively analyzed. The subjects were divided into the quintile by UAGT to urine creatinine ratio (UAGT/Cr) level. The primary outcomes of interest were composite renal event, which included decline in kidney function and onset of end-stage renal disease during follow-up periods. The median follow-up duration was 6.257 years. Cox regression model analysis unveiled that the risk of composite renal event was significantly higher in the fifth quintile (adjusted hazard ratio 1.528, 95% confidence interval 1.156 to 2.021) compared to that of the first quartile. The association between high UAGT/Cr level and adverse renal outcome remained consistent in sensitivity analyses, including the analysis of the cause-specific hazard model. Subgroup analyses revealed that the association of UAGT level with renal outcomes is modified by certain clinical contexts, such as BMI and albuminuria. In conclusion, high UAGT level is associated with adverse renal outcomes in patients with non-dialysis CKD. Further studies are warranted to elaborate and expand the predictive role of UAGT as a biomarker for renal outcomes in CKD.
    Type of Medium: Online Resource
    ISSN: 2218-273X
    URL: Article
    DOI: 10.3390/biom12091280
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2701262-1
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  • 6
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    Online Resource
    In Vitro Prebiotic Effects of Malto-Oligosaccharides Containing Water-Soluble Dietary Fiber
    MDPI AG ; 2020
    In:  Molecules Vol. 25, No. 21 ( 2020-11-09), p. 5201-
    Details
    In: Molecules, MDPI AG, Vol. 25, No. 21 ( 2020-11-09), p. 5201-
    Abstract: This study measured the proliferative activity of malto-oligosaccharide (MOS) as a prebiotic against Bifidobacteria, resistance to digestion in vitro, and changes during in vitro fermentation by human fecal microorganisms. It consisted of 21.74%, 18.84%, and 11.76% of maltotriose, maltotetraose, and maltopentaose produced by amylase (HATT), respectively. When 1% of MOS was added to a modified PYF medium as the carbon source, proliferation of Bifidobacterium breve was increased significantly. During the in vitro digestion test, MOS was partially degraded by intestinal enzymes. Fermentation characteristics by human fecal microorganisms were evaluated by adding 1% galacto-oligosaccharide (GOS), as well as 1% and 2% MOS as carbon sources to the basal medium, respectively. In comparison with the addition of 1% of MOS and GOS, the total short chain fatty acid (SCFA) content increased over time when 2% of MOS was added. The species diversity and richness of intestinal microbiota increased significantly with 2% MOS compared to those with 1% GOS. In addition, the 2% addition of MOS reduced intestinal pathobiont microorganisms and increased commensal microorganisms including Bifidobacterium genus. Collectively, MOS produced by amylase increased the SCFA production and enhanced the growth of beneficial bacteria during in vitro fermentation by human fecal microbiota.
    Type of Medium: Online Resource
    ISSN: 1420-3049
    URL: Article
    DOI: 10.3390/molecules25215201
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
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  • 7
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    Online Resource
    Changes in the Diversity of Human Skin Microbiota to Cosmetic Serum Containing Prebiotics: Results from a Randomized Controlled Trial
    MDPI AG ; 2020
    In:  Journal of Personalized Medicine Vol. 10, No. 3 ( 2020-08-17), p. 91-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 10, No. 3 ( 2020-08-17), p. 91-
    Abstract: Prebiotic treatment may rebalance the skin microbiota by regulating the growth of harmful and beneficial microorganisms. In this randomized, double-blind, placebo-controlled clinical trial (N = 60), we evaluated the effects of a cosmetic serum containing galacto-oligosaccharides (GOS) on the balance of the skin microbiota by measuring various skin parameters. The skin water-holding capacity between the control (ND) and experimental (NF) groups was significantly different after 8 weeks of serum treatment (p 〈 0.05). Similarly, changes in transepidermal water loss (TEWL) and the erythema index in the ND and NF groups were significantly different (p 〈 0.05). Furthermore, the wrinkle depth and Staphylococcus aureus population decreased in the NF group compared with those in the ND group (p 〈 0.05). The mean form factor, Shannon index, and Pediococcus population were significantly increased in the post-NF group compared with those in the post-ND group (p 〈 0.05). Finally, in the ND group, water-holding capacity was positively correlated with Enhydrobacter, whereas Enterobacteriaceae was negatively correlated with TEWL in the NF group. These results suggest that GOS inhibit the growth of harmful skin microbes and increase the population of beneficial microbes.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm10030091
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2662248-8
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  • 8
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    Online Resource
    Predictive Model for High Coronary Artery Calcium Score in Young Patients with Non-Dialysis Chronic Kidney Disease
    MDPI AG ; 2021
    In:  Journal of Personalized Medicine Vol. 11, No. 12 ( 2021-12-15), p. 1372-
    Details
    In: Journal of Personalized Medicine, MDPI AG, Vol. 11, No. 12 ( 2021-12-15), p. 1372-
    Abstract: Cardiovascular disease is a major complication of chronic kidney disease. The coronary artery calcium (CAC) score is a surrogate marker for the risk of coronary artery disease. The purpose of this study is to predict outcomes for non-dialysis chronic kidney disease patients under the age of 60 with high CAC scores using machine learning techniques. We developed the predictive models with a chronic kidney disease representative cohort, the Korean Cohort Study for Outcomes in Patients with Chronic Kidney Disease (KNOW-CKD). We divided the cohort into a training dataset (70%) and a validation dataset (30%). The test dataset incorporated an external dataset of patients that were not included in the KNOW-CKD cohort. Support vector machine, random forest, XGboost, logistic regression, and multi-perceptron neural network models were used in the predictive models. We evaluated the model’s performance using the area under the receiver operating characteristic (AUROC) curve. Shapley additive explanation values were applied to select the important features. The random forest model showed the best predictive performance (AUROC 0.87) and there was a statistically significant difference between the traditional logistic regression model and the test dataset. This study will help identify patients at high risk of cardiovascular complications in young chronic kidney disease and establish individualized treatment strategies.
    Type of Medium: Online Resource
    ISSN: 2075-4426
    URL: Article
    DOI: 10.3390/jpm11121372
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
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  • 9
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    Online Resource
    Urinary Phosphorus Excretion and Cardiovascular Outcomes in Patients with Pre-Dialysis Chronic Kidney Disease: The KNOW-CKD Study
    MDPI AG ; 2023
    In:  Nutrients Vol. 15, No. 10 ( 2023-05-10), p. 2267-
    Details
    In: Nutrients, MDPI AG, Vol. 15, No. 10 ( 2023-05-10), p. 2267-
    Abstract: The relationship between 24-h urinary phosphorus excretion (24 h UPE) and cardiovascular disease in patients with pre-dialysis chronic kidney disease (CKD) has rarely been studied, despite the fact that the relationship between serum phosphorus level and the risk of a cardiovascular event is well established. A total of 1701 patients with pre-dialysis CKD were finally included for the analyses and were divided into tertiles by 24 h UPE (first tertile (T1, 349.557 (mean) ± 88.413 (standard deviation)), second tertile (T2, 557.530 ± 50.738), and third tertile (T3, 851.695 ± 171.593). The study outcome was a six-point major adverse cardiac event (MACE). The median follow-up duration was 7.992 years. Kaplan–Meier curve analysis visualized that the cumulative incidences of a six-point MACE (p = 0.029) significantly differed from 24 h UPE levels, as the incidence rate of the study outcomes was highest in T1 and lowest in T3. Cox proportional hazard models unveiled that, compared to T1, the risk of a six-point MACE was significantly decreased in T3 (adjusted hazard ratio (HR) 0.376, 95% confidence interval (CI) 0.207 to 0.683). The restricted cubic spline curve analysis visualized an inverted S-shaped association between 24 h UPE level and the risk of a six-point MACE, indicating a significantly increased risk of a six-point MACE in patients with a low 24 h UPE level. In conclusion, low 24 h UPE is associated with adverse cardiovascular outcomes in patients with CKD. Our finding emphasizes that low 24 h UPE should not be a reliable marker for dietary restriction of phosphorus that essentially leads to better outcomes in patients with CKD.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu15102267
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2518386-2
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  • 10
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    Non-High-Density Lipoprotein Cholesterol and Progression of Chronic Kidney Disease: Results from the KNOW-CKD Study
    MDPI AG ; 2022
    In:  Nutrients Vol. 14, No. 21 ( 2022-11-07), p. 4704-
    Details
    In: Nutrients, MDPI AG, Vol. 14, No. 21 ( 2022-11-07), p. 4704-
    Abstract: As the relation between serum non-high-density lipoprotein cholesterol (nHDL) level and renal outcomes has never been investigated in patients with non-dialysis chronic kidney disease (CKD) yet, we here aimed to unveil the association of nHDL with CKD progression. A total of 2152 patients with non-dialysis CKD at stages 1 to 5 from the KNOW-CKD study were categorized into the tertile (i.e., 1st (T1), 2nd (T2), and 3rd (T3) tertiles) by nHDL, and were prospectively analyzed. The primary outcome was the composite renal event, defined as a composite of decline of kidney function or onset of end-stage renal disease. Kaplan–Meier survival curves analysis demonstrated that the cumulative incidence of the composite renal event was significantly increased in T1 and T3, compared to T2 (p = 0.028, by Log-rank test). Cox regression analysis revealed that both T1 (adjusted hazard ratio 1.309, 95% confidence interval 1.074–1.595) and T3 (adjusted hazard ratio 1.272, 95% confidence interval 1.040–1.556) are associated with significantly increased risk of a composite renal event, compared to T2. The restricted cubic spline plot demonstrated a non-linear, U-shaped association between nHDL and the risk of a composite renal event. In conclusion, both low and high serum nHDL levels are associated with increased risk of CKD progression.
    Type of Medium: Online Resource
    ISSN: 2072-6643
    URL: Article
    DOI: 10.3390/nu14214704
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2518386-2
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