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1.
Oncol Rep ; 47(2)2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34841437

RESUMO

Renal cell carcinoma (RCC) is an aggressive genitourinary malignancy which has been associated with a poor prognosis, particularly in patients with metastasis, its major subtypes being clear cell RCC (ccRCC), papillary PCC (pRCC) and chromophobe RCC (chRCC). The presence of intracellular lipid droplets (LDs) is considered to be a hallmark of ccRCC. The importance of an altered lipid metabolism in ccRCC has been widely recognized. The elongation of very­long­chain fatty acid (ELOVL) catalyzes the elongation of fatty acids (FAs), modulating lipid composition, and is required for normal bodily functions. However, the involvement of elongases in RCC remains unclear. In the present study, the expression of ELOVL2 in ccRCC was examined; in particular, high levels of seven ELOVL isozymes were observed in primary tumors. Of note, elevated ELOVL2 expression levels were observed in ccRCC, as well as in pRCC and chRCC. Furthermore, a higher level of ELOVL2 was significantly associated with the increased incidence of a poor prognosis of patients with ccRCC and pRCC. The CRISPR/Cas9­mediated knockdown of ELOVL2 resulted in the suppression of the elongation of long­chain polyunsaturated FAs and increased LD production in renal cancer cells. Moreover, ELOVL2 ablation resulted in the suppression of cellular proliferation via the induction of apoptosis in vitro and the attenuation of tumor growth in vivo. On the whole, the present study provides new insight into the tumor proliferation mechanisms involving lipid metabolism, and suggests that ELOVL2 may be an attractive novel target for RCC therapy.

2.
Neurosci Res ; 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34856199

RESUMO

Sleep pressure, the driving force of the homeostatic sleep regulation, is accumulated during wakefulness and dissipated during sleep. Sleep deprivation (SD) has been used as a method to acutely increase animal's sleep pressure for investigating the molecular changes under high sleep pressure. However, SD induces changes not only reflecting increased sleep pressure but also inevitable stresses and prolonged wake state itself. The Sik3Sleepy mutant mice (Sleepy) exhibit constitutively high sleep pressure despite sleeping longer, and have been useful as a model of increased sleep pressure. Here we conducted a cross-comparison of brain metabolomic profiles between SD versus ad lib slept mice, as well as Sleepy mutant versus littermate wild-type mice. Targeted metabolome analyses of whole brains quantified 203 metabolites in total, of which 43 metabolites showed significant changes in SD, whereas three did in Sleepy mutant mice. The large difference in the number of differential metabolites highlighted limitations of SD as methodology. The cross-comparison revealed that a decrease in betaine and an increase in imidazole dipeptides are associated with high sleep pressure in both models. These metabolites may be novel markers of sleep pressure at the whole-brain level. Furthermore, we found that intracerebroventricular injection of imidazole dipeptides increased subsequent NREM sleep time, suggesting the possibility that imidazole dipeptides may participate in the regulation of sleep in mice.

3.
Small ; : e2102979, 2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34713587

RESUMO

In atomic force microscopy, the cantilever probe is a critical component whose properties determine the resolution and speed at which images with nanoscale resolution can be obtained. Traditional cantilevers, which have moderate resonant frequencies and high quality factors, have relatively long response times and low bandwidths. In addition, cantilevers can be easily damaged by excessive deformation, and tips can be damaged by wear, requiring them to be replaced frequently. To address these issues, new cantilever probes that have hollow cross-sections and walls of nanoscale thicknesses made of alumina deposited by atomic layer deposition are introduced. It is demonstrated that the probes exhibit spring constants up to ≈100 times lower and bandwidths up to ≈50 times higher in air than their typical solid counterparts, allowing them to react to topography changes more quickly. Moreover, it is shown that the enhanced robustness of the hollow cantilevers enables them to withstand large bending displacements more readily and to be more resistant to tip wear.

4.
Cardiovasc Diabetol ; 20(1): 174, 2021 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479567

RESUMO

BACKGROUND: Although both a history of cerebrovascular disease (CVD) and glucose abnormality are risk factors for CVD, few large studies have examined their association with subsequent CVD in the same cohort. Thus, we compared the impact of prior CVD, glucose status, and their combinations on subsequent CVD using real-world data. METHODS: This is a retrospective cohort study including 363,627 men aged 18-72 years followed for ≥ 3 years between 2008 and 2016. Participants were classified as normoglycemia, borderline glycemia, or diabetes defined by fasting plasma glucose, HbA1c, and antidiabetic drug prescription. Prior and subsequent CVD (i.e. ischemic stroke, transient ischemic attack, and non-traumatic intracerebral hemorrhage) were identified according to claims using ICD-10 codes, medical procedures, and questionnaires. RESULTS: Participants' mean age was 46.1 ± 9.3, and median follow up was 5.2 (4.2, 6.7) years. Cox regression analysis showed that prior CVD + conferred excess risk for CVD regardless of glucose status (normoglycemia: hazard ratio (HR), 8.77; 95% CI 6.96-11.05; borderline glycemia: HR, 7.40, 95% CI 5.97-9.17; diabetes: HR, 5.73, 95% CI 4.52-7.25). Compared with normoglycemia, borderline glycemia did not influence risk of CVD, whereas diabetes affected subsequent CVD in those with CVD- (HR, 1.50, 95% CI 1.34-1.68). In CVD-/diabetes, age, current smoking, systolic blood pressure, high-density lipoprotein cholesterol, and HbA1c were associated with risk of CVD, but only systolic blood pressure was related to CVD risk in CVD + /diabetes. CONCLUSIONS: Prior CVD had a greater impact on the risk of CVD than glucose tolerance and glycemic control. In participants with diabetes and prior CVD, systolic blood pressure was a stronger risk factor than HbA1c. Individualized treatment strategies should consider glucose tolerance status and prior CVD.

5.
J Orthop Sci ; 2021 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-34404611

RESUMO

BACKGROUND: Central sensitization is one cause of chronic low back pain. Lifestyle and psychosocial factors are involved in the exacerbation of central sensitization. However, the combined effects of these factors on central sensitization in patients with chronic low back pain are unclear. The objective of this study was to investigate the combined effects of lifestyle and psychosocial factors on central sensitization in patients with chronic low back pain. METHODS: This was a cross-sectional study. The participants were recruited from three orthopedic clinics for a total of 70 patients with chronic low back pain. Data were analyzed using hierarchical multiple regression analysis. In Model 1, lifestyle factors such as sleep quality, physical activity, sitting time, and perceived stress were included. Model 2 included psychosocial factors (pain catastrophizing, anxiety, and depression). RESULTS: The data showed that sleep (b = 0.30) and perceived stress (b = 0.47) were significantly correlated in Model 1, and anxiety (b = 0.41) and perceived stress (b = 0.27) were significantly correlated in Model 2. Furthermore, contributions from sleep (b = 0.14) decreased, and no significant correlations were observed. The coefficient of determination increased significantly from Model 1 to Model 2 (ΔR 2 = 0.12, p < 0.05). CONCLUSIONS: In this study, we clarified that perceived stress and anxiety were correlated with central sensitization in patients with chronic low back pain. In addition, sleep quality mediates anxiety and may be associated with central sensitization.

6.
Biomed Res Int ; 2021: 9731280, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368356

RESUMO

A fluoride-releasing adhesive system is expected to promote mineralization of demineralized dentin/enamel around a composite restoration, thereby contributing to the longevity of the restoration. Scanning electron microscopic (SEM) and transmission electron microscopic (TEM) observations revealed the formation of an "acid-base resistant zone" (ABRZ) beneath the hybrid layer when dentin was treated with a self-etch adhesive system. A thicker ABRZ was formed from the upper slope to the end of the outer lesion, indicating greater resistance against an acid-base challenge, when a fluoride-releasing self-etch adhesive system was used. The slope formation of a fluoride-releasing adhesive is believed to be due to fluoride-release from the adhesive. Quantitative assessment of the acid resistance was performed at the interface using the region of interest (ROI) mode of a digital image analysis software package. The area of the ABRZ is influenced by the concentration of fluoride release from the adhesive resin. The threshold of fluoride concentration in the adhesive may exist to influence the morphology of the ABRZ. X-ray absorption fine structure (XAFS) analysis of the dentin treated with different concentrations of NaF-mouth rinses suggested that different fluoride concentrations result in the formation of different chemical compounds, such as fluorapatite and CaF2-like structures, on the dentin surface. This may explain the differences in µTBS values and morphological appearance of the ABRZ. NaF is effective in enhancing the enamel/dentin bond durability and also helps create a high quality of ARBZ to improve the clinical success of restorations.


Assuntos
Condicionamento Ácido do Dente , Ácidos/química , Adesivos/química , Álcalis/química , Fluoretos/análise , Dentina/ultraestrutura
7.
J Bacteriol ; 203(16): e0002521, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34096778

RESUMO

Serine kinase catalyzes the phosphorylation of free serine (Ser) to produce O-phosphoserine (Sep). An ADP-dependent Ser kinase in the hyperthermophilic archaeon Thermococcus kodakarensis (Tk-SerK) is involved in cysteine (Cys) biosynthesis and most likely Ser assimilation. An ATP-dependent Ser kinase in the mesophilic bacterium Staphylococcus aureus is involved in siderophore biosynthesis. Although proteins displaying various degrees of similarity with Tk-SerK are distributed in a wide range of organisms, it is unclear if they are actually Ser kinases. Here, we examined proteins from Desulfurococcales species in Crenarchaeota that display moderate similarity with Tk-SerK from Euryarchaeota (42 to 45% identical). Tk-serK homologs from Staphylothermus marinus (Smar_0555), Desulfurococcus amylolyticus (DKAM_0858), and Desulfurococcus mucosus (Desmu_0904) were expressed in Escherichia coli. All three partially purified recombinant proteins exhibited Ser kinase activity utilizing ATP rather than ADP as a phosphate donor. Purified Smar_0555 protein displayed activity for l-Ser but not other compounds, including d-Ser, l-threonine, and l-homoserine. The enzyme utilized ATP, UTP, GTP, CTP, and the inorganic polyphosphates triphosphate and tetraphosphate as phosphate donors. Kinetic analysis indicated that the Smar_0555 protein preferred nucleoside 5'-triphosphates over triphosphate as a phosphate donor. Transcript levels and Ser kinase activity in S. marinus cells grown with or without serine suggested that the Smar_0555 gene is constitutively expressed. The genes encoding Ser kinases examined here form an operon with genes most likely responsible for the conversion between Sep and 3-phosphoglycerate of central sugar metabolism, suggesting that the ATP-dependent Ser kinases from Desulfurococcales play a role in the assimilation of Ser. IMPORTANCE Homologs of the ADP-dependent Ser kinase from the archaeon Thermococcus kodakarensis (Tk-SerK) include representatives from all three domains of life. The results of this study show that even homologs from the archaeal order Desulfurococcales, which are the most structurally related to the ADP-dependent Ser kinases from the Thermococcales, are Ser kinases that utilize ATP, and in at least some cases inorganic polyphosphates, as the phosphate donor. The differences in properties between the Desulfurococcales and Thermococcales enzymes raise the possibility that Tk-SerK homologs constitute a group of kinases that phosphorylate free serine with a wide range of phosphate donors.


Assuntos
Proteínas Arqueais/metabolismo , Desulfurococcaceae/enzimologia , Proteínas Serina-Treonina Quinases/metabolismo , Trifosfato de Adenosina/metabolismo , Proteínas Arqueais/química , Proteínas Arqueais/genética , Desulfurococcaceae/classificação , Desulfurococcaceae/genética , Temperatura Alta , Cinética , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/genética , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo
8.
J Adhes Dent ; 23(3): 233-242, 2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34060303

RESUMO

PURPOSE: To investigate the effects of several etching products prior to the application of a one-step self-etch adhesive (1-SEA) or two-step self-etch adhesive (2-SEA) on enamel by microshear bond strength (µSBS) testing and observation of the adhesive-enamel interface. MATERIALS AND METHODS: Ground human enamel surfaces were randomly assigned to one of eight groups according to the combination of surface treatments (either no conditioner [NC], ME [Multi Etchant], EC [Enamel Conditioner], or KE [K-etchant Gel]) and adhesive (ADU [Adhese Universal] or SE2 [Clearfil SE Bond 2]). All groups were further divided into two subgroups: 0 or 10,000 thermal cycles (TC). Then, the µSBS test was performed. The adhesive-enamel interface after acid-base challenge and the surface structure after conditioner application were also observed. RESULTS: With 10,000 TCs, there was no statistically significant difference between ME-ADU and NC-ADU. On the other hand, the µSBS of EC-ADU or KE-ADU was significantly higher than that of NC-ADU, while that of ME-SE2 was significantly lower than NC-SE2. There was no significant difference between EC-SE2, NC-SE2, and KE-SE2. Formation of an acid-base resistance zone (ABRZ) was confirmed in all groups. However, funnel-shaped erosion, which indicates interfacial defects, was observed in the NC-ADU, ME-ADU, and ME-SE2 groups. CONCLUSION: For enamel bonding, application of EC or KE prior to ADU increased the bond strength and created a stable adhesive-enamel interface. On the other hand, SE2 also had stable shear bond strength and interface without the use of conditioners. However, ME decreased the bonding performance of SE2.


Assuntos
Condicionamento Ácido do Dente , Colagem Dentária , Cimentos Dentários , Esmalte Dentário , Humanos , Teste de Materiais
9.
Cancer Cell ; 39(6): 793-809.e8, 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34129823

RESUMO

Upper urinary tract urothelial carcinoma (UTUC) is one of the common urothelial cancers. Its molecular pathogenesis, however, is poorly understood, with no useful biomarkers available for accurate diagnosis and molecular classification. Through an integrated genetic study involving 199 UTUC samples, we delineate the landscape of genetic alterations in UTUC enabling genetic/molecular classification. According to the mutational status of TP53, MDM2, RAS, and FGFR3, UTUC is classified into five subtypes having discrete profiles of gene expression, tumor location/histology, and clinical outcome, which is largely recapitulated in an independent UTUC cohort. Sequencing of urine sediment-derived DNA has a high diagnostic value for UTUC with 82.2% sensitivity and 100% specificity. These results provide a solid basis for better diagnosis and management of UTUC.

10.
Dent Mater J ; 40(5): 1122-1128, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33980749

RESUMO

This study aimed to assess the effects of a temporary sealing material and cleaning method of resin-coated dentin on the bond strength of computer-aided design/computer-aided manufacturing (CAD/CAM) inlay restorations. Resin-coated dentin surfaces were unsealed or temporarily sealed for 1 h or 1 week. For the temporarily sealed group, a hydraulic temporary sealing material was removed and further divided into four groups: without cleaning, cleaned with a rotational brush, a universal cleaner or an air-polishing device. Some specimens were investigated with energy dispersive X-ray spectroscopy and the others were used for microtensile bond strength (MTBS) test. A sealing material could not be removed with a rotational brush, which resulted in pretest failures in all specimens after 1 h and which resulted in low MTBS after 1 week. An air-polishing device can clean resin-coated dentin temporarily sealed with a hydraulic temporary sealing material and resulted in the similar MTBS as in the unsealed group.


Assuntos
Colagem Dentária , Adesivos Dentinários , Desenho Assistido por Computador , Dentina , Restaurações Intracoronárias , Teste de Materiais , Cimentos de Resina , Propriedades de Superfície , Resistência à Tração
11.
Diabetes Care ; 44(9): 2124-2131, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34035075

RESUMO

OBJECTIVE: To determine associations of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with new-onset coronary artery disease (CAD) or cerebrovascular disease (CVD) according to glucose status. RESEARCH DESIGN AND METHODS: Examined was a nationwide claims database from 2008 to 2016 on 593,196 individuals. A Cox proportional hazards model identified risks of CAD and CVD events among five levels of SBP and DBP. RESULTS: During the study period 2,240 CAD and 3,207 CVD events occurred. Compared with SBP ≤119 mmHg, which was the lowest quintile of SBP, hazard ratios (95% CI) for CAD/CVD in the 4 higher quintiles (120-129, 130-139, 140-149, ≥150 mmHg) gradually increased from 2.10 (1.73-2.56)/1.46 (1.27-1.68) in quintile 2 to 3.21 (2.37-4.34)/4.76 (3.94-5.75) in quintile 5 for normoglycemia, from 1.39 (1.14-1.69)/1.70 (1.44-2.01) in quintile 2 to 2.52 (1.95-3.26)/4.12 (3.38-5.02) in quintile 5 for borderline glycemia, and from 1.50 (1.19-1.90)/1.72 (1.31-2.26) in quintile 2 to 2.52 (1.95-3.26)/3.54 (2.66-4.70) in quintile 5 for diabetes. A similar trend was observed for DBP across 4 quintiles (75-79, 80-84, 85-89, and ≥90 mmHg) compared with ≥74 mmHg, which was the lowest quintile. CONCLUSIONS: Results indicated that cardiovascular risks gradually increased with increases in SBP and DBP regardless of the presence of and degree of a glucose abnormality. Further interventional trials are required to apply findings from this cohort study to clinical practice.


Assuntos
Doenças Cardiovasculares , Transtornos Cerebrovasculares , Doença da Artéria Coronariana , Hipertensão , Pressão Sanguínea , Transtornos Cerebrovasculares/epidemiologia , Estudos de Coortes , Doença da Artéria Coronariana/epidemiologia , Glucose , Humanos , Incidência , Fatores de Risco
12.
ACS Chem Biol ; 16(5): 794-799, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-33877806

RESUMO

Most kinases utilize ATP as a phosphate donor and phosphorylate a wide range of phosphate acceptors. An alternative phosphate donor is inorganic pyrophosphate (PPi), which costs only 1/1000 of ATP. To develop a method to engineer PPi-dependent kinases, we herein aimed to alter the product of PPi-dependent myo-inositol kinase from d-myo-inositol 1-phosphate to d-myo-inositol 3-phosphate. For this purpose, we introduced the myo-inositol recognition residues of the ATP-dependent myo-inositol-3-kinase into the PPi-dependent myo-inositol-1-kinase. This replacement was expected to change the 3D arrangements of myo-inositol in the active site and bring the hydroxyl group at the 3C position close to the catalytic residue. LC-MS and NMR analyses proved that the engineered enzyme successfully produced myo-inositol 3-phosphate from PPi and myo-inositol.


Assuntos
Difosfatos/química , Monoéster Fosfórico Hidrolases/química , Thermotoga maritima/enzimologia , Domínio Catalítico , Cristalização , Fosfatos de Inositol/química , Cinética , Espectroscopia de Ressonância Magnética , Proteínas Mutantes/química , Mutação , Fosforilação , Conformação Proteica , Espectrometria de Massas em Tandem
13.
Dent Mater J ; 40(5): 1086-1093, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33883354

RESUMO

In this study, the influence of primer contamination on enamel bonding was analyzed. Adper Scotchbond Multi-Purpose (SMP), CLEARFIL SE Bond 2 (SE2), Scotchbond Universal (SBU) Adhesive, and Scotchbond Etchant (35% phosphoric acid; PA) were used. Ground bovine enamels were divided into eight groups based on the bonding protocols. The bonding interfaces after an acid-base challenge were observed via scanning electron microscopy to determine the acid-base resistant zone (ABRZ). Moreover, the bonding interfaces after the nanoleakage challenge were analyzed via energy-dispersive X-ray spectroscopy. ABRZ was observed in all the samples except PA_ONLY (applied PA etching, No primer and No adhesive resin). The funnel-shaped erosion was detected only in X_SBU (applied SBU without PA etching). The nanoleakage test revealed silver patterns in some groups. The nanoleakage, i.e., the penetration of the silver ions, was detected in the groups wherein primer was applied on PA-pre-etched enamel.


Assuntos
Condicionamento Ácido do Dente , Colagem Dentária , Animais , Bovinos , Esmalte Dentário , Teste de Materiais , Microscopia Eletrônica de Varredura , Ácidos Fosfóricos , Cimentos de Resina , Propriedades de Superfície , Resistência à Tração
14.
Org Lett ; 23(8): 3058-3063, 2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33822636

RESUMO

A five-step total synthesis of (±)-aspidospermidine (1) based on a lactam strategy is reported. Our synthesis features an iridium-catalyzed reductive Michael addition/[3+2] cycloaddition cascade to give a tricyclic ketone intermediate from a simple lactam via an azomethine ylide. The developed strategy enables easily available lactams to be used as stable surrogates of multisubstituted amines and would be applicable to a unified total synthesis of complex Aspidosperma alkaloids.

15.
Dent Mater J ; 40(4): 903-910, 2021 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33775983

RESUMO

The purpose of this study was to investigate the influence of phosphoric acid etching, metal primer or silane coupling agent application on dentin bonding performance of a 2-step self-etch adhesive system. Human dentin surfaces were prepared and divided into four groups depending on the pre-treatment method: no pretreatment (Clearfil SE Bond 2, CONTROL); 40% phosphoric acid (K-Etchant GEL, K); metal primer (Alloy Primer, AP); or silane coupling agent (Porcelain Bond Activator, PB). The specimens were sectioned into beams, separated into 2 subgroups (n=20): no thermocyling or thermocycled (TC), and subjected to a µTBS test and an acid-base challenge for SEM observation. Statistically lower results were observed between K and AP groups, PB and CONTROL, and PB with/without TC (p<0.05). SEM images at the dentin-adhesive interface revealed that all groups produced an acid-base resistant zone (ABRZ), with a funnel-shaped erosion under the ABRZ for the K group.


Assuntos
Colagem Dentária , Adesivos Dentinários , Condicionamento Ácido do Dente , Dentina , Humanos , Teste de Materiais , Cimentos de Resina , Propriedades de Superfície , Resistência à Tração
16.
Diabetes Obes Metab ; 23(7): 1660-1665, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33769665

RESUMO

Sodium-glucose cotransporter-2 inhibitors (SGLT2) are drugs that have been reported to have several effects through the regulation of plasma volume, for example, antihypertensive effects. This study aimed to clarify the impact of long-term administration and subsequent discontinuation of the SGLT2 inhibitor tofogliflozin on estimated plasma volume (ePV), brain natriuretic peptide (BNP) and the relationship between changes in ePV, BNP and body weight (BW). Data from 157 participants with type 2 diabetes receiving tofogliflozin monotherapy in a phase 3 study were analysed. Changes in variables or correlations among them during a 52-week administration and a 2-week post-treatment period were investigated. Percent change in ePV was calculated using the Strauss formula. Significant decreases in BW, ePV and ln-transformed BNP (ln-BNP) were noted by week 52. %ΔBW was not significantly correlated with %ΔePV and Δln-BNP, while %ΔePV was significantly correlated with Δln-BNP. Two weeks after discontinuation of tofogliflozin, BW, ePV and ln-BNP were significantly increased. %ΔBW was significantly correlated with %ΔePV and Δln-BNP. Furthermore, ePV and BNP were significantly higher than baseline levels.


Assuntos
Diabetes Mellitus Tipo 2 , Preparações Farmacêuticas , Inibidores do Transportador 2 de Sódio-Glicose , Compostos Benzidrílicos/efeitos adversos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Glucose , Glucosídeos , Humanos , Volume Plasmático , Sódio , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Perda de Peso
17.
Cancer Immunol Immunother ; 70(9): 2529-2543, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33570675

RESUMO

Intravesical Bovis bacillus Calmette-Guérin (BCG) therapy is the most effective immunotherapy for bladder cancer, but it sometime causes serious side effects because of its inclusion of live bacteria. It is necessary to develop a more active but less toxic immunotherapeutic agent. Trehalose 6,6'-dimycolate (TDM), the most abundant hydrophobic glycolipid of the BCG cell wall, has been reported to show various immunostimulatory activities such as granulomagenesis and adjuvant activity. Here, we developed cationic liposomes incorporating TDM purified from Mycobacterium bovis BCG Connaught, and we investigated the antitumor effect of the cationic liposome TDM (Lip-TDM). Lip-TDM exerted an antitumor effect in bladder cancer, colon cancer, and melanoma-bearing mouse models that was comparable or even superior to that of BCG, with no body weight loss or granuloma formation. The antitumor effect of Lip-TDM disappeared in two types of mice: those with depletion of CD8+ T cells, and those with knockout of macrophage-inducible C-type lectin (Mincle) which recognize TDM. Lip-TDM treatment enhanced the maturation and migration of dendritic cells in the tumor microenvironment in a Mincle-dependent manner. Our results elucidate mechanisms that underlie Lip-TDM treatment and suggest that Lip-TDM has potential as a safe and effective treatment for various cancers.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Fatores Corda/administração & dosagem , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Fatores Imunológicos/administração & dosagem , Mycobacterium bovis , Adjuvantes Imunológicos , Animais , Antineoplásicos Imunológicos/química , Antineoplásicos Imunológicos/isolamento & purificação , Linfócitos T CD8-Positivos/metabolismo , Fracionamento Químico , Fatores Corda/química , Fatores Corda/isolamento & purificação , Citocinas/metabolismo , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Feminino , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Imunofenotipagem , Infusões Parenterais , Lipossomos , Ativação Linfocitária , Camundongos , Estrutura Molecular , Mycobacterium bovis/química , Solventes , Resultado do Tratamento , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Bioorg Med Chem ; 34: 116041, 2021 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-33549907

RESUMO

Madangamines are marine natural products isolated from Xestospongia ingens, and madangamine A-E with a different D-ring structure have been reported. We have reported that madangamine A has strong anti-proliferative activity against various human cancer cell lines. In this study, to clarify the anti-proliferative activity of madangamine A, we searched for molecular target of the madangamine A in human cells. Treatment with madangamine A increased the levels of LC3-II and p62, autophagy-related proteins, concomitant with growth inhibition. Moreover, madangamine A resulted in lysosome enlargement and increase in lysosomal pH, which are same phenomena observed in chloroquine-treated cells. These results suggest that madangamine A is a novel lysosome inhibitor, and the anti-proliferative activity of madangamine A is due to the inhibition of lysosome function.


Assuntos
Autofagia/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Poríferos/química , Animais , Produtos Biológicos , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/química , Humanos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Estrutura Molecular , Regulação para Cima
19.
Mol Brain ; 14(1): 30, 2021 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-33568175

RESUMO

Metabolites underlying brain function and pathology are not as well understood as genes. Here, we applied a novel metabolomics approach to further understand the mechanisms of memory processing in sleep. As hippocampal dentate gyrus neurons are known to consolidate contextual fear memory, we analyzed real-time changes in metabolites in the dentate gyrus in different sleep-wake states in mice. Throughout the study, we consistently detected more than > 200 metabolites. Metabolite profiles changed dramactically upon sleep-wake state transitions, leading to a clear separation of phenotypes between wakefulness and sleep. By contrast, contextual fear memory consolidation induced less obvious metabolite phenotypes. However, changes in purine metabolites were observed upon both sleep-wake state transitions and contextual fear memory consolidation. Dietary supplementation of certain purine metabolites impaired correlations between conditioned fear responses before and after memory consolidation. These results point toward the importance of purine metabolism in fear memory processing during sleep.


Assuntos
Medo/fisiologia , Consolidação da Memória/fisiologia , Metabolômica , Sono/fisiologia , Administração Oral , Animais , Camundongos Endogâmicos C57BL , Purinas/administração & dosagem , Purinas/metabolismo , Vigília/fisiologia
20.
Dent Mater J ; 40(3): 719-726, 2021 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-33518687

RESUMO

This study evaluated the effect of temporary sealing materials and cleaning protocols on the bond strength of resin cement applied to dentin using resin-coating technique. Scotchbond Universal Adhesive and Filtek Supreme Ultra Flowable were applied to bovine dentin. Forty-five specimens were divided into the following three groups according to the temporary sealing materials: Cav-: CAVITON EX, Vas-: COCOA BUTTER and FIT SEAL, and Sep-: Washable SEP and FIT SEAL. Each material was placed on resin-coated dentin. After 1-week water storage, one of the following three cleaning protocols was performed: -WA: washed with water, -BR: brushed with PRESSAGE, and -AF: cleaned with AIR-FLOW. Microtensile bond strength test and EDS analysis were conducted. Irrespective of the cleaning protocol used, Washable SEP demonstrated less residual debris on resin-coated dentin, resulting in high bond strength. Regardless of the temporary sealing material applied, AIR-FLOW demonstrated less residual debris, resulting in high bond strength.


Assuntos
Colagem Dentária , Cimentos de Resina , Animais , Bovinos , Resinas Compostas , Dentina , Adesivos Dentinários , Teste de Materiais , Propriedades de Superfície , Resistência à Tração
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