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1.
J Biol Res (Thessalon) ; 28(1): 22, 2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34814951

RESUMO

BACKGROUND: Peroxiredoxins (Prxs) are antioxidant enzymes that protect cells from oxidative stress induced by several factors. They regulate several signaling pathways, such as metabolism, immune response, and intracellular reactive oxygen species (ROS) homeostasis. Epithelial-mesenchymal transition (EMT) is a transforming process that induces the loss of epithelial features of cancer cells and the gain of the mesenchymal phenotype. The EMT promotes metastasis and cancer cell progression mediated by several pathways, such as mitogen-activated protein kinases (MAPKs) and epigenetic regulators. METHODS: We used Prx6 overexpressed and downregulated HCT116 cells to study the mechanism between Prx6 and colon cancer. The expression of Prx6, GAPDH, Snail, Twist1, E-cadherin, Vimentin, N-cadherin, ERK, p-ERK, p38, p-p38, JNK, and p-JNK were detected by Western blotting. Additionally, an animal study for xenograft assay was conducted to explore the function of Prx6 on tumorigenesis. Cell proliferation and migration were determined by IncuCyte Cell Proliferation and colony formation assays. RESULTS: We confirmed that the expression of Prx6 and EMT signaling highly occurs in HCT116 compared with that in other colon cancer cell lines. Prx6 regulates the EMT signaling pathway by modulating EMT-related transcriptional repressors and mesenchymal genes in HCT116 colon cancer cells. Under the Prx6-overexpressed condition, HCT116 cells proliferation increased significantly. Moreover, the HCT116 cells proliferation decreased in the siPrx6-treated cells. Eleven days after HCT116 cell injection, Prx6 was overexpressed in the HCT116-injected mice, and the tumor volume increased significantly compared with that of the control mice. Furthermore, Prx6 regulates EMT signaling through p38 phosphorylation in colon cancer cells. CONCLUSION: We suggested that Prx6 regulates EMT signaling pathway through p38 phosphorylation modulation in HCT116 colon cancer cells.

2.
PLoS One ; 16(11): e0260309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34807958

RESUMO

AIM: Liver cirrhosis and features of muscle or adipose tissues may affect the severity of acute pancreatitis (AP). We aimed to evaluate the impact of body composition parameters and liver cirrhosis on the severity of AP in patients with alcohol-induced AP (AAP). METHODS: Patients with presumed AAP who underwent CT within one week after admission were retrospectively enrolled. L3 sectional areas of abdominal fat and muscle, and mean muscle attenuations (MMAs) were quantified. The presence of liver cirrhosis was determined using clinical and CT findings. Factors potentially associated with moderately severe or severe AP were included in the multivariable logistic regression analysis. RESULTS: A total of 242 patients (47.0 ± 12.6 years, 215 males) with presumed AAP were included. The mild and moderately severe/severe (MSS) groups included 137 (56.6%) and 105 patients (43.4%), respectively. Patients in the MSS group had higher rates of liver cirrhosis, organ failure, and local complications. Among body composition parameters, mean MMA (33.4 vs 36.8 HU, P<0.0001) and abdominal muscle mass (126.5 vs 135.1 cm2, P = 0.029) were significantly lower in the MSS group. The presence of liver cirrhosis (OR, 4.192; 95% CI, 1.620-10.848) was found to be a significant risk factor for moderately severe or severe AP by multivariable analysis. CONCLUSION: The results of this study suggest that liver cirrhosis has a significant impact on the severity of AAP. Of the body composition parameters examined, MMA and abdominal muscle mass showed potential as promising predictors.

3.
Sci Rep ; 11(1): 20536, 2021 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-34654852

RESUMO

The influence of body fat on arterial stiffness remains controversial. This study was performed to investigate the associations between four different types of body fat parameters and brachial-ankle pulse wave velocity (baPWV). A total of 3758 subjects (mean age, 53.4 ± 8.8 years; females, 36.3%) who underwent health check-up were retrospectively analyzed. Anthropometric parameters including body mass index (BMI), waist circumference (WC) and waist-hip ratio (WHR) were assessed, and visceral fat area (VFA) was calculated by bioelectrical impedance analysis. In simple linear correlation analyses, baPWV was associated with WC, WHR and VFA (P < 0.001 for each), but not with BMI (P = 0.175). In multivariable analyses, BMI and WC were not associated with baPWV (P > 0.05 for each). Even after controlling for potential confounders, higher baPWV was significantly associated not only with higher WHR [for > 0.90 in men and > 0.85 in women: odds ratio (OR), 1.23; 95% confidence interval (CI), 1.06-1.42; P = 0.005; for the highest tertile compared to the lowest tertile: OR, 1.38; 95% CI, 1.15-1.66; P < 0.001], but also with higher VFA (for ≥ 100 cm2: OR, 1.39; 95% CI, 1.20-1.60; P < 0.001; for the highest tertile compared to the lowest tertile: OR, 1.77; 95% CI, 1.48-2.12; P < 0.001). Our study showed that baPWV was correlated with WHR and VFA, but not with BMI and WC. This implies that arterial stiffness may be more strongly associated with abdominal obesity than overall obesity.

4.
Antioxidants (Basel) ; 10(10)2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34679770

RESUMO

Glutathione peroxidase 1 (Gpx1) and peroxiredoxin 2 (Prdx2) belong to the thiol peroxidase family of antioxidants, and have been studied for their antioxidant functions and roles in cancers. However, the physiological significance of Gpx1 and Prdx2 during vertebrate embryogenesis are lacking. Currently, we investigated the functional roles of Gpx1 and Prdx2 during vertebrate embryogenesis using Xenopus laevis as a vertebrate model. Our investigations revealed the zygotic nature of gpx1 having its localization in the eye region of developing embryos, whereas prdx2 exhibited a maternal nature and were localized in embryonic ventral blood islands. Furthermore, the gpx1-morphants exhibited malformed eyes with incompletely detached lenses. However, the depletion of prdx2 has not established its involvement with embryogenesis. A molecular analysis of gpx1-depleted embryos revealed the perturbed expression of a cryba1-lens-specific marker and also exhibited reactive oxygen species (ROS) accumulation in the eye regions of gpx1-morphants. Additionally, transcriptomics analysis of gpx1-knockout embryos demonstrated the involvement of Wnt, cadherin, and integrin signaling pathways in the development of malformed eyes. Conclusively, our findings indicate the association of gpx1 with a complex network of embryonic developmental pathways and ROS responses, but detailed investigation is a prerequisite in order to pinpoint the mechanistic details of these interactions.

5.
Lung Cancer ; 161: 189-196, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34624614

RESUMO

INTRODUCTION: Computed tomography (CT) and fluorodeoxyglucose-positron-emission-tomography (FDG-PET) measurements of mediastinal lymph nodes (MLNs) of patients with non-small-cell-lung-cancers (NSCLCs) ≤ 30 mm in maximum diameter are recommended for pre-surgical prediction of MLN metastases. METHODS: We reviewed all patients at Mount Sinai Health System enrolled in the Initiative for Early Lung Cancer Research on Treatment (IELCART), prospective cohort between 2016 and 2020, who had pre-surgical FDG-PET and underwent surgery with MLN resection and/or pre-operative endobronchial ultrasound (EBUS) for a first primary NSCLC ≤ 30 mm in maximum diameter on pre-surgical CT. RESULTS: Among 470 patients, none with part-solid (n = 63) or nonsolid (n = 23) NSCLCs had MLN metastases. Solid NSCLCs were identified in 384 patients, none in typical carcinoid (n = 48) or NSCLC ≤ 10 mm in maximum diameter (n = 47, including 8 typical carcinoids) had MLN metastases. Among the remaining 297 patients with solid NSCLCs 10.1-30.0 mm, 7 (2.4%) had MLN metastases. Area-under-the-curve (AUC) for predicting MLN metastases in solid NSCLCs 10.1-30.0 mm, using the CT maximum short-axis MLN diameter was 0.62 (95% CI:0.44-0.81, p = 0.18) and using the highest SUVmax of any MLN, AUC was 0.58 (95% CI:0.39-0.78,p = 0.41). Neither AUCs were significantly different from chance alone. Optimal cutoff for prediction of MLN metastases was ≥ 18.9 mm for CT maximum short-axis diameter [sensitivity 14.3% (95%CI:0.0%-57.9%); specificity 100.0% (95%CI:98.9%-100.0%)] and for highest SUVmax was ≥ 11.7 [sensitivity 14.3% (95%CI:0.0%-57.9%) and specificity 99.7% (95%CI:98.3%-100.0%)]. CONCLUSIONS: CT and SUVmax had low sensitivity but high specificity for predicting MLN metastases in solid NSCLCs 10.1-30.0 mm. Clinical Stage IA NSCLCs ≤ 30 mm should be based on CT maximum tumor diameter and MLN maximum short-axis diameter ≤ 20 mm.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/diagnóstico , Carcinoma Pulmonar de Células não Pequenas/patologia , Fluordesoxiglucose F18 , Humanos , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/patologia , Linfonodos/patologia , Metástase Linfática , Estadiamento de Neoplasias , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Estudos Retrospectivos
6.
Free Radic Biol Med ; 176: 322-334, 2021 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-34637923

RESUMO

Strategies for cancer treatment have traditionally focused on suppressing cancer cell behavior, but many recent studies have demonstrated that regulating the tumor microenvironment (TME) can also inhibit disease progression. Macrophages are major TME components, and the direction of phenotype polarization is known to regulate tumor behavior, with M2-like polarization promoting progression. It is also known that reactive oxygen species (ROS) in macrophages drive M2 polarization, and M2 polarization promote lung cancer progression. Lung cancer patients with lower expression of the antioxidant enzyme peroxiredoxin 5 (Prx5) demonstrate poorer survival. This study revealed that Prx5 deficiency in macrophages induced M2 macrophage polarization by lung cancer. We report that injection of lung cancer cells produced larger tumors in Prx5-deficit mice than wild-type mice independent of cancer cell Prx5 expression. Through co-culture with lung cancer cell lines, Prx5-deficient macrophages exhibited M2 polarization, and reduced expression levels of the M1-associated inflammatory factors iNOS, TNFα, and Il-1ß. Moreover, these Prx5-deficient macrophages promoted the proliferation and migration of co-cultured lung cancer cells. Conversely, suppression of ROS generation by N-acetyl cysteine (NAC) inhibited the M2-like polarization of Prx5-deficient macrophages, increased expression levels of inflammatory factors, inhibited the proliferation and migration of co-cultured lung cancer cells, and suppressed tumor growth in mice. These findings suggest that blocking the M2 polarization of macrophages may promote lung cancer regression.


Assuntos
Neoplasias Pulmonares , Peroxirredoxinas , Animais , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/genética , Ativação de Macrófagos , Macrófagos , Camundongos , Peroxirredoxinas/genética , Espécies Reativas de Oxigênio , Microambiente Tumoral
7.
Int J Mol Sci ; 22(17)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34502346

RESUMO

Peroxiredoxins (PRDXs) are expressed in the ovary and during ovulation. PRDX1 activity related to the immuno-like response during ovulation is unknown. We investigated the roles of Prdx1 on TLR4 and ERK1/2 signaling from the ovulated cumulus-oocyte complex (COC) using Prdx1-knockout (K/O) and wild-type (WT) mice. Ovulated COCs were collected 12 and 16 h after pregnant mare serum gonadotropin/hCG injection. PRDX1 protein expression and COC secretion factors (Il-6, Tnfaip6, and Ptgs2) increased 16 h after ovulated COCs of the WT mice were obtained. We treated the ovulated COCs in mice with LPS (0.5 µg/mL) or hyaluronidase (Hya) (10 units/mL) to induce TLR4 activity. Intracellular reactive oxygen species (ROS), cumulus cell apoptosis, PRDX1, TLR4/P38/ERK1/2 protein expression, and COC secretion factors' mRNA levels increased in LPS- and Hya-treated COCs. The ERK inhibitor (U0126) and Prdx1 siRNA affected TLR4/ERK1/2 expression. The number and cumulus expansion of ovulated COCs by ROS were impaired in Prdx1 K/O mice but not in WT ones. Prdx1 gene deletion induced TLR4/P38/ERK1/2 expression and cumulus expansion genes. These results show the controlling roles of PRDX1 for TLR4/P38/ERK1/2 signaling activity in ovulated mice and the interlink of COCs with ovulation.


Assuntos
Células do Cúmulo/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Oócitos/metabolismo , Ovulação , Peroxirredoxinas/fisiologia , Receptor 4 Toll-Like/metabolismo , Animais , Células Cultivadas , Células do Cúmulo/citologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/genética , Oócitos/citologia , Receptor 4 Toll-Like/genética
8.
Comput Biol Med ; 136: 104762, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34399195

RESUMO

BACKGROUND: Narcolepsy is marked by pathologic symptoms including excessive daytime drowsiness and lethargy, even with sufficient nocturnal sleep. There are two types of narcolepsy: type 1 (with cataplexy) and type 2 (without cataplexy). Unlike type 1, for which hypocretin is a biomarker, type 2 narcolepsy has no adequate biomarker to identify the causality of narcoleptic phenomenon. Therefore, we aimed to establish new biomarkers for narcolepsy using the body's systemic networks. METHOD: Thirty participants (15 with type 2 narcolepsy, 15 healthy controls) were included. We used the time delay stability (TDS) method to examine temporal information and determine relationships among multiple signals. We quantified and analyzed the network connectivity of nine biosignals (brainwaves, cardiac and respiratory information, muscle and eye movements) during nocturnal sleep. In particular, we focused on the differences in network connectivity between groups according to sleep stages and investigated whether the differences could be potential biomarkers to classify both groups by using a support vector machine. RESULT: In rapid eye movement sleep, the narcolepsy group displayed more connections than the control group (narcolepsy connections: 24.47 ± 2.87, control connections: 21.34 ± 3.49; p = 0.022). The differences were observed in movement and cardiac activity. The performance of the classifier based on connectivity differences was a 0.93 for sensitivity, specificity and accuracy, respectively. CONCLUSION: Network connectivity with the TDS method may be used as a biomarker to identify differences in the systemic networks of patients with narcolepsy type 2 and healthy controls.


Assuntos
Cataplexia , Narcolepsia , Humanos , Sono , Fases do Sono , Sono REM
9.
Cells ; 10(8)2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34440750

RESUMO

Canines are useful in mammalian preclinical studies because they are larger than rodents and share many diseases with humans. Canine fetal fibroblast cells (CFFs) are an easily accessible source of somatic cells. However, they are easily driven to senescence and become unusable with continuous in vitro culture. Therefore, to overcome these deficiencies, we investigated whether tetracycline-inducible L-myc gene expression promotes self-renewal activity and tumorigenicity in the production of induced conditional self-renewing fibroblast cells (iCSFCs). Here, we describe the characterization of a new iCSFC line immortalized by transduction with L-myc that displays in vitro self-renewal ability without tumorigenic capacity. We established conditionally inducible self-renewing fibroblast cells by transducing CFF-3 cells with L-myc under the tetracycline-inducible gene expression system. In the absence of doxycycline, the cells did not express L-myc or undergo self-renewal. The iCSFCs had a fibroblast-like morphology, normal chromosome pattern, and expressed fibroblast-specific genes and markers. However, the iCSFCs did not form tumors in a soft agar colony-forming assay. We observed higher expression of three ES modules (core pluripotency genes, polycomb repressive complex genes (PRC), and MYC-related genes) in the iCSFCs than in the CFF-3 cells; in particular, the core pluripotency genes (OCT4, SOX2, and NANOG) were markedly up-regulated compared with the PRC and MYC module genes. These results demonstrated that, in canine fetal fibroblasts, L-myc tetracycline-inducible promoter-driven gene expression induces self-renewal capacity but not tumor formation. This study suggests that L-myc gene-induced conditional self-renewing fibroblast cells can be used as an in vitro tool in a variety of biomedical studies related to drug screening.


Assuntos
Autorrenovação Celular/fisiologia , Proteínas Proto-Oncogênicas c-myc/genética , Animais , Proliferação de Células , Reprogramação Celular , Cães , Feminino , Feto/citologia , Feto/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Fase G1 , Proteínas do Grupo Polycomb/metabolismo , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas c-myc/metabolismo
10.
PLoS One ; 16(8): e0256083, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34403431

RESUMO

AIMS: Metabolic syndrome (MS) is a global health problem associated with an increased risk of diabetes mellitus (DM), cardiovascular disease (CVD), and cancer. Body composition parameters, including obesity, visceral adiposity, and sarcopenia contribute to the development of MS and CVD. Previous studies have investigated the association of individual body composition parameters with MS. Studies analyzing the association between multiple body composition parameters and MS have been rare. We aimed to investigate the association between MS and multiple body composition parameters, including obesity, visceral adiposity, and sarcopenia. METHODS: A total of 13,620 subjects who underwent voluntary routine checkups at the Health Care Center of our institution between October 2014 and December 2019 were enrolled. Only data from the first examination of subjects who underwent repeated checkups were included. Clinical and laboratory data were collected. Skeletal muscle mass and visceral fat area (VFA) were measured using bioelectrical impedance analysis. Appendicular skeletal muscle mass (ASM) was divided by body weight (in kg) and expressed as a percentage (calculated as, ASM% = ASM × 100/Weight). Data were compared between the groups based on obesity, VFA, and ASM%. Logistic regression analysis was performed to determine the risk of MS in each group. RESULTS: Body mass index and VFA were significantly higher in subjects with MS than in those without MS. ASM% was significantly lower in subjects with MS than in those without MS. Subjects with obesity, visceral adiposity, or sarcopenia had a higher prevalence of MS than those without. As the number of metabolic components increased from 0 to 5, we identified a decreasing trend of ASM% and an increasing trend of VFA and BMI (P for trend < 0.001 for all). In the paired analyses, all the three body composition parameters showed additive effects in predicting MS. In the logistic regression analysis, the three parameters were associated with an increased risk of MS after adjustment for age, sex, hypertension, DM, dyslipidemia, smoking, alcohol intake, and C-reactive protein. CONCLUSIONS: Obesity, visceral adiposity, and sarcopenia showed additive effects on MS prediction. Subjects with obesity, visceral adiposity, or sarcopenia were significantly associated with the increased risk of MS after adjustment for multiple confounders. Increasing skeletal muscle and reducing visceral fat may be strategies for the prevention or treatment of MS.

11.
J Thorac Dis ; 13(5): 3160-3170, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-34164206

RESUMO

Depression and anxiety are emotional disorders that commonly affect patients with esophageal cancer. As a result of its high morbidity, mortality, and complication rates, this population is at particularly high risk for developing or exacerbating affective disorders; even when compared to patients with other forms of cancer. Many of the medical conditions and social behaviors that predispose patients to this disease are also independently associated with affective disorders, and likely compound their effects. Unfortunately, in the existing literature, there is wide variability in study design and diagnostic criteria. There is no standard method of evaluation, many studies are limited to written surveys, and widespread mental health screening is not included as a part of routine care. As a result, the prevalence of these illnesses remains elusive. Additionally, psychiatric and psychosocial illness can affect compliance with surveillance and treatment, and gaps in knowledge may ultimately influence patient outcomes and survival. This review will discuss the existing literature on depression and anxiety in patients with esophageal cancer. It will highlight current methods of psychological evaluation, the prevalence of affective disorders in this population, and their effects on treatment, compliance, and outcomes. It will also discuss possible screening tools, treatments and interventions for these comorbid illnesses that may improve oncologic outcomes as well as quality of life.

12.
J Surg Oncol ; 124(4): 529-539, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34081346

RESUMO

BACKGROUND: The Ivor Lewis esophagectomy (ILE) remains the procedure of choice for localized middle or lower esophageal carcinoma. Nevertheless, anastomotic leak remains a common complication with rates from 3% to 25% and a stricture rate as high as 40%. The frequency of these complications suggests that the procedure itself may have inherent limitations including the use of potentially ischemic tissue for the esophagogastric anastomosis. We introduce a modified technique that reduces operative steps, preserves blood supply, and uses a modified esophagogastric anastomosis. METHODS: All consecutive patients undergoing ILE with the described modified technique were identified. An esophagram was performed on postoperative day six or seven. To ensure that all cases were identified, anastomotic leaks were defined as any radiographic evidence of contrast extravasation. RESULTS: A total of 110 patients underwent the modified esophagectomy with 2 anastomotic leaks (1.82%) and zero strictures. There was 1 late death but no early deaths (<30 or 90 days) or early re-admissions (<30 days). The average number of risk factors was 2.12, and 98 patients (90%) had at least 1 risk factor in their medical history. CONCLUSIONS: The modifications proposed simplify procedural steps, limit unnecessary dissection and introduce a technique that ends the practice of connecting ischemic tissue. We believe this technique contributes to surgical durability and reduces the rate of postoperative leak and eliminates stricture.


Assuntos
Fístula Anastomótica/prevenção & controle , Constrição Patológica/prevenção & controle , Neoplasias Esofágicas/cirurgia , Esofagectomia/efeitos adversos , Complicações Pós-Operatórias/prevenção & controle , Procedimentos Cirúrgicos Reconstrutivos/métodos , Idoso , Fístula Anastomótica/etiologia , Constrição Patológica/etiologia , Neoplasias Esofágicas/patologia , Feminino , Seguimentos , Gastrectomia/métodos , Humanos , Laparoscopia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/etiologia , Prognóstico , Toracotomia/métodos
13.
Surg Endosc ; 35(9): 5392-5396, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34115216

RESUMO

BACKGROUND: A large release of droplets is often expected around the periphery of the digestive endoscope insertion site. Therefore, a sense of alarm over infection because of droplets that may be released during digestive endoscopy examination is increasing. This study aimed to investigate the droplets released during digestive endoscopy using a high-speed camera. METHODS: We utilized a high-speed camera (FASTCAM SA-3, Photron Limited) capable of recording small, transparent droplets with a black background and high-brightness lighting. The obtained video files were analyzed using post-processing software. We divided the 20 models into the control (a spray bottle model and a cough model) and experimental groups (digestive endoscopy models). The sedative, proficiency of digestive endoscopy and the amount of gas injected were modulated to change the level of released droplets. RESULTS: For the control groups, droplets were clearly observed using a high-speed camera. However, no droplet larger than 10 µm in size was observed in the experimental groups. Furthermore, the changes in the sedative, proficiency of digestive endoscopy, and amount of gas injected did not affect droplet formation. CONCLUSIONS: Based on high-speed camera photography, the risk of droplet generation during digestive endoscopy was not higher than that during violent expiratory events, such as coughing and sneezing.


Assuntos
Tosse , Endoscópios , Endoscopia Gastrointestinal , Humanos , Projetos Piloto
14.
Cancers (Basel) ; 13(5)2021 Mar 03.
Artigo em Inglês | MEDLINE | ID: mdl-33802319

RESUMO

Surgery is a mainstay of treatment allowing for debulking of tumor and expansion of the lung for improvement in median survival and quality of life for patients with malignant pleural mesothelioma (MPM). Although optimal surgical technique remains open for debate-extrapleural pneumonectomy (EPP) vs. pleurectomy/decortication (P/D)-minimally invasive surgery (VATS-P/D) remains underutilized in the management of MPM. We examined whether VATS-P/D is a feasible alternative to EPP and P/D. We evaluated the New York Statewide Planning and Research Cooperative System (SPARCS) from 2007-2017 to assess the short-term complications of EPP vs. P/D, including a subanalysis of open P/D vs. VATS-P/D. There were 331 patients with open surgery; 269 with P/D and 62 with EPP. There were 384 patients with P/D; 269 were open and 115 VATS. Rates of any complication were similar between EPP and P/D patients, but EPP had significantly higher rates of cardiovascular complications. After adjusting for confounders, those with a VATS approach were less likely to have any complication, compared to an open approach and significantly less likely to have a pulmonary complication. VATS-P/D remains a viable alternative to radical surgery in MPM patients allowing for improved short-term outcomes.

15.
Pharmaceuticals (Basel) ; 14(4)2021 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33916253

RESUMO

Stroke is a serious, adverse neurological event and the third leading cause of death and disability worldwide. Most strokes are caused by a block in cerebral blood flow, resulting in neurological deficits through the death of brain tissue. Recombinant tissue plasminogen activator (rt-PA) is currently the only immediate treatment medication for stroke. The goal of rt-PA administration is to reduce the thrombus and/or embolism via thrombolysis; however, the administration of rt-PA must occur within a very short therapeutic timeframe (3 h to 6 h) after symptom onset. Components of the pathological mechanisms involved in ischemic stroke can be used as potential biomarkers in current treatment. However, none are currently under investigation in clinical trials; thus, further studies investigating biomarkers are needed. After ischemic stroke, microglial cells can be activated and release inflammatory cytokines. These cytokines lead to severe neurotoxicity via the overactivation of microglia in prolonged and lasting insults such as stroke. Thus, the balanced regulation of microglial activation may be necessary for therapy. Stem cell therapy is a promising clinical treatment strategy for ischemic stroke. Stem cells can increase the functional recovery of damaged tissue after post-ischemic stroke through various mechanisms including the secretion of neurotrophic factors, immunomodulation, the stimulation of endogenous neurogenesis, and neovascularization. To investigate the use of stem cell therapy for neurological diseases in preclinical studies, however, it is important to develop imaging technologies that are able to evaluate disease progression and to "chase" (i.e., track or monitor) transplanted stem cells in recipients. Imaging technology development is rapidly advancing, and more sensitive techniques, such as the invasive and non-invasive multimodal techniques, are under development. Here, we summarize the potential risk factors and biomarker treatment strategies, stem cell-based therapy and emerging multimodal imaging techniques in the context of stroke. This current review provides a conceptual framework for considering the therapeutic targets and directions for the treatment of brain dysfunctions, with a particular focus on ischemic stroke.

16.
Mar Drugs ; 19(3)2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33804171

RESUMO

The proteolytic processing of amyloid precursor protein (APP) by ß-secretase (BACE1) and γ-secretase releases amyloid-ß peptide (Aß), which deposits in amyloid plaques and contributes to the initial causative events of Alzheimer's disease (AD). In the present study, the regulatory mechanism of APP processing of three phlorotannins was elucidated in Swedish mutant APP overexpressed N2a (SweAPP N2a) cells. Among the tested compounds, dieckol exhibited the highest inhibitory effect on both intra- and extracellular Aß accumulation. In addition, dieckol regulated the APP processing enzymes, such as α-secretase (ADAM10), ß-secretase, and γ-secretase, presenilin-1 (PS1), and their proteolytic products, sAPPα and sAPPß, implying that the compound acts on both the amyloidogenic and non-amyloidogenic pathways. In addition, dieckol increased the phosphorylation of protein kinase B (Akt) at Ser473 and GSK-3ß at Ser9, suggesting dieckol induced the activation of Akt, which phosphorylated GSK-3ß. The specific phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 triggered GSK-3ß activation and Aß expression. In addition, co-treatment with LY294002 noticeably blocked the effect of dieckol on Aß production, demonstrating that dieckol promoted the PI3K/Akt signaling pathway, which in turn inactivated GSK-3ß, resulting in the reduction in Aß levels.


Assuntos
Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Benzofuranos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/fisiopatologia , Animais , Linhagem Celular , Cromonas/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Camundongos , Morfolinas/farmacologia , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taninos/farmacologia
17.
Cells ; 10(4)2021 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-33923707

RESUMO

The overall five-year survival rate for late-stage patients of ovarian cancer is below 29% due to disease recurrence and drug resistance. Cancer stem cells (CSCs) are known as a major contributor to drug resistance and recurrence. Accordingly, therapies targeting ovarian CSCs are needed to overcome the limitations of present treatments. This study evaluated the effect of trimebutine maleate (TM) targeting ovarian CSCs, using A2780-SP cells acquired by a sphere culture of A2780 epithelial ovarian cancer cells. TM is indicated as a gastrointestinal motility modulator and is known to as a peripheral opioid receptor agonist and a blocker for various channels. The GI50 of TM was approximately 0.4 µM in A2780-SP cells but over 100 µM in A2780 cells, demonstrating CSCs specific growth inhibition. TM induced G0/G1 arrest and increased the AV+/PI+ dead cell population in the A2780-SP samples. Furthermore, TM treatment significantly reduced tumor growth in A2780-SP xenograft mice. Voltage gated calcium channels (VGCC) and calcium-activated potassium channels (BKCa) were overexpressed on ovarian CSCs and targeted by TM; inhibition of both channels reduced A2780-SP cells viability. TM reduced stemness-related protein expression; this tendency was reproduced by the simultaneous inhibition of VGCC and BKCa compared to single channel inhibition. In addition, TM suppressed the Wnt/ß-catenin, Notch, and Hedgehog pathways which contribute to many CSCs characteristics. Specifically, further suppression of the Wnt/ß-catenin pathway by simultaneous inhibition of BKCa and VGCC is necessary for the effective and selective action of TM. Taken together, TM is a potential therapeutic drug for preventing ovarian cancer recurrence and drug resistance.


Assuntos
Reposicionamento de Medicamentos , Células-Tronco Neoplásicas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Trimebutina/uso terapêutico , Cálcio/metabolismo , Canais de Cálcio/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Feminino , Humanos , Ativação do Canal Iônico/efeitos dos fármacos , Subunidades alfa do Canal de Potássio Ativado por Cálcio de Condutância Alta/metabolismo , Modelos Biológicos , Células-Tronco Neoplásicas/efeitos dos fármacos , Subunidades Proteicas/metabolismo , Sódio/metabolismo , Canais de Sódio/metabolismo , Fatores de Transcrição/metabolismo , Trimebutina/química , Trimebutina/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos
18.
Redox Rep ; 26(1): 53-61, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33719938

RESUMO

Objectives: Although glutamate is an essential factor in the neuronal system, excess glutamate can produce excitotoxicity. We previously reported that Peroxiredoxin 5 (Prx5) protects neuronal cells from glutamate toxicity via its antioxidant effects. However, it is unclear whether cytosolic or mitochondrial Prx5 provides greater neuroprotection. Here, we investigated differences in the neuroprotective effects of cytosolic and mitochondrial Prx5.Methods: We analyzed patterns of cytosolic and mitochondrial H2O2 generation in glutamate toxicity using HyPer protein. And then, we confirmed the change of intracellular ROS level and apoptosis with respective methods. The mitochondrial dynamics was assessed with confocal microscope imaging and western blotting.Results: We found that the level of mitochondrial H2O2 greatly increased compared to cytosolic H2O2 and it affected cytosolic H2O2 generation after glutamate treatment. In addition, we confirmed that mitochondrial Prx5 provides more effective neuroprotection than cytosolic Prx5.Discussion: Overall, our study reveals the mechanisms of cytosolic and mitochondrial ROS in glutamate toxicity. Our findings suggest that mitochondrial ROS and Prx5 are attractive therapeutic targets and that controlling these factors be useful for the prevention of neurodegenerative diseases.

19.
Stem Cell Res ; 51: 102199, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33529979

RESUMO

Human induced pluripotent stem cells with indefinite propagation in vitro provide a potential donor source of cells including erythroid cells for human therapy. Since group O D-negative (RhD-) blood cells are considered as universal donors for transfusion, it is compelling to derive iPSC line from group O/RhD- sample as a new cellular source to generate universal RBCs. The resulting iPSC line derived from group O/RhD- somatic source showed typical features of pluripotent stem cells and could provide an unprecedented cellular tool to develop universal therapeutics for blood transfusion.


Assuntos
Células-Tronco Pluripotentes Induzidas , Células-Tronco Pluripotentes , Medula Óssea , Diferenciação Celular , Células Eritroides , Humanos
20.
Inflammation ; 44(2): 714-724, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33150538

RESUMO

Excessive microglial cell activation in the brain can lead to the production of various neurotoxic factors (e.g., pro-inflammatory cytokines, nitric oxide) which can, in turn, initiate neurodegenerative processes. Recent research has been reported that mitochondrial dynamics regulate the inflammatory response of lipopolysaccharide (LPS). Isoliquiritigenin (ISL) is a compound found in Glycyrrhizae radix with anti-inflammatory and antioxidant properties. In this study, we investigated the function of ISL on the LPS-induced pro-inflammatory response in BV-2 microglial cells. We showed that ISL reduced the LPS-induced increase in pro-inflammatory mediators (e.g., nitric oxide and pro-inflammatory cytokines) via the inhibition of ERK/p38/NF-κB activation and the generation of reactive oxygen species (ROS). Furthermore, ISL inhibited the excessive mitochondrial fission induced by LPS, regulating mitochondrial ROS generation and pro-inflammatory response by suppressing the calcium/calcineurin pathway to dephosphorylate Drp1 at the serine 637 residue. Interestingly, the ISL pretreatment reduced the number of apoptotic cells and levels of cleaved caspase3/PARP, compared to LPS-treated cells. Our findings suggested that ISL ameliorated the pro-inflammatory response of microglia by inhibiting dephosphorylation of Drp1 (Ser637)-dependent mitochondrial fission. This study provides the first evidence for the effects of ISL against LPS-induced inflammatory response related and its link to mitochondrial fission and the calcium/calcineurin pathway. Consequently, we also identified the protective effects of ISL against LPS-induced microglial apoptosis, highlighting the pharmacological role of ISL in microglial inflammation-mediated neurodegeneration.

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