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Recent advancements in machine learning potentials (MLPs) have significantly impacted the fields of chemistry, physics, and biology by enabling large-scale first-principles simulations. Among different machine learning approaches, kernel-based MLPs distinguish themselves through their ability to handle small datasets, quantify uncertainties, and minimize over-fitting. Nevertheless, their extensive computational requirements present considerable challenges. To alleviate these, sparsification methods have been developed, aiming to reduce computational scaling without compromising accuracy. In the context of isothermal and isobaric ML molecular dynamics (MD) simulations, achieving precise pressure estimation is crucial for reproducing reliable system behavior under constant pressure. Despite progress, sparse kernel MLPs struggle with precise pressure prediction. Here, we introduce a virial kernel function that significantly enhances the pressure estimation accuracy of MLPs. Additionally, we propose the active sparse Bayesian committee machine (BCM) potential, an on-the-fly MLP architecture that aggregates local sparse Gaussian process regression (SGPR) MLPs. The sparse BCM potential overcomes the steep computational scaling with the kernel size, and a predefined restriction on the size of kernel allows for fast and efficient on-the-fly training. Our advancements facilitate accurate and computationally efficient machine learning-enhanced MD (MLMD) simulations across diverse systems, including ice-liquid coexisting phases, Li10Ge(PS6)2 lithium solid electrolyte, and high-pressure liquid boron nitride.
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Background: Research on job training and job satisfaction has been conducted from various perspectives. Job training is thought to be associated with job satisfaction, which is known as an important factor for depression among workers. We hypothesized that job training duration could influence depression through potential mediators (job satisfaction, motivation to work, and work engagement). Methods: This study encompassed participants from the sixth Korean Working Conditions Survey (KWCS), conducted between 2020 and 2021. To show the relationships between demographic or occupational characteristics and risk of depression, a χ2 test was conducted. The association between job training duration, potential mediators, and risk of depression was analyzed by constructing multiple logistic regression models. The mediating effects of potential mediators on job training duration and risk of depression was evaluated with flexible mediation analysis with weighting-based methods. Results: The final study population consisted of 25,294 participants. Longer job training duration significantly decreased risk of depression after adjusting for confounders. In the group that received the longest job training duration (≥ 10 days), compared with the group without job training, the odds ratio (OR) for high risk of depression was 0.46 (95% confidence interval [CI], 0.39-0.54). Each three potential mediators showed statistically significant indirect effects and direct effect. Although indirect effects were not strong compared to direct effect, motivation to work had the strongest mediating effect in this study, with an OR of 0.94 (95% CI, 0.92-0.95). Conclusions: Job training duration was found to have a statistically significant negative association on the risk of depression, and three mediators partially mediating this effect. Although the mechanism was unknown, our findings suggest that job training has a positive influence on workers' mental health. Furthermore, by suggesting the possibility of other pathways existing between job training and depression, we provide directions for future research.
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Background: Cardio-cerebrovascular diseases (CVDs) are the most common cause of death worldwide. Various CVD risk assessment tools have been developed. In South Korea, the Korea Occupational Safety & Health Agency (KOSHA) and the National Health Insurance Service (NHIS) have provided CVD risk assessments with health checkups. Since 2018, the KOSHA guide has stated that NHIS CVD risk assessment tool could be used as an alternative of KOSHA assessment tool for evaluating CVD risk of workers. The objective of this study was to determine the correlation and agreement between the KOSHA and the NHIS CVD risk assessment tools. Methods: Subjects of this study were 17,485 examinees aged 20 to 64 years who had undergone medical examinations from January 2021 to December 2021 at a general hospital. We classified subjects into low-risk, moderate-risk, high-risk, and highest-risk groups according to KOSHA and NHIS's CVD risk assessment tools. We then compared them with cross-analysis, Spearman correlation analysis, and linearly weighted kappa coefficient. Results: The correlation between KOSHA and NHIS tools was statistically significant (p-value < 0.001), with a correlation coefficient of 0.403 and a kappa coefficient of 0.203. When we compared risk group distribution using KOSHA and NHIS tools, CVD risk of 6,498 (37.1%) participants showed a concordance. Compared to the NHIS tool, the KOSHA tool classified 9,908 (56.7%) participants into a lower risk category and 1,079 (6.2%) participants into a higher risk category. Conclusions: In this study, KOSHA and NHIS tools showed a moderate correlation with a fair agreement. The NHIS tool showed a tendency to classify participants to higher CVD risk group than the KOSHA tool. To prevent CVD more effectively, a higher estimation tool among verified CVD risk assessment methods should be selected and managements such as early intervention and treatment of risk factors should be performed targeting the high-risk group.
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Nigrospora (Xylariales, Apiosporaceae) consists of species of terrestrial plant endophytes and pathogens. Nigrospora has also been reported in marine environments such as mangroves, sea fans, and macroalgae. However, limited research has been conducted on Nigrospora associated with macroalgae. Here, we isolated Nigrospora species from three types of algae (brown, green, and red algae) from Korean islands (Chuja, Jeju, and Ulleung) based on phylogenetic analyses of multigenetic markers: the internal transcribed spacers (ITS), beta-tubulin (BenA), and translation elongation factor 1 (TEF1-α). A total of 17 Nigrospora strains were isolated from macroalgae and identified as nine distinct species. The majority of Nigrospora species (seven) were found on brown algae, followed by red algae (three), and then green algae (two). To our understanding, this study represents the first account of N. cooperae, N. covidalis, N. guilinensis, N. lacticolonia, N. osmanthi, N. pyriformis, and N. rubi occurring in marine environments. Additionally, this study provides the first report of the occurrence of N. cooperae, N. covidalis, N. guilinensis, N. lacticolonia, and N. osmanthi in South Korea. This study will provide valuable insights for future research exploring the functions of fungi in macroalgal communities.
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Glioblastoma (GBM) is the most lethal brain cancer with a dismal prognosis. Stem-like GBM cells (GSCs) are a major driver of GBM propagation and recurrence; thus, understanding the molecular mechanisms that promote GSCs may lead to effective therapeutic approaches. Through in vitro clonogenic growth-based assays, we determined mitogenic activities of the ligand molecules that are implicated in neural development. We have identified that semaphorin 3A (Sema3A), originally known as an axon guidance molecule in the CNS, promotes clonogenic growth of GBM cells but not normal neural progenitor cells (NPCs). Mechanistically, Sema3A binds to its receptor neuropilin-1 (NRP1) and facilitates an interaction between NRP1 and TGF-ß receptor 1 (TGF-ßR1), which in turn leads to activation of canonical TGF-ß signaling in both GSCs and NPCs. TGF-ß signaling enhances self-renewal and survival of GBM tumors through induction of key stem cell factors, but it evokes cytostatic responses in NPCs. Blockage of the Sema3A/NRP1 axis via shRNA-mediated knockdown of Sema3A or NRP1 impeded clonogenic growth and TGF-ß pathway activity in GSCs and inhibited tumor growth in vivo. Taken together, these findings suggest that the Sema3A/NRP1/TGF-ßR1 signaling axis is a critical regulator of GSC propagation and a potential therapeutic target for GBM.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Semaforina-3A/metabolismo , Semaforina-3A/farmacologia , Glioblastoma/patologia , Neuropilina-1/genética , Neoplasias Encefálicas/patologia , Fator de Crescimento Transformador betaRESUMO
Despite years of research into its pathobiology and continuing clinical trials for novel therapies, the prognosis for patients with glioblastoma (GBM) remains dismal. An important obstacle against treatment efficacy may be a high degree of intra- and inter-tumoral heterogeneity within GBMs, which may be caused by the presence of self-renewing GBM stem cells (GSCs). Recent advances in multi-omics technology introduce new possibilities for applying personalized strategies to GBM therapy. As drug discovery is accelerating with the transition from non-selective, cytotoxic therapy to a precision, targeted approach, the appropriate in vivo platform for GBM is critical for validating drug targets and prioritizing candidates for clinical studies, for co-development of companion diagnostics and, ultimately, for drug approval. Here we will describe GBM orthotopic patient-derived xenografts (PDXs) as more useful, clinically relevant resources for individually tailored strategies for GBM.
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Neoplasias Encefálicas , Glioblastoma , Medicina de Precisão/métodos , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , Animais , Humanos , Medicina de Precisão/tendênciasRESUMO
Small non-coding RNAs called miRNAs are key regulators in various biological processes, including tumor initiation, propagation, and metastasis in glioblastoma as well as other cancers. Recent studies have shown the potential for oncogenic miRNAs as therapeutic targets in glioblastoma. However, the application of antisense oligomers, or anti-miRs, to the brain is limited due to the blood-brain barrier (BBB), when administered in the traditional systemic manner. To induce a therapeutic effect in glioblastoma, anti-miR therapy requires a robust and effective delivery system to overcome this obstacle. To bypass the BBB, different delivery administration methods for anti-miRs were evaluated. Stereotaxic surgery was performed to administer anti-Let-7 through intratumoral (ITu), intrathecal (ITh), and intraventricular (ICV) routes, and each method's efficacy was determined by changes in the expression of anti-Let-7 target genes as well as by immunohistochemical analysis. ITu administration of anti-miRs led to a high rate of anti-miR delivery to tumors in the brain by both bolus and continuous administration. In addition, ICV administration, compared with ITu administration, showed a greater distribution of the miR across entire brain tissues. This study suggests that local administration methods are a promising strategy for anti-miR treatment and may overcome current limitations in the treatment of glioblastoma in preclinical animal models.
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Antagomirs/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Encefálicas/tratamento farmacológico , Glioblastoma/tratamento farmacológico , MicroRNAs/antagonistas & inibidores , Animais , Barreira Hematoencefálica , Humanos , Injeções Intraventriculares , Injeções Espinhais , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The EGFR-targeted monoclonal antibodies are a valid therapeutic strategy for patients with metastatic colorectal cancer (mCRC). However, only a small subset of mCRC patients has therapeutic benefits and there are high demands for EGFR therapeutics with a broader patient pool and more potent efficacy. In this study, we report GC1118 exhibiting a different character in terms of binding epitope, affinity, mode of action, and efficacy from other anti-EGFR antibodies. Structural analysis of the EGFR-GC1118 crystal complex revealed that GC1118 recognizes linear, discrete N-terminal epitopes of domain III of EGFR, critical for EGF binding but not overlapping with those of other EGFR-targeted antibodies. GC1118 exhibited superior inhibitory activity against high-affinity EGFR ligands in terms of EGFR binding, triggering EGFR signaling, and proliferation compared with cetuximab and panitumumab. EGFR signaling driven by low-affinity ligands, on the contrary, was well inhibited by all the antibodies tested. GC1118 demonstrated robust antitumor activity in tumor xenografts with elevated expression of high-affinity ligands in vivo, whereas cetuximab did not. Considering the significant role of high-affinity EGFR ligands in modulating tumor microenvironment and inducing resistance to various cancer therapeutics, our study suggests a potential therapeutic advantage of GC1118 in terms of efficacy and a range of benefited patient pool. Mol Cancer Ther; 15(2); 251-63. ©2015 AACR.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Antineoplásicos/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Epitopos/metabolismo , Receptores ErbB/química , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/metabolismo , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Feminino , Humanos , Ligantes , Camundongos , Modelos Moleculares , Ligação Proteica , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Glioblastoma (GBM) is the most aggressive and most lethal brain tumor. As current standard therapy consisting of surgery and chemo-irradiation provides limited benefit for GBM patients, novel therapeutic options are urgently required. Forkhead box M1 (FoxM1) transcription factor is an oncogenic regulator that promotes the proliferation, survival, and treatment resistance of various human cancers. The roles of FoxM1 in GBM remain incompletely understood, due in part to pleotropic nature of the FoxM1 pathway. Here, we show the roles of FoxM1 in GBM stem cell maintenance and radioresistance. ShRNA-mediated FoxM1 inhibition significantly impeded clonogenic growth and survival of patient-derived primary GBM cells with marked downregulation of Sox2, a master regulator of stem cell phenotype. Ectopic expression of Sox2 partially rescued FoxM1 inhibition-mediated effects. Conversely, FoxM1 overexpression upregulated Sox2 expression and promoted clonogenic growth of GBM cells. These data, with a direct binding of FoxM1 in the Sox2 promoter region in GBM cells, suggest that FoxM1 regulates stemness of primary GBM cells via Sox2. We also found significant increases in FoxM1 and Sox2 expression in GBM cells after irradiation both in vitro and in vivo orthotopic tumor models. Notably, genetic or a small-molecule FoxM1 inhibitor-mediated FoxM1 targeting significantly sensitized GBM cells to irradiation, accompanying with Sox2 downregulation. Finally, FoxM1 inhibition combined with irradiation in a patient GBM-derived orthotopic model significantly impeded tumor growth and prolonged the survival of tumor bearing mice. Taken together, these results indicate that the FoxM1-Sox2 signaling axis promotes clonogenic growth and radiation resistance of GBM, and suggest that FoxM1 targeting combined with irradiation is a potentially effective therapeutic approach for GBM.
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Neoplasias Encefálicas/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Fatores de Transcrição Forkhead/genética , Glioblastoma/patologia , Fatores de Transcrição SOXB1/genética , Animais , Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/terapia , Proteína Forkhead Box M1 , Fatores de Transcrição Forkhead/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica , Glioblastoma/mortalidade , Glioblastoma/terapia , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Células-Tronco Neoplásicas/citologia , Regiões Promotoras Genéticas/genética , Interferência de RNA , RNA Interferente Pequeno , Tolerância a Radiação/genética , Fatores de Transcrição SOXB1/biossíntese , Transdução de Sinais/genéticaRESUMO
Vascular endothelial growth factor (VEGF) and its receptors are considered the primary cause of tumor-induced angiogenesis. Specifically, VEGFR-2/kinase insert domain receptor (KDR) is part of the major signaling pathway that plays a significant role in tumor angiogenesis, which is associated with the development of various types of tumor and metastasis. In particular, KDR is involved in tumor angiogenesis as well as cancer cell growth and survival. In this study, we evaluated the therapeutic potential of TTAC-0001, a fully human antibody against VEGFR-2/KDR. To assess the efficacy of the antibody and pharmacokinetic (PK) relationship in vivo, we tested the potency of TTAC-0001 in glioblastoma and colorectal cancer xenograft models. Antitumor activity of TTAC-0001 in preclinical models correlated with tumor growth arrest, induction of tumor cell apoptosis, and inhibition of angiogenesis. We also evaluated the combination effect of TTAC-0001 with a chemotherapeutic agent in xenograft models. We were able to determine the relationship between PK and the efficacy of TTAC-0001 through in vivo single-dose PK study. Taken together, our data suggest that targeting VEGFR-2 with TTAC-0001 could be a promising approach for cancer treatment.
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Anticorpos Monoclonais/imunologia , Neoplasias/imunologia , Neovascularização Patológica/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/imunologia , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais Humanizados , Antineoplásicos/imunologia , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Área Sob a Curva , Linhagem Celular Tumoral , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/imunologia , Glioblastoma/metabolismo , Células HCT116 , Células HT29 , Humanos , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias/irrigação sanguínea , Neoplasias/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/prevenção & controle , Resultado do Tratamento , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The present study was conducted to investigate the effects of resveratrol on the insulin signaling pathway in the liver of obese mice. To accomplish this, we administered resveratrol to high fat diet-induced obese mice and examined the levels of protein phosphorylation in the liver using an antibody array. The phosphorylation levels of 10 proteins were decreased in the high fat diet and resveratrol (HFR) fed group relative to the levels in the high fat diet (HF) fed group. In contrast, the phosphorylation levels of more than 20 proteins were increased in the HFR group when compared with the levels of proteins in the HF group. Specifically, the phosphorylation levels of Akt (The308, Tyr326, Ser473) were restored to normal by resveratrol when compared with the levels in the HF group. In addition, the phosphorylation levels of IRS-1 (Ser636/Ser639), PI-3K p85-subunit α/γ (Tyr467/Tyr199), PDK1 (Ser241), GSK-3α (S21) and GSK-3 (Ser9), which are involved in the insulin signaling pathway, were decreased in the HF group, whereas the levels were restored to normal in the HFR group. Overall, the results show that resveratrol restores the phosphorylation levels of proteins involved in the insulin signaling pathway, which were decreased by a high fat diet.
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Anti-Inflamatórios/farmacologia , Insulina/fisiologia , Fígado/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Imunofluorescência , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Fosforilação , Proteínas/metabolismo , ResveratrolRESUMO
Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.
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Anti-Inflamatórios/farmacologia , Resistência à Insulina/fisiologia , Insulina/fisiologia , Transdução de Sinais/efeitos dos fármacos , Estilbenos/farmacologia , Células 3T3-L1 , Proteínas Quinases Ativadas por AMP/metabolismo , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Animais , Western Blotting , Células Cultivadas , Meios de Cultivo Condicionados , Gorduras na Dieta/farmacologia , Inflamação/metabolismo , Fígado/citologia , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/induzido quimicamente , Obesidade/metabolismo , Fosforilação , Reação em Cadeia da Polimerase em Tempo Real , ResveratrolRESUMO
In our previous study, an anti-angiotensin I converting enzyme (ACE) peptide (Ala-His-Ile-Ile-Ile, MW: 565.3Da) was isolated from Styela clava flesh tissue. In this study the fractions obtained during the isolation process and the finally purified peptide were examined to see if they had vasorelaxation effects in isolated rat aortas, and then the peptide was investigated for anti-hypertensive effect in spontaneously hypertensive rats (SHRs). The induction of vasorelaxation in the rat aortas was observed with the isolated fractions and the peptide from the enzymatic hydrolysate of S. clava flesh tissue and could be markedly blocked by pretreatment with the nitric oxide synthase (NOS) inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME). In human endothelial cells, NO synthesis was found to be increased and eNOS phosphorylation was upregulated when the cells were cultured with the purified peptide. Furthermore, systolic blood pressure was reduced by administration of the potent vasorelaxation peptide in SHRs.
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Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Anti-Hipertensivos/administração & dosagem , Hipertensão/tratamento farmacológico , Óxido Nítrico/metabolismo , Peptídeos/administração & dosagem , Urocordados/química , Vasodilatação/efeitos dos fármacos , Sequência de Aminoácidos , Inibidores da Enzima Conversora de Angiotensina/química , Animais , Anti-Hipertensivos/química , Aorta/efeitos dos fármacos , Aorta/fisiopatologia , Pressão Sanguínea/efeitos dos fármacos , Humanos , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Técnicas In Vitro , Masculino , Dados de Sequência Molecular , Óxido Nítrico Sintase/metabolismo , Peptídeos/química , Peptidil Dipeptidase A/metabolismo , Ratos , Ratos Endogâmicos SHR , Ratos Sprague-Dawley , Vasodilatadores/administração & dosagem , Vasodilatadores/químicaRESUMO
Cooking processes that gelatinize granules or disrupt structure might increase the glucose and insulin responses because a disruption of the structure of starch by gelatinization increases its availability for digestion and absorption in the small intestine. We hypothesized that the uncooked form of rice, which has a relatively low degree of gelatinization even though in powder form, would result in lower metabolic glucose and insulin responses compared with cooked rice (CR). To assess the effects of the gelatinization of rice on metabolic response of glucose and insulin, we investigated the glucose and insulin responses to 3 rice meals of different gelatinization degree in female college students (n = 12): CR (76.9% gelatinized), uncooked rice powder (UP; 3.5% gelatinized), and uncooked freeze-dried rice powder (UFP; 5.4% gelatinized). Uncooked rice powders (UP and UFP) induced lower glucose and insulin responses compared with CR. The relatively low gelatinization degree of UPs resulted in low metabolic responses in terms of the glycemic index (CR: 72.4% vs UP: 49.7%, UFP: 59.8%) and insulin index (CR: 94.8% vs UP: 74.4%, UFP: 68.0%). In summary, UPs that were less gelatinized than CR induced low postprandial glucose and insulin responses.