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1.
J Obstet Gynaecol Res ; 50(8): 1383-1391, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38777330

RESUMO

OBJECTIVE: This study aimed to examine maternal and neonatal factors in cesarean deliveries due to dystocia, including cephalopelvic disproportion, latent-phase prolongation, and fetal malposition or malpresentation. Additionally, we sought to compare the differences between the dystocia subgroups. METHOD AND MATERIALS: This retrospective case-control study included women who delivered between January 2010 and June 2021 after 37 weeks of pregnancy and underwent abdominal-pelvic CT scans within 5 years before and after delivery. Neonatal factors were extracted from medical charts immediately after delivery. RESULTS: Among the 292 women studied, those with cesarean deliveries for dystocia were older (mean ± SD, 34.2 ± 4.27 vs. 32.2 ± 3.8, p-value = 0.002), had higher pre-pregnancy BMI (22.7 ± 3.67 vs. 21.4 ± 3.48, p-value = 0.012) and term-BMI (27.4 ± 3.72 vs. 25.9 ± 3.66, p-value = 0.010), shorter interspinous distance (ISD, the distance between ischial spine) (10.8 ± 0.76 vs. 11.2 ± 0.85 cm, p-value = 0.003), and longer head circumference (HC) (35 ± 1.47 vs. 34.4 ± 1.36 cm, p-value = 0.003) compared to those who had vaginal deliveries. Univariate logistic regression for dystocia revealed associations between HC/maternal height and HC/ISD ratios (OR, 2.02 [95% confidence interval, CI, 1.4 ~ 2.92], 12.13 [3.2 ~ 46.04], respectively). Multivariate logistic analysis indicated that maternal age, ISD, and HC were significant factors for dystocia (OR, 1.11 [95% CI, 1.01 ~ 1.21], 0.49 [0.26 ~ 0.91], 1.53 [1.07 ~ 2.19], respectively). The subgroup with latent-phase prolongation exhibited the lowest birthweight/term-BMI ratio (124 ± 18.8 vs. 113 ± 10.3 vs. 134 ± 19.1, p-value = 0.013). CONCLUSION: The HC/ISD ratio emerged as a crucial predictor of dystocia, suggesting that reducing term-BMI could potentially mitigate latent-phase prolongation. Further research assessing the maternal mid-pelvis during pregnancy and labor is warranted, along with efforts to reduce BMI during pregnancy.


Assuntos
Distocia , Cabeça , Humanos , Feminino , Gravidez , Estudos Retrospectivos , Adulto , Estudos de Casos e Controles , Recém-Nascido , Cabeça/diagnóstico por imagem , Desproporção Cefalopélvica/diagnóstico por imagem , Pelve/diagnóstico por imagem , Cesárea/estatística & dados numéricos , Cefalometria
2.
Int J Mol Sci ; 25(11)2024 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-38892219

RESUMO

Anoctamin1 (ANO1), a calcium-activated chloride channel, is overexpressed in a variety of cancer cells, including prostate cancer, and is involved in cancer cell proliferation, migration, and invasion. Inhibition of ANO1 in these cancer cells exhibits anticancer effects. In this study, we conducted a screening to identify novel ANO1 inhibitors with anticancer effects using PC-3 human prostate carcinoma cells. Screening of 2978 approved and investigational drugs revealed that hemin is a novel ANO1 inhibitor with an IC50 value of 0.45 µM. Notably, hemin had no significant effect on intracellular calcium signaling and cystic fibrosis transmembrane conductance regulator (CFTR), a cyclic AMP (cAMP)-regulated chloride channel, and it showed a weak inhibitory effect on ANO2 at 3 µM, a concentration that completely inhibits ANO1. Interestingly, hemin also significantly decreased ANO1 protein levels and strongly inhibited the cell proliferation and migration of PC-3 cells in an ANO1-dependent manner. Furthermore, it strongly induced caspase-3 activation, PARP degradation, and apoptosis in PC-3 cells. These findings suggest that hemin possesses anticancer properties via ANO1 inhibition and could be considered for development as a novel treatment for prostate cancer.


Assuntos
Anoctamina-1 , Antineoplásicos , Hemina , Proteínas de Neoplasias , Neoplasias da Próstata , Humanos , Masculino , Anoctamina-1/metabolismo , Anoctamina-1/antagonistas & inibidores , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Hemina/farmacologia , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Células PC-3 , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia
3.
Int J Mol Sci ; 24(2)2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36674697

RESUMO

Anoctamin1 (ANO1), a calcium-activated chloride channel, is involved in the proliferation, migration, and invasion of various cancer cells including head and neck squamous cell carcinoma, lung cancer, and prostate cancer. Inhibition of ANO1 activity or downregulation of ANO1 expression in these cancer cells is known to exhibit anticancer effects. Resveratrol, a natural polyphenol abundant in wines, grapes, berries, soybeans, and peanuts, shows a wide variety of biological effects including anti-inflammatory, antioxidant, and anticancer activities. In this study, we investigated the effects of two stereoisomers of resveratrol on ANO1 activity and found that cis- and trans-resveratrol inhibited ANO1 activity with different potencies. Cis- and trans-resveratrol inhibited ANO1 channel activity with IC50 values of 10.6 and 102 µM, respectively, and had no significant effect on intracellular calcium signaling at 10 and 100 µM, respectively. In addition, cis-resveratrol downregulated mRNA and protein expression levels of ANO1 more potently than trans-resveratrol in PC-3 prostate cancer cells. Cis- and trans-resveratrol significantly reduced cell proliferation and cell migration in an ANO1-dependent manner, and both resveratrol isomers strongly increased caspase-3 activity, PARP cleavage, and apoptotic sub-G1 phase ratio in PC-3 cells. These results revealed that cis-resveratrol is a potent inhibitor of ANO1 and exhibits ANO1-dependent anticancer activity against human metastatic prostate cancer PC-3 cells.


Assuntos
Neoplasias de Cabeça e Pescoço , Neoplasias da Próstata , Masculino , Humanos , Resveratrol/farmacologia , Células PC-3 , Anoctamina-1/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Proteínas de Neoplasias/metabolismo
4.
J Prosthet Dent ; 128(4): 575-588, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34294418

RESUMO

STATEMENT OF PROBLEM: Selective laser melting (SLM) additive manufacturing (AM) technologies provide an alternative to conventional casting and milling procedures in fabricating metal-ceramic dental prostheses. However, the quality of porcelain bond strength to the SLM AM cobalt-chromium (Co-Cr) metal framework of a dental restoration is unclear. PURPOSE: The purpose of this systematic review and meta-analysis was to identify in vitro studies that reported the porcelain bond strength to SLM AM Co-Cr dental metal alloys and compare the porcelain bond strength values to cast, milled, and additively manufactured Co-Cr dental alloys. MATERIAL AND METHODS: An electronic systematic review was performed in different databases: MEDLINE/PubMed, EMBASE, World of Science, Cochrane, and Scopus. A manual search was also conducted. Studies that reported the porcelain bond strength to SLM Co-Cr metal alloys and in the English language were included. Two investigators evaluated the quality assessment of the studies by applying the JBI critical appraisal checklist for quasi-experimental studies (nonrandomized experimental studies). A third investigator was consulted to resolve lack of consensus. Two subgroups were created based on the test used, 3-point bend and shear bond strength tests. The porcelain bond strength of cast, milled, and AM Co-Cr dental alloys were compared. The I2 statistic and its associated P value were used to assess the heterogeneity between studies. The Eger test was used for determining significance of the funnel pots. RESULTS: A total of 216 studies were collected from the electronic and manual searches. After independently evaluating the titles and abstracts by the reviewers, 26 articles were identified. Three of these were excluded after full-text revision. The porcelain bond strength comparison between the cast and AM alloys for the 3-point bend subgroup revealed a significant result for overall effect (P<.001) favoring the SLM method with considerable heterogeneity (I2=83%, P<.001). Furthermore, the porcelain bond strength comparison between cast and milled alloys for the shear bond strength subgroup revealed a significant test for overall effect (P=.04) favoring milled procedures with a nonsignificant unimportant heterogeneity (I2= 0%, P<.47) and for the 3-point bend subgroup (P<.001) favoring milled specimens with a significant considerable heterogeneity (I2=79%, P<.001). CONCLUSIONS: The metal manufacturing method had no effect on the porcelain bond strength to Co-Cr dental metal alloys.


Assuntos
Colagem Dentária , Porcelana Dentária , Porcelana Dentária/química , Ligas de Cromo/química , Ligas Metalo-Cerâmicas/química , Teste de Materiais , Propriedades de Superfície , Cobalto , Cromo , Ligas Dentárias
5.
J Prosthet Dent ; 126(4): 459-463, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32981717

RESUMO

A technique to merge facial and intraoral digital scans guided by an additively manufactured intraoral scan body is described. The technique facilitates facially driven treatment planning of restorative procedures in situations where a cone beam computed tomography scan is not indicated. Furthermore, the intraoral scan body can be customized to the size of the patient's arch to improve patient comfort and simplify the digitalization procedures.


Assuntos
Tomografia Computadorizada de Feixe Cônico , Imageamento Tridimensional , Desenho Assistido por Computador , Face/diagnóstico por imagem , Humanos , Planejamento de Assistência ao Paciente
6.
J Prosthodont ; 30(7): 636-641, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33942953

RESUMO

This report describes a technique to obtain a 3D virtual representation of a maxillary edentulous patient guided by an additively manufactured intraoral scan body. The intraoral scan body incorporated a custom tray and occlusion rim which facilitated the acquiring of a digital definitive cast, maxillary occlusion rim position, interocclusal registration, and guided the integration of the facial scans. The technique simplified the design and manufacturing of the maxillary overdenture.


Assuntos
Revestimento de Dentadura , Boca Edêntula , Desenho Assistido por Computador , Humanos , Maxila/diagnóstico por imagem , Boca Edêntula/diagnóstico por imagem
7.
J Org Chem ; 85(16): 10994-11005, 2020 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-32674567

RESUMO

A highly efficient synthetic route to new quinone-indolizine hybrids was accomplished from quinones and N-substituted pyrrole-2-carboxaldehydes via a domino Michael addition-aldol condensation-aromatization sequence through which the central pyridine ring was constructed in atom-economical and environment-friendly manner. Post modification of the resulting products was also demonstrated, enabling further expansion of this heterocyclic chemical space. Biological evaluation of the quinone-indolizine hybrids revealed potent anticancer effects in human prostate adenocarcinoma cells (PC-3) and oral adenosquamous carcinoma cells (CAL-27).


Assuntos
Indolizinas , Benzoquinonas , Humanos , Estrutura Molecular , Quinonas/farmacologia
8.
Bioorg Chem ; 101: 104000, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32592976

RESUMO

Chemical territory bearing a 2,2-dimethyl-2H-chromene motif was expanded by utilizing an o-hydroxy aldehyde group of 5-hydroxy-2,2-dimethyl-2H-chromene-6-carbaldehyde as a synthetic handle to install distinctive morphology and functionality of each scaffold. Cell based assays and in silico docking analysis led us to discover that these new compounds exhibit inhibitory effect on anoctamin1 (ANO1). ANO1 is amplified and highly expressed in various carcinomas including prostate cancer, esophageal cancer, breast cancer, and pancreatic cancer. Biological assays revealed that (E)-1-(7,7-dimethyl-7H-furo[2,3-f]chromen-2-yl)-3-(1H-pyrrol-2-yl)prop-2-en-1-one (3n, Ani-FCC) is a novel, potent and selective ANO1 inhibitor with an IC50 value of 1.23 µM. 3n showed 144 times stronger activity on ANO1 inhibition than ANO2 inhibition and did not alter the chloride channel activity of CFTR and the intracellular calcium signaling. Notably, 3n strongly decreased cell viability of PC-3 and FaDu cells expressing high levels of ANO1 with a decrease in ANO1 protein levels. In addition, 3n significantly enhanced apoptosis via activation of caspase 3 and cleavage of PARP in PC-3 and FaDu cells. This study shows that a novel ANO1 inhibitor, 3n, can be a potential candidate for the treatment of cancers overexpressing ANO1, such as prostate cancer and esophageal cancer.


Assuntos
Anoctamina-1/antagonistas & inibidores , Benzopiranos/farmacologia , Proteínas de Neoplasias/antagonistas & inibidores , Anoctamina-1/metabolismo , Apoptose/efeitos dos fármacos , Benzopiranos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Descoberta de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração Inibidora 50 , Proteínas de Neoplasias/metabolismo
9.
Int J Mol Sci ; 21(14)2020 Jul 14.
Artigo em Inglês | MEDLINE | ID: mdl-32674502

RESUMO

Lupus nephritis (LN) is the most frequent phenotype in patients with systemic lupus erythematosus (SLE) and has a high rate of progression to end-stage renal disease, in spite of intensive treatment and maintenance therapies. Recent evidence suggests that protease-activated receptor-2 (PAR2) is a therapeutic target for glomerulonephritis. In this study, we performed a cell-based high-throughput screening and identified a novel potent PAR2 antagonist, punicalagin (PCG, a major polyphenol enriched in pomegranate), and evaluated the effects of PCG on LN. The effect of PCG on PAR2 inhibition was observed in the human podocyte cell line and its effect on LN was evaluated in NZB/W F1 mice. In the human podocyte cell line, PCG potently inhibited PAR2 (IC50 = 1.5 ± 0.03 µM) and significantly reduced the PAR2-mediated activation of ERK1/2 and NF-κB signaling pathway. In addition, PCG significantly decreased PAR2-induced increases in ICAM-1 and VCAM-1 as well as in IL-8, IFN-γ, and TNF-α expression. Notably, the intraperitoneal administration of PCG significantly alleviated kidney injury and splenomegaly and reduced proteinuria and renal ICAM-1 and VCAM-1 expression in NZB/W F1 mice. Our results suggest that PCG has beneficial effects on LN via inhibition of PAR2, and PCG is a potential therapeutic agent for LN.


Assuntos
Taninos Hidrolisáveis/farmacologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/metabolismo , Receptor PAR-2/metabolismo , Animais , Linhagem Celular , Feminino , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Células NIH 3T3 , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Proteinúria/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo
10.
Int J Mol Sci ; 21(18)2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32899792

RESUMO

Anoctamin1 (ANO1), a calcium-activated chloride channel, is frequently overexpressed in several cancers, including human prostate cancer and oral squamous cell carcinomas. ANO1 plays a critical role in tumor growth and maintenance of these cancers. In this study, we have isolated two new compounds (1 and 2) and four known compounds (3-6) from Mallotus apelta. These compounds were evaluated for their inhibitory effects on ANO1 channel activity and their cytotoxic effects on PC-3 prostate cancer cells. Interestingly, compounds 1 and 2 significantly reduced both ANO1 channel activity and cell viability. Electrophysiological study revealed that compound 2 (Ani-D2) is a potent and selective ANO1 inhibitor, with an IC50 value of 2.64 µM. Ani-D2 had minimal effect on cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel activity and intracellular calcium signaling. Notably, Ani-D2 significantly reduced ANO1 protein expression levels and cell viability in an ANO1-dependent manner in PC-3 and oral squamous cell carcinoma CAL-27 cells. In addition, Ani-D2 strongly reduced cell migration and induced activation of caspase-3 and cleavage of PARP in PC-3 and CAL-27 cells. This study revealed that a novel ANO1 inhibitor, Ani-D2, has therapeutic potential for the treatment of several cancers that overexpress ANO1, such as prostate cancer and oral squamous cell carcinoma.


Assuntos
Anoctamina-1/antagonistas & inibidores , Mallotus (Planta)/metabolismo , Extratos Vegetais/farmacologia , Animais , Anoctamina-1/metabolismo , Anoctamina-1/fisiologia , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Sinalização do Cálcio/efeitos dos fármacos , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Canais de Cloreto/metabolismo , Humanos , Neoplasias Bucais/metabolismo , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiologia , Células PC-3 , Ratos
11.
J Prosthodont ; 29(5): 436-442, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32144856

RESUMO

Facial and intraoral scanners as well as additive manufacturing (AM) technologies can be integrated to virtually plan restorative procedures. The present article describes a digital workflow protocol for treatment planning an esthetic rehabilitation using direct composite restorations. The combination of facial digitalization and intraoral scans allowed a facially driven diagnostic waxing, while additive manufacturing technologies facilitate the translation of the digital waxing into the patient´s mouth through an AM 3-piece silicone index which was designed into a buccal and a lingual clear flexible silicone indices that were fitted into a clear and rigid custom tray. This procedure facilitated the treatment planning procedures as well as assisted the direct composite restoration procedures, providing several advantages compared with conventional procedures such as precise translation of the digital diagnostic waxing into the patient´s mouth, horizontal path of insertion of the silicone index, and minimized time of the clinical intervention.


Assuntos
Desenho Assistido por Computador , Planejamento de Prótese Dentária , Estética Dentária , Humanos , Silicones , Fluxo de Trabalho
12.
J Clin Med ; 13(5)2024 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-38592700

RESUMO

(1) Background: This study investigated the epidemiology and viral connections of Henoch-Schönlein purpura (HSP) using information from the Korea Disease Control and Prevention Agency and the Health Insurance Review and Assessment database. (2) Method: Between 2016 and 2019, a total of 25,443 patients with HSP were identified, with 51.3% of patients under the age of 20 years and the highest incidence in March. (3) Results: The autoregressive integrated moving average model and Granger causality test were used to analyze the association between the virus positivity detection rate and HSP incidence. (4) Conclusions: The incidence of HSP was associated with rotavirus, bocavirus, parainfluenza virus, and respiratory syncytial virus in individuals under 20 years of age, whereas adenovirus, respiratory syncytial virus, and norovirus were associated with individuals above that age.

13.
Pharmaceuticals (Basel) ; 17(2)2024 Feb 09.
Artigo em Inglês | MEDLINE | ID: mdl-38399447

RESUMO

The epidermal growth factor receptor (EGFR), also known as ErbB1 and HER1, belongs to the receptor tyrosine kinase family. EGFR serves as the primary driver in non-small-cell lung cancer (NSCLC) and is a promising therapeutic target for NSCLC. In this study, we synthesized a novel chemical library based on a benzofuran-indole hybrid scaffold and identified 8aa as a potent and selective EGFR inhibitor. Interestingly, 8aa not only showed selective anticancer effects against NSCLC cell lines, PC9, and A549, but it also showed significant inhibitory effects against the double mutant L858R/T790M EGFR, which frequently occurs in NSCLC. In addition, in PC9 and A549 cells, 8aa potently blocked the EGFR signaling pathway, cell viability, and cell migration. These findings suggest that 8aa, a benzofuran-indole hybrid derivative, is a novel EGFR inhibitor that may be a potential candidate for the treatment of NSCLC patients with EGFR mutations.

14.
Acta Biomater ; 183: 50-60, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38871200

RESUMO

Spinal cord injury (SCI) is associated with substantial healthcare challenges, frequently resulting in enduring sensory and motor deficits alongside various chronic complications. While advanced regenerative therapies have shown promise in preclinical research, their translation into clinical application has been limited. In response, this study utilized a comprehensive network meta-analysis to evaluate the effectiveness of neural stem/progenitor cell (NSPC) transplantation across animal models of SCI. We analyzed 363 outcomes from 55 distinct studies, categorizing the treatments into NSPCs alone (cell only), NSPCs with scaffolds (cell + scaffold), NSPCs with hydrogels (cell + hydrogel), standalone scaffolds (scaffold), standalone hydrogels (hydrogel), and control groups. Our analysis demonstrated significant enhancements in motor recovery, especially in gait function, within the NSPC treatment groups. Notably, the cell only group showed considerable improvements (standardized mean difference [SMD], 2.05; 95 % credible interval [CrI]: 1.08 to 3.10, p < 0.01), as did the cell + scaffold group (SMD, 3.73; 95 % CrI: 2.26 to 5.22, p < 0.001) and the cell + hydrogel group (SMD, 3.37; 95 % CrI: 1.02 to 5.78, p < 0.05) compared to controls. These therapeutic combinations not only reduced lesion cavity size but also enhanced neuronal regeneration, outperforming the cell only treatments. By integrating NSPCs with supportive biomaterials, our findings pave the way for refining these regenerative strategies to optimize their potential in clinical SCI treatment. Although there is no overall violation of consistency, the comparison of effect sizes between individual treatments should be interpreted in light of the inconsistency. STATEMENT OF SIGNIFICANCE: This study presents a comprehensive network meta-analysis exploring the efficacy of neural stem cell (NSC) transplantation, with and without biomaterials, in animal models of spinal cord injury (SCI). We demonstrate that NSCs, particularly when combined with biomaterials like scaffolds or hydrogels, significantly enhance motor and histological recovery post-SCI. These findings underscore the potential of NSC-based therapies, augmented with biomaterials, to advance SCI treatment, offering new insights into regenerative strategies that could significantly impact clinical practices.


Assuntos
Materiais Biocompatíveis , Células-Tronco Neurais , Traumatismos da Medula Espinal , Traumatismos da Medula Espinal/terapia , Traumatismos da Medula Espinal/patologia , Células-Tronco Neurais/transplante , Células-Tronco Neurais/citologia , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Humanos , Transplante de Células-Tronco , Hidrogéis/química , Hidrogéis/farmacologia , Recuperação de Função Fisiológica , Metanálise em Rede , Alicerces Teciduais/química
15.
Front Pharmacol ; 15: 1430548, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39130626

RESUMO

Background: Protease-activated receptor 1 (PAR1) is expressed in human platelets and can be activated by low concentrations of thrombin. Vorapaxar, a selective antagonist of PAR1, inhibits thrombin-induced calcium mobilization in human platelet, which is associated with an increased risk of bleeding. Conversely, the administration of a positive allosteric modulator (PAM) of PAR1 may pose a substantial risk of thrombosis due to inducing excessive platelet activation. In this study, we discovered a novel PAM of PAR1 and investigated the effect of enhanced PAR1 activation by PAM of PAR1 on platelet activation. Methods: To find PAMs of PAR1, a cell-based screen was performed in HT29 cells, and finally, gestodene, an oral contraceptive drug (OC), was identified as a novel PAM of PAR1. The mechanism of action of gestodene and its effects on platelet activation were investigated in human megakaryocytic leukemia cell line MEG-01 cells and human platelet. Results: Gestodene enhanced both thrombin- and PAR1-activating peptide (AP)-induced intracellular calcium levels in a dose-dependent manner without altering PAR2 and PAR4 activity. Gestodene significantly increased PAR1-AP-induced internalization of PAR1 and phosphorylation of ERK1/2, and the enhancing effects were significantly blocked by vorapaxar. Furthermore, gestodene potently increased PAR1-AP induced morphological changes in MEG-01 cells. Remarkably, in human blood, gestodene exerted a robust augmentation of PAR1-AP-induced platelet aggregation, and vorapaxar effectively attenuated the gestodene-induced enhancement of platelet aggregation mediated by PAR1. Conclusion: Gestodene is a selective PAM of PAR1 and suggest one possible mechanism for the increased risk of venous thromboembolism associated with OCs containing gestodene.

16.
Food Sci Biotechnol ; 33(1): 171-180, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38186621

RESUMO

Following 3R (reduction, refinement, and replacement) principles, we employed the rat liver S9 fraction to mimic liver metabolism of curcumol having high in vitro IC50 on cancer cells. In HCT116 and HT29 colon cancer cells, the metabolites of curcumol by S9 fraction exerted more enhanced activity in inducing cell cycle arrest and apoptosis via regulating the expression of cyclin D1, CDK1, p21, PARP and Bcl-2 than curcumol. In addition, oral administration of curcumol at 4 mg/kg BW significantly suppressed the development of colon tumor induced by azoxymethane/dextran sulfate sodium, and induced cell cycle arrest and apoptosis in tumor tissues. In mass analysis, curcumenol and curzerene were identified as the metabolites of curcumol by S9 fraction metabolism. Taken together, curcumol metabolites showed the enhanced suppressive effect on colon cancer, suggesting that S9 fraction can be considered as simple, fast, and bio-mimicking platform for the screening of chemical libraries on different chronic diseases.

17.
Sci Rep ; 13(1): 21518, 2023 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-38057379

RESUMO

Highly prevalent hepatitis B and hepatitis C virus (HBV and HCV) infections have been reported among individuals with diabetes. Given the frequently asymptomatic nature of hepatitis and the challenges associated with screening in some vulnerable populations such as diabetes patients, we conducted an investigation into the performance of various machine learning models for the identification of hepatitis in diabetic patients while also evaluating the significance of features. Analyzing NHANES data from 2013 to 2018, machine learning models were evaluated; random forest (RF), support vector machine (SVM), eXtreme Gradient Boosting (XGBoost), and least absolute shrinkage and selection operator (LASSO) along with stacked ensemble model. We performed hyperparameter tuning to improve the performance of the model, and selected important predictors using the best performance model. LASSO showed the highest predictive performance (AUC-ROC = 0.810) rather than other models. Illicit drug use, poverty, and race were highly ranked as predictive factors for developing hepatitis in diabetes patients. Our study demonstrated that a machine-learning-based model performed optimally in the detection of hepatitis among diabetes patients, achieving high performance. Furthermore, models and predictors evaluated from the current study, we expect, could be supportive information for developing screening or treatment methods for hepatitis care in diabetes patients.


Assuntos
Diabetes Mellitus , Hepatite A , Hepatite B , Hepatite C , Viroses , Humanos , Inquéritos Nutricionais , Hepatite B/diagnóstico , Hepatite B/epidemiologia , Hepatite C/complicações , Hepatite C/diagnóstico , Hepatite C/epidemiologia , Diabetes Mellitus/epidemiologia , Aprendizado de Máquina
18.
Sci Rep ; 13(1): 3365, 2023 02 27.
Artigo em Inglês | MEDLINE | ID: mdl-36849501

RESUMO

The Maf polymorphic toxin system is involved in conflict between strains found in pathogenic Neisseria species such as Neisseria meningitidis and Neisseria gonorrhoeae. The genes encoding the Maf polymorphic toxin system are found in specific genomic islands called maf genomic islands (MGIs). In the MGIs, the MafB and MafI encode toxin and immunity proteins, respectively. Although the C-terminal region of MafB (MafB-CT) is specific for toxic activity, the underlying enzymatic activity that renders MafB-CT toxic is unknown in many MafB proteins due to lack of homology with domain of known function. Here we present the crystal structure of the MafB2-CTMGI-2B16B6/MafI2MGI-2B16B6 complex from N. meningitidis B16B6. MafB2-CTMGI-2B16B6 displays an RNase A fold similar to mouse RNase 1, although the sequence identity is only ~ 14.0%. MafB2-CTMGI-2B16B6 forms a 1:1 complex with MafI2MGI-2B16B6 with a Kd value of ~ 40 nM. The complementary charge interaction of MafI2MGI-2B16B6 with the substrate binding surface of MafB2-CTMGI-2B16B6 suggests that MafI2MGI-2B16B6 inhibits MafB2-CTMGI-2B16B6 by blocking access of RNA to the catalytic site. An in vitro enzymatic assay showed that MafB2-CTMGI-2B16B6 has ribonuclease activity. Mutagenesis and cell toxicity assays demonstrated that His335, His402 and His409 are important for the toxic activity of MafB2-CTMGI-2B16B6, suggesting that these residues are critical for its ribonuclease activity. These data provide structural and biochemical evidence that the origin of the toxic activity of MafB2MGI-2B16B6 is the enzymatic activity degrading ribonucleotides.


Assuntos
Ilhas Genômicas , Neisseria meningitidis , Animais , Camundongos , Interleucina-6 , Neisseria , Ribonucleases , Proteínas Proto-Oncogênicas c-maf
19.
PLoS One ; 18(8): e0289814, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37561690

RESUMO

OBJECTIVE: To predict the interspinous distance (ISD) using the relationship between female height and pelvimetric measures on magnetic resonance (MR) images. METHODS: We obtained measurements of the pubic arch angle (PAA), inlet-anteroposterior (AP) distance, mid-pelvis AP distance, outlet-AP distance, ISD, and ischial tuberosity distance using 710 pelvic MR images from nonpregnant reproductive-aged (21-50 years) women from January 2014 to June 2020. Patient height was also assessed from medical records. We determined the formula for predicting ISD using multiple regression analysis. RESULTS: The mean ± standard deviation of the height, PAA, inlet-AP distance, mid-pelvis AP distance, outlet-AP distance, ISD, and ischial tuberosity distance were 160.0 ± 5.5 cm, 87.31 ± 6.6°, 129.7 ± 9.0 mm, 119.7 ± 8.5 mm, 111.71 ± 8.90 mm, 108.88 ± 8.0 mm, and 121.97 ± 11.8 mm, respectively. Two significant regression formulas for predicting ISD were identified as follows: ISD = 0.24973 × height - 0.06724 × inlet-AP distance + 0.12166 × outlet-AP distance + 0.29233 × ischial tuberosity distance + 0.32524 × PAA (P < 0.001, R2 = 0.9973 [adjusted R2 = 0.9973]) and ISD = 0.40935 × height + 0.49761 × PAA (P < 0.001, R2 = 0.9965 [adjusted R2 = 0.9965]). CONCLUSION: ISD is the best predictor of obstructed labor. This study predicted ISD with 99% explanatory power using only the height and PAA. The PAA can be measured by transperineal ultrasound. This formula may successfully predict vaginal delivery or cephalopelvic disproportion.


Assuntos
Distocia , Pelve , Gravidez , Humanos , Feminino , Adulto , Pelve/diagnóstico por imagem , Parto Obstétrico/métodos , Pelvimetria/métodos , Imageamento por Ressonância Magnética/métodos
20.
Pharmaceutics ; 15(4)2023 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-37111617

RESUMO

Numerous cathepsin B inhibitors have been developed and are under investigation as potential cancer treatments. They have been evaluated for their ability to inhibit cathepsin B activity and reduce tumor growth. However, they have shown critical limitations, including low anticancer efficacy and high toxicity, due to their low selectivity and delivery problems. In this study, we developed a novel peptide and drug conjugate (PDC)-based cathepsin B inhibitor using cathepsin-B-specific peptide (RR) and bile acid (BA). Interestingly, this RR and BA conjugate (RR-BA) was able to self-assemble in an aqueous solution, and as a result, it formed stable nanoparticles. The nano-sized RR-BA conjugate showed significant cathepsin B inhibitory effects and anticancer effects against mouse colorectal cancer (CT26) cells. Its therapeutic effect and low toxicity were also confirmed in CT26 tumor-bearing mice after intravenous injection. Therefore, based on these results, the RR-BA conjugate could be developed as an effective anticancer drug candidate for inhibiting cathepsin B in anticancer therapy.

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