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  • 1
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    Online Resource
    Modeling Hypoxic Stress In Vitro Using Human Embryonic Stem Cells Derived Cardiomyocytes Matured by FGF4 and Ascorbic Acid Treatment
    MDPI AG ; 2021
    In:  Cells Vol. 10, No. 10 ( 2021-10-14), p. 2741-
    Details
    In: Cells, MDPI AG, Vol. 10, No. 10 ( 2021-10-14), p. 2741-
    Abstract: Mature cardiomyocytes (CMs) obtained from human pluripotent stem cells (hPSCs) have been required for more accurate in vitro modeling of adult-onset cardiac disease and drug discovery. Here, we found that FGF4 and ascorbic acid (AA) induce differentiation of BG01 human embryonic stem cell–cardiogenic mesoderm cells (hESC-CMCs) into mature and ventricular CMs. Co-treatment of BG01 hESC-CMCs with FGF4+AA synergistically induced differentiation into mature and ventricular CMs. FGF4+AA-treated BG01 hESC-CMs robustly released acute myocardial infarction (AMI) biomarkers (cTnI, CK-MB, and myoglobin) into culture medium in response to hypoxic injury. Hypoxia-responsive genes and potential cardiac biomarkers proved in the diagnosis and prognosis of coronary artery diseases were induced in FGF4+AA-treated BG01 hESC-CMs in response to hypoxia based on transcriptome analyses. This study demonstrates that it is feasible to model hypoxic stress in vitro using hESC-CMs matured by soluble factors.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells10102741
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2661518-6
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  • 2
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    The Activation of the LIMK/Cofilin Signaling Pathway via Extracellular Matrix–Integrin Interactions Is Critical for the Generation of Mature and Vascularized Cardiac Organoids
    MDPI AG ; 2023
    In:  Cells Vol. 12, No. 16 ( 2023-08-09), p. 2029-
    Details
    In: Cells, MDPI AG, Vol. 12, No. 16 ( 2023-08-09), p. 2029-
    Abstract: The generation of mature and vascularized human pluripotent stem cell-derived cardiac organoids (hPSC-COs) is necessary to ensure the validity of drug screening and disease modeling. This study investigates the effects of cellular aggregate (CA) stemness and self-organization on the generation of mature and vascularized hPSC-COs and elucidates the mechanisms underlying cardiac organoid (CO) maturation and vascularization. COs derived from 2-day-old CAs with high stemness (H-COs) and COs derived from 5-day-old CAs with low stemness (L-COs) were generated in a self-organized microenvironment via Wnt signaling induction. This study finds that H-COs exhibit ventricular, structural, metabolic, and functional cardiomyocyte maturation and vessel networks consisting of endothelial cells, smooth muscle cells, pericytes, and basement membranes compared to L-COs. Transcriptional profiling shows the upregulation of genes associated with cardiac maturation and vessel formation in H-COs compared with the genes in L-COs. Through experiments with LIMK inhibitors, the activation of ROCK-LIMK-pCofilin via ECM–integrin interactions leads to cardiomyocyte maturation and vessel formation in H-COs. Furthermore, the LIMK/Cofilin signaling pathway induces TGFβ/NODAL and PDGF pathway activation for the maturation and vascularization of H-COs. The study demonstrates for the first time that LIMK/Cofilin axis activation plays an important role in the generation of mature and vascularized COs.
    Type of Medium: Online Resource
    ISSN: 2073-4409
    URL: Article
    DOI: 10.3390/cells12162029
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2661518-6
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  • 3
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    Online Resource
    Thymosin β4-Enhancing Therapeutic Efficacy of Human Adipose-Derived Stem Cells in Mouse Ischemic Hindlimb Model
    MDPI AG ; 2020
    In:  International Journal of Molecular Sciences Vol. 21, No. 6 ( 2020-03-21), p. 2166-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 21, No. 6 ( 2020-03-21), p. 2166-
    Abstract: Thymosin β4 (Tβ4) is a G-actin sequestering protein that contributes to diverse cellular activities, such as migration and angiogenesis. In this study, the beneficial effects of combined cell therapy with Tβ4 and human adipose-derived stem cells (hASCs) in a mouse ischemic hindlimb model were investigated. We observed that exogenous treatment with Tβ4 enhanced endogenous TMSB4X mRNA expression and promoted morphological changes (increased cell length) in hASCs. Interestingly, Tβ4 induced the active state of hASCs by up-regulating intracellular signaling pathways including the PI3K/AKT/mTOR and MAPK/ERK pathways. Treatment with Tβ4 significantly increased cell migration and sprouting from microbeads. Moreover, additional treatment with Tβ4 promoted the endothelial differentiation potential of hASCs by up-regulating various angiogenic genes. To evaluate the in vivo effects of the Tβ4-hASCs combination on vessel recruitment, dorsal window chambers were transplanted, and the co-treated mice were found to have a significantly increased number of microvessel branches. Transplantation of hASCs in combination with Tβ4 was found to improve blood flow and attenuate limb or foot loss post-ischemia compared to transplantation with hASCs alone. Taken together, the therapeutic application of hASCs combined with Tβ4 could be effective in enhancing endothelial differentiation and vascularization for treating hindlimb ischemia.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms21062166
    Language: English
    Publisher: MDPI AG
    Publication Date: 2020
    detail.hit.zdb_id: 2019364-6
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  • 4
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    Risk Factors for Emergency Department Presentations after the Initiation of Opioid Analgesics in Non-Cancer Patients in Korea: A Nationwide Study
    MDPI AG ; 2023
    In:  Medicina Vol. 59, No. 3 ( 2023-03-07), p. 519-
    Details
    In: Medicina, MDPI AG, Vol. 59, No. 3 ( 2023-03-07), p. 519-
    Abstract: Background and Objectives: Opioid use in Korea is lower than in other developed countries. However, recent studies have reported an increase in opioid prescriptions and the number of chronic opioid users. The current status of adverse events (AEs) associated with opioid analgesics in Korea is unclear. This nested case–control study aimed to evaluate the influence of opioid analgesic use patterns on all emergency department (ED) visits and opioid-related ED visits after opioid analgesic initiation using the national claims database. Materials and Methods: Adult non-cancer patients who initiated non-injectable opioid analgesics (NIOA) between January 2017 and June 2018 were included. We defined the case group as patients who visited the ED within six months of opioid initiation, and the control group was selected in a 1:1 ratio using an exact matching method. Results: A total of 97,735 patients (13.58%) visited the ED within six months of NIOA initiation. Nearly 32% of cases were linked to opioid-related AEs. The most frequent AEs were falls and fractures (61.27%). After adjusting for covariates, opioid initiation at the ED was associated with all-cause or opioid-related ED visits (adjusted odds ratio (aOR) = 3.19, 95% confidence interval (CI) = 3.09–3.29; aOR = 3.82, 95% CI = 3.62–4.04, respectively). Chronic NIOA use was associated with all-cause and opioid-related ED visits (aOR = 1.32, 95% CI = 1.23–1.40; aOR = 1.56, 95% CI = 1.39–1.76, respectively). Conclusion: This study found that 13% of non-cancer patients visited the ED within six months of NIOA initiation. In addition, the NIOA use pattern was significantly associated with all-cause and opioid-related ED visits.
    Type of Medium: Online Resource
    ISSN: 1648-9144
    URL: Article
    DOI: 10.3390/medicina59030519
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2088820-X
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  • 5
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    Online Resource
    Development and Validation of Enzyme-Linked Immunosorbent Assay for Group B Streptococcal Polysaccharide Vaccine
    MDPI AG ; 2021
    In:  Vaccines Vol. 9, No. 6 ( 2021-05-21), p. 545-
    Details
    In: Vaccines, MDPI AG, Vol. 9, No. 6 ( 2021-05-21), p. 545-
    Abstract: Streptococcus agalactiae (group B Streptococcus, GBS) is a leading cause of neonatal sepsis and meningitis in infants. Limitations of prenatal GBS screening and intrapartum antibiotic prophylaxis render developing GBS vaccines a high priority. In this study, we developed an enzyme-linked immunosorbent assay (ELISA) for the practical and large-scale evaluation of GBS capsular polysaccharide (PS) vaccine immunogenicity against three main serotypes, Ia, III, and V. GBS-ELISA was developed and subsequently validated using a standardized curve-fitting four-parameter logistic method. Specificity was measured using adsorption of serum with homologous and heterologous PS. Homologous adsorption showed a ≥75% inhibition of all three serotypes, whereas with heterologous PS, IgG GBS-ELISA inhibited only ≤25% of serotypes III and V. However, with serotype Ia, IgG antibody levels decreased by 〉 50%, even after adsorption with heterologous PS (III or V). In comparison, the inhibition opsonophagocytic killing assay (OPA) of serotypes Ia GBS exhibited a reduction in opsonophagocytic activity of only 20% and 1.1% for serotypes III and V GBS, respectively. The precision of the GBS-ELISA was assessed in five independent experiments using four serum samples. The coefficient of variation was 〈 5% for all three serotypes. This standardized GBS-ELISA would be useful for GBS vaccine development and its evaluation.
    Type of Medium: Online Resource
    ISSN: 2076-393X
    URL: Article
    DOI: 10.3390/vaccines9060545
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2703319-3
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  • 6
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    Synthetic TGF-β Signaling Agonist-Treated Dendritic Cells Induce Tolerogenicity and Antirheumatic Effects
    MDPI AG ; 2022
    In:  Current Issues in Molecular Biology Vol. 44, No. 9 ( 2022-08-24), p. 3809-3821
    Details
    In: Current Issues in Molecular Biology, MDPI AG, Vol. 44, No. 9 ( 2022-08-24), p. 3809-3821
    Abstract: The newly synthesized compound TGF-β signaling agonist (T74) is a small molecule associated with the TGF-β receptor signaling pathway. Tolerogenic dendritic cells (tDCs) have been used to examine immunosuppressive and anti-inflammatory effects in multiple autoimmune disease models. The aim of this study was to investigate whether treatment of DCs with T74 has an antirheumatic effect in a mouse model of collagen-induced arthritis (CIA). Bone marrow-derived cells were obtained from DBA/1J mice and differentiated into DCs. T74-treated DCs (T74-DCs) were generated by treating bone marrow-derived DCs with LPS, type II collagen, and T74. T74-DCs expressed lower levels of surface molecules and inflammatory cytokines associated with antigen presentation and T cell stimulation. The ability of T74-DCs to differentiate effector T cells was lower than that of T74-untreated DCs (NT-DCs), but T74-DCs increased the regulatory T (Treg) cell differentiation in vitro. DBA/1J mice received two subcutaneous (s.c.) injections of type II collagen to establish CIA. Mice then received two s.c. injections of T74-DCs or NT-DCs. Joint inflammation was ameliorated in the paws of T74-DC-treated mice. Additionally, Treg populations in T74-DC-treated mice were higher than in NT-DC-treated or PBS-treated CIA mice. Taken together, these results demonstrate that T74 induces tolerance in DCs, and that T74-mediated DCs exert antirheumatic effects via induction of Tregs.
    Type of Medium: Online Resource
    ISSN: 1467-3045
    URL: Article
    DOI: 10.3390/cimb44090261
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2090836-2
    SSG: 12
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  • 7
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    Pharmacokinetics of a Fixed-Dose Combination Product of Dapagliflozin and Linagliptin and Its Comparison with Co-Administration of Individual Tablets in Healthy Humans
    MDPI AG ; 2022
    In:  Pharmaceutics Vol. 14, No. 3 ( 2022-03-08), p. 591-
    Details
    In: Pharmaceutics, MDPI AG, Vol. 14, No. 3 ( 2022-03-08), p. 591-
    Abstract: Dapagliflozin, a selective sodium–glucose co-transporter-2 inhibitor, and linagliptin, a competitive, reversible dipeptidyl peptidase-4 inhibitor, are commonly prescribed antidiabetic medications in general clinics. Since there are several merits to combining them in a fixed-dose combination product, this study investigated the pharmacokinetic equivalence between the individual component (IC) and fixed-combination drug product (FCDP) forms of dapagliflozin and linagliptin. A randomized, open-label, single-dose crossover study was conducted. All participants (n = 48) were randomly allocated to group A (period 1: ICs, period 2: FCDP) or group B (period 1: FCDP, period 2: ICs), and each group received either a single dose of IN-C009 (FCDP) or single doses of both dapagliflozin and linagliptin. There was no statistically significant difference found between the pharmacokinetic variables of FCDP and IC. The values of estimated geometric mean ratios and the 90% confidence interval for both maximum concentration and area under the plasma drug concentration–time curve were within the range of 0.8–1.25 for both dapagliflozin and linagliptin. The results of the clinical study demonstrated comparable pharmacokinetic characteristics between IC and FCDP forms of dapagliflozin and linagliptin. The combined use of dapagliflozin and linagliptin was safe and tolerable in both formulations.
    Type of Medium: Online Resource
    ISSN: 1999-4923
    URL: Article
    DOI: 10.3390/pharmaceutics14030591
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2527217-2
    SSG: 15,3
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  • 8
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    Gene Dose-Dependent and Additive Effects of ABCG2 rs2231142 and SLC2A9 rs3733591 Genetic Polymorphisms on Serum Uric Acid Levels
    MDPI AG ; 2022
    In:  Metabolites Vol. 12, No. 12 ( 2022-11-29), p. 1192-
    Details
    In: Metabolites, MDPI AG, Vol. 12, No. 12 ( 2022-11-29), p. 1192-
    Abstract: This study aimed to evaluate whether the single nucleotide polymorphisms of ATP-binding cassette subfamily G member 2 (ABCG2) and solute carrier family 2 member 9 (SLC2A9) affect individual blood uric acid levels using pyrosequencing. ABCG2 (rs2231142, rs72552713, rs2231137), SLC2A9 (rs3734553, rs3733591, rs16890979), and individual uric acid levels were prospectively analyzed in 250 healthy young Korean male participants. Prominent differences in uric acid levels of the alleles were observed in the SLC2A9 rs3733591 polymorphism: wild-type (AA) vs. heterozygote (AG), 0.7 mg/dL (p 〈 0.0001); AA vs. mutant type (GG), 1.32 mg/dL (p 〈 0.0001); and AG vs. GG, 0.62 mg/dL (p 〈 0.01). In ABCG2 single nucleotide polymorphisms (SNPs), the statistically significant differences in uric acid levels were only found in rs2231142 between CC vs. AA (1.06 mg/dL; p 〈 0.001), and CC vs. CA (0.59 mg/dL; p 〈 0.01). Serum uric acid levels based on the ABCG2 and SLC2A9 diplotype groups were also compared. The uric acid levels were the lowest in the CC/AA diplotype and highest in the AA/AG diplotype. In addition, the SNP SLC2A9 rs3733591 tended to increase the uric acid levels when the ABCG2 rs2231142 haplotypes were fixed. In conclusion, both the ABCG2 rs2231142 and SLC2A9 rs3733591 polymorphisms may additively elevate blood uric acid levels.
    Type of Medium: Online Resource
    ISSN: 2218-1989
    URL: Article
    DOI: 10.3390/metabo12121192
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662251-8
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  • 9
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    SFRP4 and CDX1 Are Predictive Genes for Extragastric Recurrence of Early Gastric Cancer after Curative Resection
    MDPI AG ; 2022
    In:  Journal of Clinical Medicine Vol. 11, No. 11 ( 2022-05-29), p. 3072-
    Details
    In: Journal of Clinical Medicine, MDPI AG, Vol. 11, No. 11 ( 2022-05-29), p. 3072-
    Abstract: Extragastric recurrence of early gastric cancer (EGC) after curative resection is rare, but prognosis has been poor in previous reports. Recently, single patient classifier (SPC) genes, such as secreted frizzled-related protein 4 (SFRP4) and caudal-type homeobox 1 (CDX1), were associated with prognosis and chemotherapy response in stage II–III gastric cancer. The aim of our study is, therefore, to elucidate predictive factors for extragastric recurrence of EGC after curative resection, including with the expression of SPC genes. We retrospectively reviewed electronic medical records of 1974 patients who underwent endoscopic or surgical curative resection for EGC. We analyzed clinicopathological characteristics to determine predictive factors for extragastric recurrence. Total RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue and amplified by real-time reverse transcription polymerase chain reaction to evaluate expression of SPC genes. Overall incidences of extragastric recurrence were 0.9%. In multivariate analysis, submucosal invasion (odds ratio [OR] = 6.351, p = 0.032) and N3 staging (OR = 171.512, p = 0.012) were independent predictive factors for extragastric recurrence. Mean expression of SFRP4 in extragastric recurrence (−2.8 ± 1.3) was significantly higher than in the control group (−4.3 ± 1.6) (p = 0.047). Moreover, mean expression of CDX1 in extragastric recurrence (−4.6 ± 2.0) was significantly lower than in the control group (−2.4 ± 1.8) (p = 0.025). Submucosal invasion and metastasis of more than seven lymph nodes were independent predictive factors for extragastric recurrence. In addition, SFRP4 and CDX1 may be novel predictive markers for extragastric recurrence of EGC after curative resection.
    Type of Medium: Online Resource
    ISSN: 2077-0383
    URL: Article
    DOI: 10.3390/jcm11113072
    Language: English
    Publisher: MDPI AG
    Publication Date: 2022
    detail.hit.zdb_id: 2662592-1
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  • 10
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    Optimal Preclinical Conditions for Using Adult Human Multipotent Neural Cells in the Treatment of Spinal Cord Injury
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 5 ( 2021-03-04), p. 2579-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 5 ( 2021-03-04), p. 2579-
    Abstract: Stem cell-based therapeutics are amongst the most promising next-generation therapeutic approaches for the treatment of spinal cord injury (SCI), as they may promote the repair or regeneration of damaged spinal cord tissues. However, preclinical optimization should be performed before clinical application to guarantee safety and therapeutic effect. Here, we investigated the optimal injection route and dose for adult human multipotent neural cells (ahMNCs) from patients with hemorrhagic stroke using an SCI animal model. ahMNCs demonstrate several characteristics associated with neural stem cells (NSCs), including the expression of NSC-specific markers, self-renewal, and multi neural cell lineage differentiation potential. When ahMNCs were transplanted into the lateral ventricle of the SCI animal model, they specifically migrated within 24 h of injection to the damaged spinal cord, where they survived for at least 5 weeks after injection. Although ahMNC transplantation promoted significant locomotor recovery, the injection dose was shown to influence treatment outcomes, with a 1 × 106 (medium) dose of ahMNCs producing significantly better functional recovery than a 3 × 105 (low) dose. There was no significant gain in effect with the 3 × 106 ahMNCs dose. Histological analysis suggested that ahMNCs exert their effects by modulating glial scar formation, neuroprotection, and/or angiogenesis. These data indicate that ahMNCs from patients with hemorrhagic stroke could be used to develop stem cell therapies for SCI and that the indirect injection route could be clinically relevant. Moreover, the optimal transplantation dose of ahMNCs defined in this preclinical study might be helpful in calculating its optimal injection dose for patients with SCI in the future.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms22052579
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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