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1.
J Gastrointest Oncol ; 15(3): 1153-1164, 2024 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-38989418

RESUMO

Background: Laparoscopic liver resection (LLR) has been accepted as a safe and effective treatment for hepatocellular carcinoma (HCC). However, its impact on elderly patients remains uncertain. This study aimed to compare the efficacy and safety of LLR with open liver resection (OLR) in elderly HCC patients. Methods: We conducted a search across the Ovid-Medline, Ovid-EMBASE, and Cochrane Library to identify comparative studies involving primary HCC in elderly patients (≥65 years). Efficacy-related outcomes encompassed overall survival (OS) and disease-free survival (DFS), while safety-related outcomes included post-operative mortality, complications, and length of stay (LOS). Results: We identified nine eligible cohort studies comprising 1,599 patients. LLR demonstrated comparable 3- and 5-year DFS [hazard ratio (HR) =1.00, 95% confidence interval (CI): 0.98-1.02; HR =1.02, 95% CI: 0.99-1.05] and 3- and 5-year OS (HR =1.01, 95% CI: 0.99-1.02; HR =1.02, 95% CI: 0.99-1.06, respectively) compared to OLR. In terms of safety, there was no significant difference between LLR and OLR in in-hospital mortality [odds ratio (OR) =0.19; 95% CI: 0.02-1.69], 30-day mortality (OR =0.33; 95% CI: 0.03-3.20), and 90-day mortality (OR =0.70; 95% CI: 0.32-1.53). Additionally, LLR presented fewer overall complications (OR =0.53; 95% CI: 0.41-0.67), a lower rate of major complications (OR =0.51; 95% CI: 0.35-0.74), a reduced incidence of liver failure (OR =0.56; 95% CI: 0.33-0.94), and a shorter LOS compared to OLR (mean difference: -14.47 days). Conclusions: LLR exhibited comparable clinical efficacy and superior safety and fewer complications when compared to OLR in elderly patients with HCC requiring surgery.

2.
Gut Liver ; 18(4): 695-708, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38712397

RESUMO

Background/Aims: : With increased life expectancy, the management of elderly hepatocellular carcinoma (HCC) patients became a crucial issue, yet it is still challenging due to comorbidities and high surgical risks. While surgical resection is considered as primary treatment for eligible HCC patients, systematic evidence on its outcomes in elderly patients remains scarce. In this review, we aimed to analyze the efficacy and safety outcomes of surgical resection in elderly HCC patients. Methods: : The studies included in this meta-analysis were selected from Ovid-MEDLINE, Ovid-Embase, CENTRAL, KoreaMed, KMbase, and KISS databases following a predefined protocol. Efficacy outcomes included overall survival and disease-free survival, while the safety outcomes included postoperative mortality and complications. Results: : Patients in the elderly group (≥65 years) who underwent surgery exhibited non-inferior overall survival (hazard ratio [HR], 1.26; 95% confidence interval [CI], 0.92 to 1.74) and disease-free survival (HR, 1.03; 95% CI, 0.99 to 1.08) compared to the non-elderly group. Overall postoperative mortality exhibited no statistical difference (odds ratio [OR], 1.07; 95% CI, 0.87 to 1.31), but 30-day, 90-day, and in-hospital mortality were higher in the elderly group. The incidence of overall complications was higher in the elderly group (OR, 1.44; 95% CI, 1.22 to 1.69). Sensitivity analysis for the super elderly group (≥80 years) showed significantly higher in-hospital mortality compared to the non-super elderly group (OR, 2.51; 95% CI, 1.16 to 5.45). Conclusions: : The efficacy outcome of surgical resection in the elderly HCC patients was not worse than that in the non-elderly HCC patients, while in-hospital mortality and complications rates were higher. Therefore, surgical resection should be purposefully considered in the elderly population, with careful candidate selection.


Assuntos
Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Complicações Pós-Operatórias , Humanos , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Idoso , Hepatectomia/métodos , Hepatectomia/mortalidade , Hepatectomia/efeitos adversos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Resultado do Tratamento , Intervalo Livre de Doença , Feminino , Masculino , Fatores Etários , Idoso de 80 Anos ou mais
3.
Clin Lab ; 70(5)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38747932

RESUMO

BACKGROUND: Parainfluenza virus (PIV) is a significant etiological agent of acute lower respiratory tract infections (ALRIs) in infants and young children. The present study has been conducted to investigate the prevalence of recently identified respiratory viruses. METHODS: In total, 543 oropharyngeal or nasopharyngeal swab samples collected from hospitalized patients with acute respiratory symptoms (ARS) between January and December 2021 (5,653 females and 4,950 males) were tested for respiratory viruses using RT-PCR. RESULTS: At least one respiratory virus was detected by RT-PCR in 119 out of 175 samples (68%). The most frequently detected virus was human rhinovirus (HRV) (34, 6.5%), followed by human parainfluenza viruses (HPIVs) (19, 3.6%), human bocavirus (HBoV) (8, 1.5%), human adenovirus (HAdV) (7, 1.3%), and human respiratory syncytial virus (HRSV) (4, 0.8%). HPIV-3 accounted for 3.6% (19/175) of all viral pathogens and was the second most frequently detected viral pathogen in our study. HPIV-3 infections peaked in the fall (November) of 2021. Phylogenetic analysis of the coding region of the viral protein HA revealed that all 35 (100%) of 35 HPIV-infected patients were infected with HPIV-3. CONCLUSIONS: HPIV was an important causative pathogen associated with ALRI in children hospitalized in Korea in the late fall of 2021, as the social distancing rules for COVID-19 were relaxed. These findings highlight the im-portance of HPIV as a cause of ALRI.


Assuntos
Infecções Respiratórias , Humanos , Feminino , Masculino , Lactente , Pré-Escolar , Prevalência , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Infecções Respiratórias/diagnóstico , Criança , República da Coreia/epidemiologia , Infecções por Paramyxoviridae/epidemiologia , Infecções por Paramyxoviridae/virologia , Infecções por Paramyxoviridae/diagnóstico , Adolescente
4.
Nat Commun ; 15(1): 2017, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38443376

RESUMO

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observe that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cellular analyses, we discover that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr forms a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhances Plk4's functionality by promoting its relocalization to the procentriole assembly and induces centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogates Vpr's capacity to induce these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induces multiple centrosomes and aneuploidy in human primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.


Assuntos
HIV-1 , Linfócitos T , Humanos , Centrossomo , Carcinogênese , Transformação Celular Neoplásica , Aneuploidia , Linfócitos T CD4-Positivos
5.
J Craniofac Surg ; 2024 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-38393303

RESUMO

This study aimed to measure masticatory performance (MP) using ß-carotene gummy jelly to investigate its relationship with skeletal properties in decompensated patients diagnosed with skeletal class III malocclusion. The study included 78 patients (38 men and 40 women) diagnosed with skeletal class III malocclusion without temporomandibular joint disorder and periodontal disease. MP was measured using a new masticatory measuring device and ß-carotene in the gummy jelly. Lateral and posteroanterior cephalograms were obtained, and skeletal properties (Me deviation, ANB, SNB, APDI, Wits, ODI, facial axis, body length, ramus length, SN-GoGn, anterior facial height, posterior facial height, saddle angle, articular angle, and gonial angle) were evaluated. MP differences according to age and sex and the effect of skeletal properties on MP were analyzed using multiple linear regression analysis. The MP of all patients was 3690.55±1428.77 mm², MP of the male group was 4043.05±1498.09 mm², and MP of the female group was 3355.68±1272.19 mm². Among the items investigated, the variable that affected MP was posterior facial height. Posterior facial height showed a positive correlation (P=0.022). There was no significant difference between MP and other skeletal properties (P>0.05). The severity of the hypodivergency in skeletal class III could affect MP. The relationship between facial asymmetry or skeletal relation and MP could not be explained in this study.

6.
Curr Oncol ; 31(1): 324-334, 2024 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-38248106

RESUMO

Although the disease burden of elderly cancer patients is rapidly increasing, reliable scientific information, value and preference information of domestic patients, and standardized guidelines for determining the treatment of elderly cancer patients are lacking. The aim of this study is to compare the therapeutic effects of radiofrequency ablation (RFA) and surgery in hepatocellular carcinoma (HCC) patients aged 65 years or older. For the meta-analysis, the databases including PubMed (MEDLINE), EMBASE, OVID Medline, and the Cochrane Library were systematically searched. After the abstract-based review by two investigators, selected manuscripts were read in detail. The surgery group showed higher overall survival (OS) (HR 1.44, 95% CI 1.22-1.70) and disease-free survival (DFS) (HR 1.40, 95% CI 1.00-1.97) than the RFA group. This was also shown in small HCC of less than 3 cm (OS, HR 1.42, 95% CI 1.00-2.03; DFS, HR 1.32, 95% CI 0.91-1.91). This might be related to the high local recurrence in the RFA group (OR 4.90, 95% 2.16-11.08). On the other hand, adverse events were significantly lower in the RFA group (OR 0.22, 95% CI 0.14-0.36), which led to a decrease in the duration of hospital stay (mean difference -14.88 days, 95% CI -22.44--7.32). In elderly HCC patients, survival in the surgery group was significantly higher than in the RFA group, but various complications tended to increase; so, appropriate patient selection is required.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Ablação por Radiofrequência , Idoso , Humanos , Carcinoma Hepatocelular/cirurgia , Neoplasias Hepáticas/cirurgia , Bases de Dados Factuais , Intervalo Livre de Doença
7.
Infect Chemother ; 56(1): 37-46, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38014729

RESUMO

BACKGROUND: Human papillomavirus (HPV) infection is a major global disease burden and the main cause of cervical cancer. Certain HPV genotypes, with are the most common etiologic pathogens and cause a significant disease burden, are being targeted for vaccine development. However, few studies have focused on the comparative effectiveness of the bivalent HPV (2v-HPV), quadrivalent HPV (4v-HPV), and nonavalent HPV (9v-HPV) vaccines against HPV strain-specific infection. This study investigated the comparative effects of these vaccines against genotype-specific infection. MATERIALS AND METHODS: We conducted a pairwise and network meta-analysis of published randomized clinical trials of HPV vaccines according to sex and HPV infection status for nine HPV genotypes (HPV 6/11/16/18/31/33/45/52/58). RESULTS: Overall, 10 randomized controlled trials (12 articles) were included in this study. In the network meta-analysis, no statistically significant differences were observed in the prevention of carcinogenic HPV strains (16/18/31/33/45/52/58) between the 2v-HPV and 4v-HPV vaccines in female HPV infection-naïve populations. However, the 9v-HPV vaccine showed a significantly superior effect compared with 2v-HPV and 4v-HPV vaccines in preventing HPV 31/33/45/52/58 infections. Although 2v-HPV and 4v-HPV vaccines provided some cross-protection against HPV 31/33/45/52/58 infections, the effect was significant only on HPV 31 infection. For HPV 16 and 18, neither statistically significant nor small differences were found in the prevention of HPV infection among the 2v-HPV, 4v-HPV, and 9v-HPV vaccines. CONCLUSION: Our study complements previous understanding of how the effect of HPV vaccines differs according to the HPV genotype. This is important because HPV genotype prevalence varies among countries. We advocate for continued efforts in vaccinating against HPV, while public health agencies should consider the difference in the vaccine effect and HPV genotype prevalence when implementing HPV vaccination in public vaccination programs.

8.
BMC Health Serv Res ; 23(1): 1388, 2023 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-38082399

RESUMO

BACKGROUND: We determined the cost-effectiveness of the anti-vascular endothelial growth factor (VEGF) intravitreal injection versus panretinal photocoagulation (PRP) for patients with proliferative diabetic retinopathy (PDR) in South Korea. METHODS: We simulated four treatment strategies using PRP and the anti-VEGF injection by constructing a Markov model for a hypothetical cohort of 50-year-old PDR patients: (1) PRP only; (2) anti-VEGF injection only; (3) PRP first; and (4) anti-VEGF injection first. RESULTS: In this cost-effectiveness analysis, compared with only-PRP, the incremental cost-effectiveness ratio was $95,456 per quality-adjusted life-year (QALY) for PRP first, $34,375 per QALY for anti-VEGF injection first, and $33,405 per QALY for anti-VEGF injection only from a healthcare perspective. From the societal and payer perspective, strategy (2) was more cost-saving and effective than (1). In the probabilistic sensitivity analysis, only-PRP was cost-effective up to the willingness-to-pay (WTP) of about $42,000, while anti-VEGF injection only was cost-effective from a healthcare perspective. From the societal and payer perspectives, regardless of the value of WTP, anti-VEGF injection only was the most cost-effective strategy. CONCLUSION: In our study, the anti-VEGF injection for PDR was cost-effective from the payer and societal perspectives.


Assuntos
Diabetes Mellitus , Retinopatia Diabética , Humanos , Pessoa de Meia-Idade , Retinopatia Diabética/tratamento farmacológico , Retinopatia Diabética/cirurgia , Ranibizumab/uso terapêutico , Análise Custo-Benefício , Inibidores da Angiogênese/uso terapêutico , Fatores de Crescimento Endotelial/uso terapêutico , Injeções Intravítreas , Análise de Custo-Efetividade , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Fotocoagulação a Laser , Diabetes Mellitus/terapia
9.
Res Sq ; 2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37645926

RESUMO

HIV-1 infection elevates the risk of developing various cancers, including T-cell lymphoma. Whether HIV-1-encoded proteins directly contribute to oncogenesis remains unknown. We observed that approximately 1-5% of CD4+ T cells from the blood of people living with HIV-1 exhibit over-duplicated centrioles, suggesting that centrosome amplification underlies the development of HIV-1-associated cancers by driving aneuploidy. Through affinity purification, biochemical, and cell biology analyses, we discovered that Vpr, an accessory protein of HIV-1, hijacks the centriole duplication machinery and induces centrosome amplification and aneuploidy. Mechanistically, Vpr formed a cooperative ternary complex with an E3 ligase subunit, VprBP, and polo-like kinase 4 (Plk4). Unexpectedly, however, the complex enhanced Plk4's functionality by promoting its relocalization to the procentriole assembly and induced centrosome amplification. Loss of either Vpr's C-terminal 17 residues or VprBP acidic region, the two elements required for binding to Plk4 cryptic polo-box, abrogated Vpr's capacity to induce all these events. Furthermore, HIV-1 WT, but not its Vpr mutant, induced multiple centrosomes and aneuploidy in primary CD4+ T cells. We propose that the Vpr•VprBP•Plk4 complex serves as a molecular link that connects HIV-1 infection to oncogenesis and that inhibiting the Vpr C-terminal motif may reduce the occurrence of HIV-1-associated cancers.

10.
Proc Natl Acad Sci U S A ; 120(35): e2305037120, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37603740

RESUMO

Polo-like kinase 1 (Plk1) is considered an attractive target for anticancer therapy. Over the years, studies on the noncatalytic polo-box domain (PBD) of Plk1 have raised the expectation of generating highly specific protein-protein interaction inhibitors. However, the molecular nature of the canonical PBD-dependent interaction, which requires extensive water network-mediated interactions with its phospholigands, has hampered efforts to identify small molecules suitable for Plk1 PBD drug discovery. Here, we report the identification of the first allosteric inhibitor of Plk1 PBD, called Allopole, a prodrug that can disrupt intracellular interactions between PBD and its cognate phospholigands, delocalize Plk1 from centrosomes and kinetochores, and induce mitotic block and cancer cell killing. At the structural level, its unmasked active form, Allopole-A, bound to a deep Trp-Phe-lined pocket occluded by a latch-like loop, whose adjoining region was required for securely retaining a ligand anchored to the phospho-binding cleft. Allopole-A binding completely dislodged the L2 loop, an event that appeared sufficient to trigger the dissociation of a phospholigand and inhibit PBD-dependent Plk1 function during mitosis. Given Allopole's high specificity and antiproliferative potency, this study is expected to open an unexplored avenue for developing Plk1 PBD-specific anticancer therapeutic agents.


Assuntos
Proteínas de Ciclo Celular , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas , Divisão do Núcleo Celular , Quinase 1 Polo-Like
11.
J Korean Med Sci ; 38(23): e195, 2023 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-37309700

RESUMO

BACKGROUND: In Korea, during the early phase of the coronavirus disease 2019 (COVID-19) pandemic, we responded to the uncertainty of treatments under various conditions, consistently playing catch up with the speed of evidence updates. Therefore, there was high demand for national-level evidence-based clinical practice guidelines for clinicians in a timely manner. We developed evidence-based and updated living recommendations for clinicians through a transparent development process and multidisciplinary expert collaboration. METHODS: The National Evidence-based Healthcare Collaborating Agency (NECA) and the Korean Academy of Medical Sciences (KAMS) collaborated to develop trustworthy Korean living guidelines. The NECA-supported methodological sections and 8 professional medical societies of the KAMS worked with clinical experts, and 31 clinicians were involved annually. We developed a total of 35 clinical questions, including medications, respiratory/critical care, pediatric care, emergency care, diagnostic tests, and radiological examinations. RESULTS: An evidence-based search for treatments began in March 2021 and monthly updates were performed. It was expanded to other areas, and the search interval was organized by a steering committee owing to priority changes. Evidence synthesis and recommendation review was performed by researchers, and living recommendations were updated within 3-4 months. CONCLUSION: We provided timely recommendations on living schemes and disseminated them to the public, policymakers and various stakeholders using webpages and social media. Although the output was successful, there were some limitations. The rigor of development issues, urgent timelines for public dissemination, education for new developers, and spread of several new COVID-19 variants have worked as barriers. Therefore, we must prepare systematic processes and funding for future pandemics.


Assuntos
COVID-19 , Criança , Humanos , Adenosina-5'-(N-etilcarboxamida) , República da Coreia , SARS-CoV-2 , Guias de Prática Clínica como Assunto
12.
Yonsei Med J ; 64(6): 366-374, 2023 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-37226563

RESUMO

PURPOSE: The strategy of latent tuberculosis infection (LTBI) treatment in household tuberculosis (TB) contacts has been expanding in South Korea. However, there is little evidence of the cost-effectiveness of LTBI treatment in patients over 35 years of age. This study aimed to evaluate the cost-effectiveness of LTBI treatment among household TB contacts in different age groups in South Korea. MATERIALS AND METHODS: An age-structured model of TB was developed based on the reports from the Korea Disease Control and Prevention Agency and the National Health Insurance Service. Quality-adjusted life-years (QALY) and the averted number of TB-related deaths were estimated along with discounted costs for a measure of incremental cost-effectiveness ratios. RESULTS: The number of cumulative active TB cases would decrease by 1564 and 7450 under the scenario of LTBI treatment for those aged <35 years and <70 years, respectively, relative to the no-treatment scenario. The treatment strategies for patients aged 0 to <35 years, <55 years, <65 years, and <70 years would add 397, 1482, 3782, and 8491 QALYs at a cost of $660, $5930, $4560, and $2530, respectively, per QALY. For the averted TB-related deaths, LTBI treatment targeting those aged 0 to <35 years, <55 years, <65 years, and <70 years would avert 7, 89, 155, and 186 deaths at a cost of $35900, $99200, $111100, and $115700 per deaths, respectively, in 20 years. CONCLUSION: The age-specific expansion policy of LTBI treatment not only for those under 35 years of age but also for those under 65 years of age among household contacts was cost-effective in terms of QALYs and averted TB deaths.


Assuntos
Tuberculose Latente , Humanos , Adulto , Idoso , Tuberculose Latente/tratamento farmacológico , Análise Custo-Benefício , República da Coreia , Programas Nacionais de Saúde
13.
Sci Rep ; 13(1): 8783, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37258791

RESUMO

Parkinson's disease (PD) is an incurable movement disorder characterized by dopaminergic cell loss, neuroinflammation, and α-synuclein pathology. Herein, we investigated the therapeutic effects of necrosulfonamide (NSA), a specific inhibitor of mixed lineage kinase domain-like protein (MLKL), in a subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. MLKL is an executor of necroptosis, a programmed cell death pathway that causes inflammation. Repeated administration of NSA resulted in the recovery of impaired motor performance and dopaminergic degeneration. Furthermore, NSA inhibited the phosphorylation, ubiquitylation, and oligomerization of MLKL, all of which are associated with MLKL cell death-inducing activity in dopaminergic cells in the substantia nigra (SN). NSA also inhibited microglial activation and reactive astrogliosis as well as the MPTP-induced expression of proinflammatory molecules such as tumor necrosis factor-α, interleukin-1ß, inducible nitric oxide synthase, and cystatin F. Furthermore, NSA inhibited α-synuclein oligomerization and phosphorylation in the SN of MPTP-treated mice by inhibiting the activity of glycogen synthase kinase 3ß and matrix metalloproteinase-3. In conclusion, NSA has anti-necroptotic, anti-inflammatory, and anti-synucleinopathic effects on PD pathology. Therefore, NSA is a potential therapeutic candidate for PD.


Assuntos
Fármacos Neuroprotetores , Doença de Parkinson , Camundongos , Animais , Doença de Parkinson/metabolismo , alfa-Sinucleína/metabolismo , Fármacos Neuroprotetores/uso terapêutico , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Doenças Neuroinflamatórias , Necroptose , Inflamação/patologia , Neurônios Dopaminérgicos/metabolismo , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças
14.
ACS Pharmacol Transl Sci ; 6(3): 422-446, 2023 Mar 10.
Artigo em Inglês | MEDLINE | ID: mdl-36926457

RESUMO

Polo-like kinase 1 (Plk1), a mitotic kinase whose activity is widely upregulated in various human cancers, is considered an attractive target for anticancer drug discovery. Aside from the kinase domain, the C-terminal noncatalytic polo-box domain (PBD), which mediates the interaction with the enzyme's binding targets or substrates, has emerged as an alternative target for developing a new class of inhibitors. Various reported small molecule PBD inhibitors exhibit poor cellular efficacy and/or selectivity. Here, we report structure-activity relationship (SAR) studies on triazoloquinazolinone-derived inhibitors, such as 43 (a 1-thioxo-2,4-dihydrothieno[2,3-e][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-one) that effectively block Plk1, but not Plk2 and Plk3 PBDs, with improved affinity and drug-like properties. The range of prodrug moieties needed for thiol group masking of the active drugs has been expanded to increase cell permeability and mechanism-based cancer cell (L363 and HeLa) death. For example, a 5-thio-1-methyl-4-nitroimidazolyl prodrug 80, derived from 43, showed an improved cellular potency (GI50 4.1 µM). As expected, 80 effectively blocked Plk1 from localizing to centrosomes and kinetochores and consequently induced potent mitotic block and apoptotic cell death. Another prodrug 78 containing 9-fluorophenyl in place of the thiophene-containing heterocycle in 80 also induced a comparable degree of anti-Plk1 PBD effect. However, orally administered 78 was rapidly converted in the bloodstream to parent drug 15, which was shown be relatively stable toward in vivo oxidation due to its 9-fluorophenyl group in comparison to unsubstituted phenyl. Further derivatization of these inhibitors, particularly to improve the systemic prodrug stability, could lead to a new class of therapeutics against Plk1-addicted cancers.

15.
Front Biosci (Landmark Ed) ; 28(12): 344, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38179767

RESUMO

BACKGROUND: Activating transcription factor 4 (ATF4) is a fundamental basic-leucine zipper transcription factor that plays a pivotal role in numerous stress responses, including endoplasmic reticulum (ER) stress and the integrated stress response. ATF4 regulates adaptive gene expression, thereby triggering stress resistance in cells. METHODS: To characterize the metabolic status of atf4-⁣/- Drosophila larvae, we conducted both metabolomic and microarray analyses. RESULTS: Metabolomic analysis demonstrated an increase in lactate levels in atf4-⁣/- mutants when compared to wild-type flies. However, there was a significant reduction in adenosine triphosphate (ATP) synthesis in the atf4-⁣/- flies, suggesting an abnormal energy metabolism in the mutant larvae. Microarray analysis unveiled that Drosophila ATF4 controls gene expression related to diverse biological processes, including lipase activity, oxidoreductase activity, acyltransferase, immune response, cell death, and transcription factor, particularly under nutrient-restricted conditions. In situ hybridization analysis further demonstrated specific augmentation of CG6283, classified as a gastric lipase, within the gastric caeca of nutrient-restricted flies. Moreover, overexpression of lipases, CG6283 and CG6295, made the flies resistant to starvation. CONCLUSIONS: These findings underscore the role of Drosophila ATF4 in responding to metabolic fluctuations and modulating gene expression associated with metabolism and stress adaptation. Dysregulation of ATF4 may detrimentally impact the development and physiology of Drosophila.


Assuntos
Fator 4 Ativador da Transcrição , Drosophila , Animais , Drosophila/genética , Drosophila/metabolismo , Fator 4 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/metabolismo , Regulação da Expressão Gênica , Estresse Fisiológico/genética , Lipase/genética , Lipase/metabolismo
16.
Polymers (Basel) ; 14(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36501711

RESUMO

The gingerols and shogaols derived from ginger have excellent antibacterial properties against oral bacteria. However, some researchers have noted their dose-dependent potential toxicity. The aim of this study was to enhance the biofunctionality and biocompatibility of the application of ginger to dental titanium screws. To increase the amount of coating of the n-hexane-fractionated ginger on the titanium surface and to control its release, ginger was loaded in different concentrations in a photo-crosslinkable GelMA hydrogel. To improve coating stability of the ginger hydrogel (GH), the wettability of the surface was modified by pre-calcification (TNC), then GH was applied on the surface. As a result, the ginger fraction, with a high content of phenolic compounds, was effective in the inhibition of the growth of S. mutans and P. gingivalis. The GH slowly released the main compounds of ginger and showed excellent antibacterial effects with the concentration. Although bone regeneration was slightly reduced with the ginger-loading concentration due to the increased contents of polyphenolic compounds, it was strongly supplemented through the promotion of osteosis formation by the hydrogel and TNC coating. Finally, we proved the biosafety and superior biofunctionalities the GH-TNC coating on a Ti implant. However, it is recommended to use an appropriate concentration, because an excessive concentration of ginger may affect the improved biocompatibility in clinical applications.

17.
Oral Health Prev Dent ; 20(1): 313-320, 2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35866677

RESUMO

PURPOSE: To examine the association between the intake of various nutrients (phosphorus, riboflavin, thiamine, niacin, vitamin C, calcium, protein, carbohydrates, and fat) and the prevalence of periodontal disease in Korean adults. MATERIALS AND METHODS: The data used for analysis were obtained from the 7th Korea National Health and Nutrition Examination Survey (2016-2018). Data from 12,689 adults aged ≥ 19 years who had a periodontal examination were analysed. Data were analysed using the Chi2 and t-tests. Multiple regression analysis was used to assess the association between the selected nutrients and periodontal diseases. RESULTS: After adjusting for sex, age, income, body mass index, diabetes, smoking, alcohol consumption, and toothbrushing frequency, a statistically significant relationship between phosphorus, carbohydrate, and fat intake and the risk of periodontal disease was identified by multiple logistic regression analysis (odds ratio [OR]: 0.80, 95% confidence interval [CI]: 0.66-0.97; OR: 0.85, 95% CI: 0.70-0.98, OR: 1.41, 95% CI: 1.13-1.75, respectively). CONCLUSION: Phosphorus, carbohydrates and fat were associated with periodontal disease. Therefore, the improvement of diet should be emphasised to prevent and manage periodontal disease. Further research is needed based on various nutrients related to periodontal disease in the future.


Assuntos
Dieta , Doenças Periodontais , Adulto , Carboidratos da Dieta/administração & dosagem , Gorduras na Dieta/administração & dosagem , Humanos , Inquéritos Nutricionais , Doenças Periodontais/epidemiologia , Fósforo/administração & dosagem , República da Coreia/epidemiologia
18.
Sci Rep ; 12(1): 10544, 2022 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-35732806

RESUMO

Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and its incidence is predicted to increase worldwide. Striatal dopamine depletion caused by substantia nigra (SN) degeneration is a pathological hallmark of PD and is strongly associated with cardinal motor and non-motor symptoms. Previous studies have reported that exercise increases neuroplasticity and promotes neurorestoration by increasing neurotrophic factors and synaptic strength and stimulating neurogenesis in PD. In the present study, we found that rotarod walking exercise, a modality of motor skill learning training, improved locomotor disturbances and reduced nigrostriatal degeneration in the subacute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. In addition, our exercise regimen improved MPTP-induced perturbation of adult neurogenesis in some areas of the brain, including the subventricular zone, subgranular zone, SN, and striatum. Moreover, rotarod walking activated the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and induced brain-derived neurotrophic factor (BDNF) expression in these regions. The results suggest that motor skill learning training using rotarod walking improves adult neurogenesis and restores motor performance by modulating the AMPK/BDNF pathway. Therefore, our findings provide evidence for neuroprotective effects and improved neuroplasticity in PD through motor skill learning training.


Assuntos
Doença de Parkinson Secundária , Caminhada , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Corpo Estriado/metabolismo , Modelos Animais de Doenças , Neurônios Dopaminérgicos/metabolismo , Ventrículos Laterais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Doença de Parkinson Secundária/induzido quimicamente , Substância Negra/metabolismo
19.
Artigo em Inglês | MEDLINE | ID: mdl-35409556

RESUMO

This study aimed to investigate the association between healthy lifestyle (HLS; i.e., diet quality, physical activity, normal weight) and periodontal diseases in Korean adults. Studying this association may help inform future intervention programs aimed at preventing the development of periodontal diseases. Raw data of the Korea National Health and Nutrition Examination Survey (KNHANES) VII (2016-2018) were used. Data from 12,689 adults aged 19 years and over who had a periodontal examination were analyzed. The associations between HLS and periodontal diseases were analyzed using multivariate logistic regression after adjusting for demographic and health factors as covariates. We found that each of the HLS (diet quality, physical activity, normal body weight) practices was significantly associated with periodontal diseases (OR: 1.32, 95% CI: 1.13-1.55; OR: 1.16, 95% CI: 1.04-1.30; OR: 1.26, 95% CI: 1.14-1.40, respectively). In particular, having poor HLS practices was identified as a risk factor for periodontal diseases (OR: 1.54, 95% CI: 1.10-2.15). HLS was associated with periodontal diseases. Thus, in addition to improving oral hygiene-the primary focus in the past-improving HLS should be emphasized for patients with periodontal diseases.


Assuntos
Peso Corporal Ideal , Doenças Periodontais , Adulto , Dieta , Exercício Físico , Estilo de Vida Saudável , Humanos , Inquéritos Nutricionais , Doenças Periodontais/epidemiologia , República da Coreia/epidemiologia
20.
Artigo em Inglês | MEDLINE | ID: mdl-35010778

RESUMO

This study aimed to identify the associated factors for protective behaviors for dental radiation exposure (PBDRE) among dental hygienists using the health belief model (HBM). The HBM, which is composed of perceived susceptibility, perceived seriousness, perceived benefits, perceived barriers, and cues to action, explains preventive behavior. In this study, self-efficacy and modifying factors were additionally applied to the HBM. The subjects of the study were 204 dental hygienists who were working at hospitals or clinics in Korea. An online survey was conducted to measure PBDRE-related factors based on the HBM and self-efficacy. The collected data were analyzed using frequency analysis, t-tests, ANOVA, Pearson's correlation analysis, and hierarchical multiple regression analysis. Regarding modifying factors, performance was found to be high when protection facilities were sufficient (ß = 0.24, p < 0.001) and low when radiation education was not received (ß = -0.16, p < 0.05). Among the HBM factors, cues to action for PBDRE (ß = 0.28, p < 0.001) was the most influential factor in the performance of PBDRE, and the effect of its perceived benefits on radiation exposure was also high (ß = 0.17, p < 0.001). Regarding the performance of PBDRE according to the HBM, providing education programs on protection can stimulate appropriate cues to action to perform PBDRE. In addition, if the benefits of PBDRE are highlighted, the performance of PBDRE by dental hygienists is increased.


Assuntos
Higienistas Dentários , Exposição à Radiação , Feminino , Comportamentos Relacionados com a Saúde , Modelo de Crenças de Saúde , Conhecimentos, Atitudes e Prática em Saúde , Humanos
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