RESUMO
Insomnia is one of the most common sleep disorders, affecting 10-15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N2-Ethyl-N4-(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A1 receptor and may have therapeutic potential for insomnia.
RESUMO
Objective: Bladder cancer survivors with neobladder experience changes in role performance and quality of life (QoL) due to various symptoms and problems, but related studies are limited. Therefore, this study attempted to explore the QoL and factors influencing it in bladder cancer survivors with neobladder. Methods: A cross-sectional descriptive design was used. Data were collected from 100 bladder cancer survivors with a neobladder using the European Organisation for Research and Treatment of Cancer QLQ-C30 and Muscle-Invasive Bladder Cancer Module, the Patient Activation Measure 13, the Enforced Social Dependency Scale, and the Multidimensional Scale of Perceived Social Support. Factors affecting the QoL were identified using multiple regression analysis. Results: QoL significantly differed by daily pad usage, need for clean intermittent catheterization, and role performance. QoL was correlated with urinary symptoms and problems, future perspective, abdominal bloating and flatulence, body image, role performance, and social support. Role performance, body image, and the need for clean intermittent catheterization were identified as the factors affecting QoL. Conclusions: The study highlights the importance of bladder cancer survivors continuing their roles at home, at work, and in society after neobladder reconstruction. Specifically, continuing recreational and social activity positively affects QoL, even if the activity range is modified. To help with their role performance, institutional support and changes in social perception are needed. Additionally, education and interventions, including body image enhancement, symptom management, and self-care, should be developed and applied to improve their QoL.
RESUMO
Anthocyanins play critical roles in protecting plant tissues against diverse stresses. The complicated regulatory networks induced by various environmental factors modulate the homeostatic level of anthocyanins. Here, we show that anthocyanin accumulation is induced by brassinosteroids (BRs) in Arabidopsis (Arabidopsis thaliana) shoots and shed light on the underlying regulatory mechanism. We observed that anthocyanin levels are altered considerably in BR-related mutants, and BRs induce anthocyanin accumulation by up-regulating the expression of anthocyanin biosynthetic genes. Our genetic analysis indicated that BRASSINAZOLE RESISTANT 1 (BZR1) and PRODUCTION OF ANTHOCYANIN PIGMENT 1 (PAP1) are essential for BR-induced anthocyanin accumulation. The BR-responsive transcription factor BZR1 directly binds to the PAP1 promoter, regulating its expression. In addition, we found that intense anthocyanin accumulation caused by the pap1-D dominant mutation is significantly reduced in BR mutants, implying that BR activity is required for PAP1 function after PAP1 transcription. Moreover, we demonstrated that BZR1 physically interacts with PAP1 to cooperatively regulate the expression of PAP1 target genes, such as TRANSPARENT TESTA 8 (TT8), DIHYDROFLAVONOL 4-REDUCTASE (DFR), and LEUKOANTHOCYANIDIN DIOXYGENASE (LDOX). Our findings indicate that BZR1 functions as an integral component of the PAP1-containing transcription factor complex, contributing to increased anthocyanin biosynthesis. Notably, we also show that functional interaction of BZR1 with PAP1 is required for anthocyanin accumulation induced by low nitrogen stress. Taken together, our results demonstrate that BR-regulated BZR1 promotes anthocyanin biosynthesis through cooperative interaction with PAP1 of the MBW complex.
RESUMO
The therapeutic efficacy of anticancer drugs loaded in liposomes composed of rigid phosphatidylcholine (PC) is hindered by the limited release of these drugs at the tumor site, which in turn hampers delivery of the drug to its intracellular target. In an attempt to improve the therapeutic efficacy of liposomal anticancer drugs, we here explored the use of empty liposomes as "trigger" vehicles to induce drug release from drug-loaded liposomes through liposome-liposome interactions. Empty liposomes containing PC in which omega-3 fatty acids comprised both fatty acid strands (Omega-L) showed a triggering effect on drug release from doxorubicin (DOX)-loaded liposomes (Caelyx). The effectiveness of this triggered-release effect was dependent on the Omega-L composition as well as the mixing ratio of Omega-L to Caelyx. Cryo-TEM and differential calorimetry studies revealed that the Omega-L effect was associated with liposome-liposome interactions that led to loosened membrane packing and increased fluidity of Caelyx. In cultured cells, the intracellular/intranuclear DOX uptake and anticancer efficacy of Caelyx was greatly improved by Omega-L pre-mixing. Intravenous injection of rats with Caelyx, premixed with Omega-L, decreased the area under the plasma concentration-time curve from time zero to time infinity and increased clearance without significantly changing the mean residence time or terminal half-life of DOX compared with Caelyx alone. Ex vivo bioimaging showed that DOX fluorescence in tumors, but not in other organs, was significantly increased by Omega-L premixing. In the mouse xenograft model, premixing of Omega-L with Caelyx suppressed tumor growth 2.5-fold compared with Caelyx. Collectively, the data provide preliminary evidence that the Omega-L-triggered drug release that occurs before and after dosing, particularly at tumor site, improved the therapeutic efficacy of Caelyx. The simple approach described here could enhance the therapeutic value of Caelyx and other anticancer drug-loaded liposomes.
Assuntos
Antineoplásicos , Doxorrubicina/análogos & derivados , Ácidos Graxos Ômega-3 , Neoplasias , Humanos , Camundongos , Ratos , Animais , Lipossomos/química , Ácidos Graxos Ômega-3/uso terapêutico , Liberação Controlada de Fármacos , Fosfatidilcolinas/química , Modelos Animais de Doenças , PolietilenoglicóisRESUMO
Tumor-derived extracellular vesicles (TDEs) have potential for therapeutic cancer vaccine applications since they innately possess tumor-associated antigens, mediate antigen presentation, and can incorporate immune adjuvants for enhanced vaccine efficacy. However, the original TDEs also contain immune-suppressive proteins. To address this, we proposed a simple yet powerful preconditioning method to improve the overall immunogenicity of the TDEs. This approach involved inducing endoplasmic reticulum (ER) stress on parental tumor cells via N-glycosylation inhibition with tunicamycin. The generated immunogenic TDEs (iTDEs) contained down-regulated immunosuppressive proteins and up-regulated immune adjuvants, effectively activating dendritic cells (DCs) in vitro. Furthermore, in vivo evidence from a tumor-bearing mouse model showed that iTDEs activated DCs, enabling cytotoxic T lymphocytes (CTLs) to target tumors, and eventually established a systemic antitumor immune response. Additionally, iTDEs significantly delayed tumor recurrence in a postsurgery model compared with control groups. These findings highlight the immense potential of our strategy for utilizing TDEs to develop effective cancer vaccines.
Assuntos
Vacinas Anticâncer , Vesículas Extracelulares , Neoplasias , Camundongos , Animais , Vacinas Anticâncer/uso terapêutico , Neoplasias/terapia , Linfócitos T Citotóxicos , Adjuvantes Imunológicos , Retículo Endoplasmático , Células DendríticasRESUMO
OBJECTIVES: Filifactor alocis is an emerging periodontal pathogen, and macrophage-produced tumor necrosis factor-α (TNF-α) plays important roles in periodontal pathogenesis. In this study, we investigated F. alocis-stimulated TNF-α production in THP-1 macrophagic cells. DESIGN: Phorbol 12-myristate 13-acetate-differentiated THP-1 macrophagic cells were challenged with F. alocis ATCC 35896 for various durations. TNF-α mRNA expression and protein secretion were determined using RT-PCR and ELISA, respectively. Activation of protein kinases and transcription factor proteins was evaluated by Western blot analysis. RESULTS: Live F. alocis stimulated THP-1 cells to produce TNF-α in a dose-dependent manner. However, glutaraldehyde-killed or heat-killed F. alocis showed no effectiveness for TNF-α induction. In contrast, both live and killed Porphyromonas gingivalis robustly increased TNF-α expression. Furthermore, F. alocis was unable to stimulate TNF-α expression in Toll-like receptor 2 (TLR2) knockout THP-1 cells. F. alocis activated all three mitogen-activated protein kinases: extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). Pharmacological inhibition of ERK and JNK, but not p38, significantly reduced F. alocis-induced TNF-α production. Finally, increased levels of phospho-c-Jun were detected in F. alocis-stimulated THP-1 cells. CONCLUSIONS: These results suggest that F. alocis induces TNF-α production in THP-1 macrophagic cells primarily by activating the TLR2, JNK, and c-Jun pathways.
RESUMO
Severe fever with thrombocytopenia syndrome virus (SFTSV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can cause the hyperproduction of inflammatory cytokines, which have pathological effects in patient including severe or fatal cytokine storms. To characterize the effect of SFTSV and SARS-CoV-2 infection on the production of cytokines in severe fever with thrombocytopenia syndrome (SFTS) and COVID-19 patients, we performed an analysis of cytokines in SFTS and COVID-19 patients and also investigated the role of interleukin-10 (IL-10) in vitro studies: lipopolysaccharide-induced THP-1-derived macrophages, SFTSV infection of THP-1 cells, and SARS-CoV-2 infection of THP-1 cells. In this study, we found that levels of both IL-10 and IL-6 were significantly elevated, the level of transforming growth factor-ß (TGF-ß) was significantly decreased and IL-10 was elevated earlier than IL-6 in severe and critical COVID-19 and fatal SFTS patients, and inhibition of IL-10 signaling decreased the production of IL-6 and elevated that of TGF-ß. Therefore, the hyperproduction of IL-10 and IL-6 and the low production of TGF-ß have been linked to cytokine storm-induced mortality in fatal SFTS and severe and critically ill COVID-19 patients and that IL-10 can play an important role in the host immune response to severe and critical SARS-CoV-2 and fatal SFTSV infection.
Assuntos
COVID-19 , Febre Grave com Síndrome de Trombocitopenia , Humanos , Síndrome da Liberação de Citocina , Citocinas , Interleucina-10 , Interleucina-6 , SARS-CoV-2 , Fator de Crescimento Transformador betaRESUMO
Severe fever with thrombocytopenia syndrome virus was first discovered in 2009 as the causative agent of severe fever with thrombocytopenia syndrome. Despite its potential threat to public health, no prophylactic vaccine is yet available. This study developed a heterologous prime-boost strategy comprising priming with recombinant replication-deficient human adenovirus type 5 (rAd5) expressing the surface glycoprotein, Gn, and boosting with Gn protein. This vaccination regimen induced balanced Th1/Th2 immune responses and resulted in potent humoral and T cell-mediated responses in mice. It elicited high neutralizing antibody titers in both mice and non-human primates. Transcriptome analysis revealed that rAd5 and Gn proteins induced adaptive and innate immune pathways, respectively. This study provides immunological and mechanistic insight into this heterologous regimen and paves the way for future strategies against emerging infectious diseases.
Assuntos
Adenovírus Humanos , Febre Grave com Síndrome de Trombocitopenia , Vacinas Virais , Animais , Camundongos , Vacinas Virais/genética , Vacinação/métodos , Linfócitos T , Vetores Genéticos/genética , Anticorpos Antivirais , Imunização Secundária/métodosRESUMO
Oxaliplatin is a platinum analog that can interfere with DNA replication and transcription. Continuous exposure to oxaliplatin results in chemoresistance; however, this mechanism is not well known. In this study, oxaliplatin-resistant (OR) colorectal cancer (CRC) cells of HCT116, HT29, SW480 and SW620 were established by gradually increasing the drug concentration to 2.5 µM. The inhibitory concentrations of cell growth by 50% (IC50) of oxaliplatin were 4.40-12.7-fold significantly higher in OR CRC cells as compared to their respective parental (PT) CRC cells. Phospho-Akt and phospho-mammalian target of rapamycin (mTOR) decreased in PT CRC cells but was overexpressed in OR CRC cells in response to oxaliplatin. In addition, an oxaliplatin-mediated decrease in phospho-AMP-activated protein kinase (AMPK) in PT CRC cells induced autophagy. Contrastingly, an increased phospho-AMPK in OR CRC cells was accompanied by a decrease in LC3B, further inducing the activity of glycolytic enzymes, such as glucose transporter 1 (GLUT1), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) and phosphofructokinase 1 (PFK1), to mediate cell survival. Inhibition of AMPK in OR CRC cells induced autophagy through inactivation of Akt/mTOR pathway and a decrease in GLUT1, PFKFB3, and PFK1. Collectively, targeting AMPK may provide solutions to overcome chemoresistance in OR CRC cells and restore chemosensitivity to anticancer drugs.
RESUMO
BACKGROUND: Recently, the duodenum has garnered interest for its role in treating metabolic diseases, including type 2 diabetes (T2DM). Multiple sessions of external photobiomodulation (PBM) in previous animal studies suggested it resulted in improved hyperglycemia, glucose intolerance, and insulin resistance with a multifactorial mechanism of action, despite the target organ of PBM not being clearly proven. This study aimed to determine whether a single session of a duodenal light-emitting diode (LED) PBM may impact the T2DM treatment in an animal model. METHODS: Goto-Kakizaki rats as T2DM models were subjected to PBM through duodenal lumen irradiation, sham procedure, or control in 1-week pilot (630 nm, 850 nm, or 630/850 nm) and 4-week follow-up (630 nm or 630/850 nm) studies. Oral glucose tolerance tests; serum glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic polypeptide, and insulin levels; liver chemistry and histology; and gut microbiome in the PBM, sham control, and control groups were evaluated. RESULTS: In the 1-week study, duodenal dual-wavelength (D, 630/850 nm) LED PBM showed improved glucose intolerance, alkaline phosphatase and cholesterol levels, and weight gain than other groups. The D-LED PBM group in the 4-week study also showed improved hyperglycemia and liver enzyme levels, with relatively preserved pancreatic islets and increased serum insulin and GLP-1 levels. Five genera (Bacteroides, Escherichia, Parabacteroides, Allobaculum, and Faecalibaculum) were significantly enriched 1 week after the D-LED PBM. Bacteroides acidifaciens significantly increased, while Lachnospiraceae significantly decreased after 1 week. CONCLUSION: A single session of D-LED PBM improved hyperglycemia and hepatic parameters through the change of serum insulin, insulin resistance, insulin expression in the pancreatic ß-cells, and gut microbiome in T2DM animal models.
Assuntos
Diabetes Mellitus Tipo 2 , Microbioma Gastrointestinal , Intolerância à Glucose , Hiperglicemia , Resistência à Insulina , Animais , Ratos , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Duodeno/metabolismo , Duodeno/patologia , Peptídeo 1 Semelhante ao Glucagon , Insulina , Fígado/metabolismoRESUMO
INTRODUCTION: A poorly differentiated lymphoepithelioma-like carcinoma (LELC) of the cervix is an extremely rare presentation. We herein present an unusual case of LELC of the cervix, which was treated with radical trachelectomy for fertility preservation. PATIENT CONCERNS: A 28-year-old female patient presented with a 1-month-history of post-coital vaginal bleeding, and a 2 cm tumor was found on gynecological sonography and magnetic resonance imaging. DIAGNOSIS: The final pathological examination established a conclusive diagnosis of LELC of the cervix. After surgery, the patient was finally diagnosed as The International Federation of Gynecology and Obstetrics (FIGO) stage IB1 with no vaginal wall or parametrium infiltration. INTERVENTIONS: Subsequently, a surgery was scheduled, and intraoperatively, we performed resection twice because of a frozen biopsy result that was resection margin-positive initially. As a result, further resection was performed, which was a 5mm thickness for each. Cisplatin adjuvant chemotherapy was administered 3 weeks after the operation to prevent recurrence. OUTCOMES: The patient has been followed for 1 year postoperatively, with an adjuvant treatment, with no evidence of tumor recurrence or metastasis. CONCLUSION: Based on this case, we highly recommend that operators should consider a deeper resection margin range than that visible on magnetic resonance imaging. More attention is needed to better understand the treatment method for LELC of the cervix. We also plan to closely monitor the patient's prognosis and fertility, and to conduct additional studies.
Assuntos
Carcinoma de Células Escamosas , Preservação da Fertilidade , Neoplasias do Colo do Útero , Gravidez , Feminino , Humanos , Adulto , Colo do Útero/cirurgia , Colo do Útero/patologia , Neoplasias do Colo do Útero/patologia , Margens de Excisão , Carcinoma de Células Escamosas/patologia , Preservação da Fertilidade/métodosRESUMO
Most proteins maintain protein homeostasis via posttranslational modifications, including the ubiquitinproteasome system. Deubiquitinating enzymes (DUBs) have essential intercellular roles, such as responses to DNA damage, proteolysis and apoptosis. Therefore, it is important to understand DUBrelated diseases to identify DUBs that target abnormally regulated proteins in cells. Ovarian tumor deubiquitinase 6A (OTUD6A) was previously reported as a downregulated DUB in HCT116 cells with p53 knockdown. Therefore, it was expected that the relationship between OTUD6A and p53 would affect cell proliferation. In the present study, putative substrates of OTUD6A related to the p53 signaling pathway were identified. Application of liquid chromatographytandem mass spectrometry and proteomic analysis led to the identification of nucleolin (known to bind p53) as a binding protein. In addition, immunoprecipitation studies determined that caspase7, an apoptotic protein, is associated with p53 signaling and is regulated by OTUD6A. It was further identified that OTUD6A regulates the protein stability of nucleolin, but not caspase7. It was also demonstrated that OTUD6A acts as a respective DUB through the deubiquitination of K48linked polyubiquitin chain of nucleolin and the K63linked polyubiquitin chain of caspase7. Furthermore, overexpression of OTUD6A induced cell proliferation via enhancing cell cycle progression of MCF7 cells. Taken together, OTUD6A may be proposed as a target for anticancer therapy.
Assuntos
Enzimas Desubiquitinantes , Neoplasias Ovarianas , Poliubiquitina , Caspase 7/metabolismo , Proliferação de Células , Enzimas Desubiquitinantes/genética , Enzimas Desubiquitinantes/metabolismo , Feminino , Humanos , Neoplasias Ovarianas/genética , Fosfoproteínas/metabolismo , Poliubiquitina/genética , Poliubiquitina/metabolismo , Proteômica , Proteínas de Ligação a RNA/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitinação , NucleolinaRESUMO
In this work, the suppression of tyrosinase-related genes, including an improvement in UV absorption effects of bioconverted CS extracts (BCS), was investigated to improve the skin-whitening effect. Total polyphenols and total flavonoids, which are bioactive components, increased 2.6- and 5.4-times in bioconversion using Lactiplantibacillus plantarum SM4, respectively, as compared to ultrasound-assisted extracts (UCS). The effect of BCS on radical scavenging activity, UV-A absorption, and tyrosinase activity inhibition, contributing to skin-whitening, were 1.3-, 1.2-, and 1.2-times higher than those of UCS, respectively. The main component identified in high-performance liquid chromatography (HPLC) was gallic acid in both UCS and BCS, which increased by 2.9-times following bioconversion. The gene expression of tyrosinase-related proteins, including TRP-1 and TRP-2 genes, was studied to confirm the suppression of melanin synthesis by BCS in order to identify the skin-whitening mechanism, and BCS decreased both genes' expression by 1.7- and 1.6-times, demonstrating that BCS effectively suppressed melanin synthesis. These findings imply that the chestnut inner shell can be employed as a cosmetic material by simultaneously inhibiting melanogenesis and enhancing UV-A absorption through bioconversion using L. plantarum SM4.
Assuntos
Oxirredutases Intramoleculares , Lactobacillus plantarum , Oxirredutases , Extratos Vegetais , Cromatografia Líquida de Alta Pressão , Expressão Gênica , Oxirredutases Intramoleculares/genética , Melaninas/biossíntese , Oxirredutases/genética , Extratos Vegetais/metabolismo , Raios UltravioletaRESUMO
Hazardous chemicals are commonly found in cereals and cereal-based products. However, most studies focus on the individual effects of these mycotoxins or metals, rather than their combined toxicity. The main objective of this study was to evaluate the combined effects of cadmium (Cd) and ochratoxin A (OTA) on intestinal barrier integrity using Caco-2 cells and pig small intestinal epithelial (PSI) cells as models of intestinal epithelial cells and to measure alterations in cell survival and barrier integrity. The combined effects on cell viability were assessed in terms of a combination of index values. These findings showed that co-exposure to Cd + OTA had synergistic effects on Caco-2 and PSI cells at 25%, 50%, and 75% inhibitory concentrations (IC25, IC50, and IC75, respectively) against cell viability. Individual Cd and OTA treatments had no effect, but combined Cd + OTA exposure resulted in synergistic down-regulation of paracellular apical junction complex proteins, such as claudin-1, occludin, and E-cadherin. The current findings indicate that the combined effects of OTA + Cd may have consequences at the gut level, which should not be underestimated when considering their risk to human health.
Assuntos
Cádmio , Micotoxinas , Humanos , Suínos , Animais , Células CACO-2 , Cádmio/toxicidade , Cádmio/metabolismo , Ocludina/metabolismo , Claudina-1/metabolismo , Células Epiteliais , Micotoxinas/toxicidade , Micotoxinas/metabolismo , Caderinas/metabolismo , Substâncias Perigosas/metabolismoRESUMO
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia. Amyloid-ß (Aß) has long been considered a key cause of neurodegeneration in the AD brain. Although the mechanisms underlying Aß-induced neurodegeneration are not fully understood, a number of recent studies have suggested that intracellular calcium overload mediates this process. In this study, we focused on the cellular function of phospholipase C-ß1 (PLCB1), which regulates calcium signaling by mediating hydrolysis of phosphatidylinositol 4,5-bisphosphate through G-protein coupled receptor pathways. First, we confirmed that acetylcholine-induced calcium release from intracellular stores of SH-SY5Y cells was significantly increased with Aß42 oligomer treatment. We further found that PLCB1 expression was upregulated in Aß42-treated cells, and PLCB1 overexpression in SH-SY5Y cells elicited the calcium overload observed in Aß-treated cells. In addition, Aß42 oligomer-induced calcium overload in SH-SY5Y cells was alleviated by knockdown of PLCB1, indicating that PLCB1 plays an essential role in the neurotoxic process initiated by Aß. The elevation of PLCB1 expression was confirmed in the brain tissues from the 5× familial AD (5×FAD) model mice. These findings suggest that PLCB1 may represent a potential therapeutic target for protecting neuronal cells against excitotoxicity in AD progression.
Assuntos
Doença de Alzheimer , Peptídeos beta-Amiloides , Cálcio , Neuroblastoma , Fosfolipase C beta , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Cálcio/metabolismo , Linhagem Celular Tumoral , Humanos , Camundongos , Neuroblastoma/metabolismo , Fragmentos de Peptídeos/metabolismo , Fosfolipase C beta/biossínteseRESUMO
Protein kinase B2 (AKT2) is involved in various cardiomyocyte signaling processes, including those important for survival and metabolism. Coxsackievirus B3 (CVB3) is one of the most common pathogens that cause myocarditis in humans. The role of AKT2 in CVB3 infection is not yet well understood. We used a cardiac-specific AKT2 knockout (KO) mouse to determine the role of AKT2 in CVB3-mediated myocarditis. CVB3 was injected intraperitoneally into wild-type (WT) and KO mice. The mice's survival rate was recorded: survival in KO mice was significantly decreased compared with WT mice (WT vs. KO: 73.3 vs. 27.1%). Myocardial damage and inflammation were significantly increased in the hearts of KO mice compared with those of WT mice. Moreover, from surface ECG, AKT2 KO mice showed a prolonged atria and ventricle conduction time (PR interval, WT vs. KO: 47.27 ± 1.17 vs. 64.79 ± 7.17 ms). AKT2 deletion induced severe myocarditis and cardiac dysfunction due to CVB3 infection. According to real-time PCR, the mRNA level of IL-1, IL-6, and TNF-α decreased significantly in KO mice compared with WT mice on Days 5 after infection. In addition, innate immune response antiviral effectors, Type I interferon (interferon-α and ß), and p62, were dramatically suppressed in the heart of KO mice. In particular, the adult cardiac myocytes isolated from the heart showed high induction of TLR4 protein in KO mice in comparison with WT. AKT2 deletion suppressed the activation of Type I interferon and p62 transcription in CVB3 infection. In cardiac myocytes, AKT2 is a key signaling molecule for the heart from damage through the activation of innate immunity during acute myocarditis.
Assuntos
Enterovirus Humano B/imunologia , Infecções por Enterovirus/imunologia , Imunidade Inata , Miocardite/imunologia , Miocárdio/imunologia , Proteínas Proto-Oncogênicas c-akt/imunologia , Doença Aguda , Animais , Enterovirus Humano B/genética , Infecções por Enterovirus/genética , Células HeLa , Humanos , Inflamação/genética , Inflamação/imunologia , Inflamação/virologia , Camundongos , Camundongos Knockout , Miocardite/genética , Miocardite/virologia , Proteínas Proto-Oncogênicas c-akt/genéticaRESUMO
PURPOSE: Literature is scarce regarding cancer care utilization during the massive outbreak of coronavirus disease 2019 (COVID-19) in the Republic of Korea. We investigated functional impairments in mental health and their relationships with depression, anxiety regarding the viral epidemic, and disruptions in healthcare service utilization among cancer patients in the COVID-19 pandemic era. MATERIALS AND METHODS: We used an online survey with questions related to the disturbances faced by patients with cancer in utilizing healthcare services in the pandemic era. Current mental health status was assessed using the Work and Social Adjustment Scale (WSAS), Stress and Anxiety to Viral Epidemics-6 (SAVE-6) scale, Patient Health Questionnaire-9 (PHQ-9), Insomnia Severity Index (ISI), Brief Resilience Scale (BRS), Cancer-Related Dysfunctional Beliefs about Sleep Scale (C-DBS), and Fear of COVID-19 over Cancer (FCC). RESULTS: Among the 221 responders, 95 (43.0%) reported disruptions in healthcare service utilization during the COVID-19 pandemic. Logistic regression analysis revealed that functional impairment in the mental health of these patients was expected due to disruptions in healthcare service utilization, high levels of depression, anxiety regarding the viral epidemic, fear of COVID over cancer, and low resilience. Mediation analysis showed that patient resilience and cancer-related dysfunctional beliefs about sleep partially mediated the effects of viral anxiety on functional impairment. CONCLUSION: In this pandemic era, patients with cancer experience depression, anxiety regarding the viral epidemic, and disruptions in healthcare service utilization, which may influence their functional impairments in mental health.
Assuntos
COVID-19 , Neoplasias , Ansiedade/epidemiologia , Ansiedade/etiologia , Ansiedade/psicologia , Atenção à Saúde , Depressão/epidemiologia , Depressão/etiologia , Depressão/psicologia , Humanos , Saúde Mental , Neoplasias/epidemiologia , Neoplasias/terapia , Pandemias , SARS-CoV-2RESUMO
Butyrates inhibit cell growth in colon cancer cells by inhibiting histone deacetylases. However, chronic exposure to butyrates induces butyrate resistance in colon cancer cells. The mechanism underlying the acquisition of resistance is not yet fully understood. Here, butyrate-resistant (BR) colon cancer cells were developed in HCT116, HT29, and SW480 human colon cancer cells and were confirmed by the increase in the inhibitory concentrations of cell growth by 50% (IC50) compared to their respective parental (PT) cells. Chronic exposure to butyrate induced autophagy via higher expression of Beclin-1 and LC3B-II. The AMP-activated protein kinase (AMPK) was downregulated along with the activation of Akt and mammalian target of rapamycin (mTOR) and decrease in acetyl-CoA carboxylase (ACC) in BR colon cancer cells compared to those in their respective PT cells. Activation of AMPK by AICAR treatment in BR colon cancer cells suppressed cell proliferation by inhibiting Akt and mTOR and activating ACC. Taken together, chronic exposure to butyrate increased butyrate resistance in human colon cancer by inducing protective autophagy through the downregulation of AMPK/ACC and activation of Akt/mTOR signaling. Activation of AMPK restored sensitivity to butyrate by the inhibition of Akt/mTOR, suggesting that AMPK could be a therapeutic target for BR colon cancers.
RESUMO
Alzheimer's disease (AD) is the most common form of dementia in the elderly population, but its underlying cause has not been fully elucidated. Recent studies have shown that microRNAs (miRNAs) play important roles in regulating the expression levels of genes associated with AD development. In this study, we analyzed miRNAs in plasma and cerebrospinal fluid (CSF) from AD patients and cognitively normal (including amyloid positive) individuals. miR-1273g-3p was identified as an AD-associated miRNA and found to be elevated in the CSF of early-stage AD patients. The overexpression of miR-1273g-3p enhanced amyloid beta (Aß) production by inducing oxidative stress and mitochondrial impairments in AD model cell lines. A biotin-streptavidin pull-down assay demonstrated that miR-1273g-3p primarily interacts with mitochondrial genes, and that their expression is downregulated by miR-1273g-3p. In particular, the miR-1273g-3p-target gene TIMM13 showed reduced expression in brain tissues from human AD patients. These results suggest that miR-1273g-3p expression in an early stage of AD notably contributes to Aß production and mitochondrial impairments. Thus, miR-1273g-3p might be a biomarker for early diagnosis of AD and a potential therapeutic target to prevent AD progression.
Assuntos
Doença de Alzheimer/genética , Regulação da Expressão Gênica , Genes Mitocondriais , MicroRNAs/genética , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/sangue , Doença de Alzheimer/líquido cefalorraquidiano , Secretases da Proteína Precursora do Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Linhagem Celular Tumoral , Regulação para Baixo/genética , Feminino , Hipocampo/patologia , Humanos , Masculino , MicroRNAs/sangue , MicroRNAs/líquido cefalorraquidiano , MicroRNAs/metabolismo , Mitocôndrias/metabolismo , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/genética , Proteínas do Complexo de Importação de Proteína Precursora Mitocondrial/metabolismo , Modelos Biológicos , Estresse Oxidativo/genética , Regulação para Cima/genéticaRESUMO
In this study, an eco-friendly and inexpensive cellulose acetate (CA) separator was fabricated and a method of making a single film by combining a polypropylene (PP) film and cellulose was proposed. The CA solution was coated on the PP film with a doctor blade and water treatment was applied to the bonded polymer to create interconnected pores and completely bond the CA onto the PP. In addition, lactic acid was added to CA to induce a plasticizing effect for abundant pore formation. The binding was confirmed using FT-IR and SEM, and the pore size generated from the CA side was found to be less than 1 µm on average. TGA was used to measure the thermal stability of the connected polymers.