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Menopause is induced by spontaneous ovarian failure and leads to life quality deterioration with various irritating symptoms. Hormonal treatment can alleviate these symptoms, but long-term treatment is closely associated with breast and uterine cancer, and stroke. Therefore, developing alternative therapies with novel anti-menopausal substances and improved safety is needed. In our study, heat-killed Bifidobacterium breve HDB7040 significantly promoted MCF-7 cell proliferation in a dose-dependent manner under estrogen-free conditions, similar to 17ß-estradiol. This strain also triggered ESR2 expression, but not ESR1, in MCF-7 cells. Moreover, administrating HDB7040 to ovariectomized (OVX) Sprague-Dawley (SD) female rats reduced estrogen deficiency-induced weight gain, fat mass, blood triglyceride, and total cholesterol levels. It also recovered collapsed trabecular microstructure by improving trabecular morphometric parameters (bone mineral density, bone volume per tissue volume, trabecular number, and trabecular separation) and decreasing blood alkaline phosphatase levels with no significant changes in uterine size and blood estradiol. HDB7040 also significantly regulated the expression of Tff1, Pgr, and Esr2, but not Esr1 in uteri of OVX rats. Heat-killed B. breve HDB7040 exerts an anti-menopausal effect via the specific regulation of ERß in vitro and in vivo, suggesting its potential as a novel substance for improving and treating menopausal syndrome.
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Bifidobacterium breve , Proliferação de Células , Receptor beta de Estrogênio , Ovariectomia , Ratos Sprague-Dawley , Útero , Animais , Feminino , Humanos , Células MCF-7 , Ratos , Receptor beta de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Proliferação de Células/efeitos dos fármacos , Menopausa , Estradiol , Temperatura Alta , Receptor alfa de Estrogênio/metabolismo , Receptor alfa de Estrogênio/genética , Fator Trefoil-1/metabolismo , Fator Trefoil-1/genética , Probióticos/administração & dosagem , Probióticos/farmacologia , Estrogênios/metabolismo , Receptores de Progesterona/metabolismoRESUMO
With the growing complexity and volume of data, visualizations have become more intricate, often requiring advanced techniques to convey insights. These complex charts are prevalent in everyday life, and individuals who lack knowledge in data visualization may find them challenging to understand. This paper investigates using Large Language Models (LLMs) to help users with low data literacy understand complex visualizations. While previous studies focus on text interactions with users, we noticed that visual cues are also critical for interpreting charts. We introduce an LLM application that supports both text and visual interaction for guiding chart interpretation. Our study with 26 participants revealed that the in-situ support effectively assisted users in interpreting charts and enhanced learning by addressing specific chart-related questions and encouraging further exploration. Visual communication allowed participants to convey their interests straightforwardly, eliminating the need for textual descriptions. However, the LLM assistance led users to engage less with the system, resulting in fewer insights from the visualizations. This suggests that users, particularly those with lower data literacy and motivation, may have over-relied on the LLM agent. We discuss opportunities for deploying LLMs to enhance visualization literacy while emphasizing the need for a balanced approach.
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In the regulation of inflammatory responses and skin homeostasis, the skin and its microbiota are closely related. Studies have reported that lactic acid bacteria extracts can improve the skin condition and microbiota. In our previous study, we developed probiotic lysates, which are efficacious in improvement of human skin cells and the skin barrier. The skin-moisturizing effect of Dermabiotics HDB (HDB) prepared with Lactiplantibacillus plantarum, and the correlation between changes in the skin microbiota and moisture contents, were evaluated and analyzed in clinical trials. The clinical parameters on the cheeks of 21 female participants were measured using biophysical tools before and after (2 weeks) using HDB or control. The skin microbes were collected and identified using 16s rRNA gene sequencing. HDB significantly improved moisture intensity, transepidermal water loss (TEWL), and hot flush level on the cheek. The beta-diversity of the skin microbiota was different from that of the control in the unweighted UniFrac principal coordinate analysis after using HDB. The genus Lawsonella demonstrated a positive correlation with TEWL and a negative correlation with the moisture contents of the keratin layer, regardless of the use of HDB and control. Conversely, after HDB use, the genus Staphylococcus was increased and associated with a lower hot flush level, while the genera of the phylum Proteobacteria tended to decrease, which is associated with an improved skin condition. Overall, HDB showed clinically proven effects, including skin moisturization with regulation of the skin microbiota.
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Microbiota , Pele , Humanos , Feminino , RNA Ribossômico 16S/genética , ProteobactériasRESUMO
A monoexponential model characterizing cerebral blood velocity dynamics at the onset of exercise may mask dynamic responses by the cerebrovasculature countering large fluctuations of middle cerebral artery blood velocity (MCAv) and cerebral perfusion pressure (CPP) oscillations. Therefore, the purpose of this study was to determine whether the use of a monoexponential model attributes initial fluctuations of MCAv at the start of exercise as a time delay (TD). Twenty-three adults (10 women, 23.9 ± 3.3 yrs; 23.7 ± 2.4 kg/m2 ) completed 2 min of rest followed by 3 mins of recumbent cycling at 50 W. MCAv, CPP, and Cerebrovascular Conductance index (CVCi), calculated as CVCi = MCAv/MAP × 100 mmHg, were collected, a lowpass filter (0.2 Hz) was applied, and averaged into 3-second bins. MCAv data were then fit to a monoexponential model [ΔMCAv(t) = Amp(1 - e-(t-TD)/τ )]. TD, tau (τ), and mean response time (MRT = TD + τ) were obtained from the model. Subjects exhibited a TD of 20.2 ± 18.1 s. TD was directly correlated with MCAv nadir (MCAvN ), r = -0.560, p = 0.007, which occurred at similar times (16.5 ± 15.3 vs. 20.2 ± 18.1 s, p = 0.967). Regressions indicated CPP as the strongest predictor of MCAvN ( R a 2 $$ {R}_a^2 $$ = 0.36). Fluctuations in MCAv were masked using a monoexponential model. To adequately understand cerebrovascular mechanisms during the transition from rest to exercise, CPP and CVCi must also be analyzed. A concurrent drop in cerebral perfusion pressure and middle cerebral artery blood velocity at the start of exercise forces the cerebrovasculature to respond to maintain cerebral blood flow. The use of a monoexponential model characterizes this initial phase as a time delay and masks this large important response.
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Circulação Cerebrovascular , Exercício Físico , Adulto , Humanos , Feminino , Velocidade do Fluxo Sanguíneo/fisiologia , Exercício Físico/fisiologia , Circulação Cerebrovascular/fisiologia , Artéria Cerebral Média/fisiologia , Descanso , Pressão Sanguínea/fisiologiaRESUMO
Lactate is a key metabolite produced from glycolytic metabolism of glucose molecules, yet it also serves as a primary carbon fuel source for many cell types. In the tumor-immune microenvironment, effect of lactate on cancer and immune cells can be highly complex and hard to decipher, which is further confounded by acidic protons, a co-product of glycolysis. Here we show that lactate is able to increase stemness of CD8+ T cells and augments anti-tumor immunity. Subcutaneous administration of sodium lactate but not glucose to mice bearing transplanted MC38 tumors results in CD8+ T cell-dependent tumor growth inhibition. Single cell transcriptomics analysis reveals increased proportion of stem-like TCF-1-expressing CD8+ T cells among intra-tumoral CD3+ cells, a phenotype validated by in vitro lactate treatment of T cells. Mechanistically, lactate inhibits histone deacetylase activity, which results in increased acetylation at H3K27 of the Tcf7 super enhancer locus, leading to increased Tcf7 gene expression. CD8+ T cells in vitro pre-treated with lactate efficiently inhibit tumor growth upon adoptive transfer to tumor-bearing mice. Our results provide evidence for an intrinsic role of lactate in anti-tumor immunity independent of the pH-dependent effect of lactic acid, and might advance cancer immune therapy.
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Linfócitos T CD8-Positivos , Neoplasias , Animais , Linhagem Celular Tumoral , Glicólise , Ácido Láctico/metabolismo , Camundongos , Neoplasias/patologia , Microambiente TumoralRESUMO
Bacterial outer membrane vesicles (OMVs) are small unilamellar proteoliposomes, which are involved in various functions including cell to cell signaling and protein excretion. Here, we have engineered the OMVs of Escherichia coli to nano-scaled bioreactors for the degradation of ß-lactam antibiotics. This was exploited by targeting a ß-lactamase (i.e., CMY-10) into the OMVs of a hyper-vesiculating E. coli BL21(DE3) mutant. The CMY-10-containing OMVs, prepared from the E. coli mutant cultures, were able to hydrolyze ß-lactam ring of nitrocefin and meropenem to a specific rate of 6.6 × 10-8 and 3.9 × 10-12 µmol/min/µm3 of OMV, which is approximately 100 and 600-fold greater than those of E. coli-based whole-cell biocatalsyts. Furthermore, CMY-10, which was encapsulated in the engineered OMVs, was much more stable against temperature and acid stresses, as compared to free enzymes in aqueous phase. The OMV-based nano-scaled reaction system would be useful for the remediation of a variety of antibiotics pollution for food and agricultural industry.
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Membrana Externa Bacteriana , Escherichia coli , Antibacterianos/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Proteínas da Membrana Bacteriana Externa/metabolismo , Escherichia coli/metabolismo , beta-Lactamas/metabolismoRESUMO
It has been shown that there is a non-random association between shape and color. However, the results of previous studies on the shape-color correspondence did not converge. To address the issue, we focused on shape complexity among a number of shape properties, particularly in terms of 3D shape, and parametrically manipulated the shape complexity and all three components of color. With two experiments, the current study aimed to closely examine the correspondence between shape complexity of 3D shape and color in terms of hue (Experiment 1), luminance, and saturation (Experiment 2). Participants were presented with the 3D shapes in either visual or visuo-haptic modes of exploration. Subsequently, they had to pick from a color palette the color best matching each shape of the object. In Experiment 1, we found that as shapes became more complex, the best associated hue changed from those with long wavelengths to ones with short wavelengths. Results of Experiment 2 demonstrated that as the shapes grew more complex, the associated luminance decreased, and saturation increased. Additionally, adding haptic exploration to visual exploration strengthened the association - for saturation in particular - with the pattern of shape-color correspondence maintained. Taken together, we demonstrated that complex shapes are associated with bluish, darker and more saturated colors, suggesting that shape complexity has a systematic relationship with color including hue, luminance, and saturation.
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The immunomodulatory effects of Lactobacillus rhamnosus HDB1258 were evaluated in mice with colitis induced by Klebsiella oxytoca (KO). L. rhamnosus HDB1258 was cultured in the lava seawater (LS) to improve its probiotic properties. It increased adhesive ability to mucin with mRNA expression levels of chaperone proteins (such as GroEL/ES, DnaKJ, and HtrA). In the in vivo experiments, administration of KO caused an inflammation on the colon with gut dysbiosis. LH group (oral gavage of HDB1258 1.0 × 109 colony forming units/day) showed that inflammatory biomarkers, including IL-1ß, TNF-α, IL-6, and PGE2, were significantly decreased to less than half of the KO group, and Th1 cells were decreased in the spleen, but Treg cells were not affected. In contrast, the expression levels of secretory IgA and IL-10 were significantly increased, and the composition of gut microbiota in the LH group tended to recover similar to normal mice without any effect on the α-diversity. In conclusion, L. rhamnosus HDB1258 cultured in the LS could regulate competitively pathogenic bacteria in imbalanced flora with its improved mucin adhesive ability and was an effective immunomodulatory adjuvant for treating colitis by its regulatory function on intestinal inflammation.
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Colite , Microbioma Gastrointestinal , Lacticaseibacillus rhamnosus , Probióticos , Animais , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/genética , Citocinas , Camundongos , Água do MarRESUMO
High expression of mitofusin-2 (MFN2), a mitochondrial fusion protein, has been frequently associated with poor prognosis of patients with cervical cancer. Here, we aimed to identify the function of MFN2 in cervical cancer to understand its influence on disease prognosis. To this end, from cervical adenocarcinoma, we performed an MTT assay and quantitative RT-PCR (qRT-PCR) analysis to assess the effects of MFN2 on the proliferation and of HeLa cells. Then, colony-formation ability and tumorigenesis were evaluated using a tumor xenograft mouse model. The migration ability related to MFN2 was also measured using a wound healing assay. Consequently, epithelial-mesenchymal transition (EMT) of MFN2-knockdowned HeLa cells originating from adenocarcinoma. markers related to MFN2 were assessed by qRT-PCR. Clinical data were analyzed using cBioPortal and The Cancer Genome Atlas. We found that MFN2 knockdown reduced the proliferation, colony formation ability, migration, and in vivo tumorigenesis of HeLa cells. Primarily, migration of MFN2-knockdowned HeLa cells decreased through the suppression of EMT. Thus, we concluded that MFN2 facilitates cancer progression and in vivo tumorigenesis in HeLa cells. These findings suggest that MFN2 could be a novel target to regulate the EMT program and tumorigenic potential in HeLa cells and might serve as a therapeutic target for cervical cancer. Taken together, this study is expected to contribute to the treatment of patients with cervical cancer.
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Familiarity and novelty are fundamental yet competing factors influencing aesthetic preference. However, whether people prefer familiar paintings or novel paintings has not been clear. Using both behavioral and eye-tracking measures, the present study aimed to investigate whether the effect of familiarity-novelty on aesthetic preference is independent or dependent on artwork properties (painting content, visual complexity) and viewer characteristics (experience in art). Participants were presented with two images of paintings, one of which was repeatedly presented but was always paired with a new painting in a randomized lateral arrangement. They were asked to indicate which of the two images they preferred with the degree of their preference. Behavioral results demonstrated an interactive influence of painting content and complexity on familiarity-novelty preference, especially alongside the distinction between representational and abstract paintings. Also, the familiarity-novelty preference was modulated by the degree of art experience, for abstract paintings in particular. Gaze results showed the differential effects of painting content, complexity, and art experience echoing the behavioral results. Taken together, the convergent results derived from behavioral and eye-tracking measures imply that novelty is an important feature of aesthetic appreciation, but its influence is modulated by properties of both the artwork and the beholder.
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Non-typhoidal salmonellosis remains a pressing public health problem worldwide. Quinolones, particularly fluoroquinolones, are widely used to treat various infections, including non-typhoidal salmonellosis, which can be a serious illness. The emergence of fluoroquinolone-resistant Salmonella has resulted in treatment failure and high mortality rates. In this study, we estimated the presence of plasmid-mediated quinolone resistance (PMQR) genes in Salmonella enterica isolated from human salmonellosis patients in South Korea from 2016 to 2019. We evaluated the association of these genes with fluoroquinolone susceptibility. Antimicrobial susceptibility tests for Salmonella isolates were performed using the Vitek II system, and the minimum inhibitory concentrations (MIC) of ciprofloxacin and levofloxacin were determined using the E-test method. Plasmid-mediated quinolone resistance (PMQR) genes were detected by PCR amplification and quinolone resistance-determining regions (QRDRs) of the gyrA and parC genes were analyzed following Sanger sequencing of the PCR products. Thirty-four Salmonella strains with reduced susceptibility to fluoroquinolones (ciprofloxacin MIC ≥ 0.125 µg/mL and levofloxacin MIC ≥ 0.25 µg/mL) were selected from 208 human clinical Salmonella isolates. Among them, 22 Salmonella strains harbored one PMQR gene (qnrA, qnrB, or qnrS), and three Salmonella strains carried two PMQR genes (qnrS and aac(6')-Ib-cr or qnrA and qnrB). qnrS was the most common PMQR gene. Serotyping revealed that Salmonella 4,[5]12:i:- (32.4%, 11/34) and Salmonella Typhimurium (29.4%, 10/34) were the two most predominant serovars, and Multi-locus sequence typing (MLST) showed that ST19 and ST34 were the most frequent sequence types. In conclusion, qnr gene-positive Salmonella 4,[5],12:i:- and Salmonella Typhimurium were the main serovars responsible for reduced susceptibility to fluoroquinolones. Therefore, our findings suggest that PMQR-positive Salmonella strains, which can be isolated from various samples including human, food, and the environment, should be carefully monitored.
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Impaired macroautophagy/autophagy has been implicated in experimental and human nonalcoholic steatohepatitis (NASH). However, the mechanism underlying autophagy dysregulation in NASH is largely unknown. Here, we investigated the role and mechanism of TXNIP/VDUP1 (thioredoxin interacting protein), a key mediator of cellular stress responses, in the pathogenesis of NASH. Hepatic TXNIP expression was upregulated in nonalcoholic fatty liver disease (NAFLD) patients and in methionine choline-deficient (MCD) diet-fed mice, as well as in palmitic acid (PA)-treated hepatocytes. Upregulation of hepatic TXNIP was positively correlated with impaired autophagy, as evidenced by a decreased number of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 beta) puncta and increased SQSTM1/p62 (sequestosome 1) expression. Deletion of the Txnip gene enhanced hepatic steatosis, inflammation, and fibrosis, accompanied by impaired autophagy and fatty acid oxidation (FAO) in MCD diet-fed mice. Mechanistically, TXNIP directly interacted with and positively regulated p-PRKAA, leading to inactivation of MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) and nuclear translocation of TFEB (transcription factor EB), which in turn promoted autophagy. Inhibition of MTORC1 by rapamycin induced autophagy and increased the expression levels of FAO-related genes and concomitantly attenuated lipid accumulation in PA-treated txnip-knockout (KO) hepatocytes, which was further abolished by silencing of Atg7. Rapamycin treatment also attenuated MCD diet-induced steatosis, inflammation, and fibrosis with increased TFEB nuclear translocation and restored FAO in txnip-KO mice. Our findings suggest that elevated TXNIP ameliorates steatohepatitis by interacting with PRKAA and thereby inducing autophagy and FAO. Targeting TXNIP may be a potential therapeutic approach for NASH.Abbreviations: ACOX1: acyl-Coenzyme A oxidase 1, palmitoyl; ACSL1: acyl-CoA synthetase long-chain family member 1; ACTA2/α-SMA: actin, alpha 2, smooth muscle, aorta; ACTB: actin beta; ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BafA1: bafilomycin A1; COL1A1/Col1α1: collagen, type I, alpha 1; CPT1A: carnitine palmitoyltransferase 1a, liver; CQ: chloroquine; DGAT1: diacylglycerol O-acyltransferase 1; DGAT2: diacylglycerol O-acyltransferase 2; ECI2/Peci: enoyl-Coenzyme A isomerase 2; EHHADH: enoyl-Coenzyme A, hydratase/3-hydroxyacyl Coenzyme A dehydrogenase; FAO: fatty acid oxidation; FASN: fatty acid synthase; FFA: free fatty acids; GFP: green fluorescent protein; GK/GYK: glycerol kinase; GOT1/AST: glutamic-oxaloacetic transaminase 1, soluble; GPAM: glycerol-3-phosphate acyltransferase, mitochondrial; GPT/ALT: glutamic pyruvic transaminase, soluble; H&E: hematoxylin and eosin; IL1B/IL-1ß: interleukin 1 beta; IL6: interleukin 6; IOD: integral optical density; KO: knockout; Leu: leupeptin; LPIN1: lipin 1; MAP1LC3B/LC3B: microtubule-associated protein 1 light chain 3 beta; MCD: methionine choline-deficient; MMP9: matrix metallopeptidase 9; mRNA: messenger RNA; MTORC1: mechanistic target of rapamycin kinase complex 1; NAFLD: nonalcoholic fatty liver diseases; NASH: nonalcoholic steatohepatitis; PA: palmitic acid; PPARA/PPARα: peroxisome proliferator activated receptor alpha; PPARG/PPARγ: peroxisome proliferator activated receptor gamma; qRT-PCR: quantitative real-time PCR; RPS6KB1/p70S6K1: ribosomal protein S6 kinase, polypeptide 1; RPTOR: regulatory associated protein of MTOR complex 1; SCD1: stearoyl-Coenzyme A desaturase 1; SEM: standard error of the mean; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; TFEB: transcription factor EB; TG: triglyceride; TGFB/TGF-ß: transforming growth factor, beta; TIMP1: tissue inhibitor of metalloproteinase 1; TNF/TNF-α: tumor necrosis factor; TXNIP/VDUP1: thioredoxin interacting protein; WT: wild-type.
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Autofagia , Proteínas de Transporte , Hepatopatia Gordurosa não Alcoólica , Tiorredoxinas , Animais , Autofagia/genética , Proteínas de Transporte/genética , Ácidos Graxos , Humanos , Metabolismo dos Lipídeos , Camundongos , Tiorredoxinas/genéticaRESUMO
Although systemic sex-specific differences in cardiovascular responses to exercise are well established, the comparison of sex-specific cerebrovascular responses to exercise has gone under-investigated especially, during high intensity exercise. Therefore, our purpose was to compare cerebrovascular responses in males and females throughout a graded exercise test (GXT). Twenty-six participants (13 Females and 13 Males, 24 ± 4 yrs.) completed a GXT on a recumbent cycle ergometer consisting of 3-min stages. Each sex completed 50W, 75W, 100W stages. Thereafter, power output increased 30W/stage for females and 40W/stage for males until participants were unable to maintain 60-80 RPM. The final stage completed by the participant was considered maximum workload(Wmax ). Respiratory gases (End-tidal CO2 , EtCO2 ), middle cerebral artery blood velocity (MCAv), heart rate (HR), non-invasive mean arterial pressure (MAP), cardiac output (CO), and stroke volume (SV) were continuously recorded on a breath-by-breath or beat-by-beat basis. Cerebral perfusion pressure, CPP = MAP (0. 7,355 distance from heart-level to doppler probe) and cerebral vascular conductance index, CVCi = MCAv/CPP 100mmHg were calculated. The change from baseline (Δ) in MCAv was similar between the sexes during the GXT (p = .091, ωp2 = 0.05). However, ΔCPP (p < .001, ωp2 = 0.25) was greater in males at intensities ≥ 80% Wmax and ΔCVCi (p = .005, ωp2 = 0.15) was greater in females at 100% Wmax . Δ End-tidal CO2 (ΔEtCO2 ) was not different between the sexes during exercise (p = .606, ωp2 = -0.03). These data suggest there are sex-specific differences in cerebrovascular control, and these differences may only be identifiable at high and severe intensity exercise.
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Circulação Cerebrovascular , Teste de Esforço/normas , Treinamento Intervalado de Alta Intensidade/métodos , Adulto , Pressão Sanguínea , Feminino , Frequência Cardíaca , Treinamento Intervalado de Alta Intensidade/normas , Humanos , Masculino , Fatores SexuaisRESUMO
Peripheral artery disease (PAD) is a manifestation of atherosclerosis in the leg arteries, which causes claudication. This may be in part due to vascular mitochondrial dysfunction and excessive reactive oxygen species (ROS) production. A mitochondrial-targeted antioxidant (MitoQ) has been shown to improve vascular mitochondrial function that, in turn, led to improved vascular function in older adults and animal models. However, the roles of vascular mitochondria in vascular function including endothelial function and arterial stiffness in patients with PAD are unknown; therefore, with the use of acute MitoQ intake, this study examined the roles of vascular mitochondria in endothelial function, arterial stiffness, exercise tolerance, and skeletal muscle function in patients with PAD. Eleven patients with PAD received either MitoQ or placebo in a randomized crossover design. At each visit, blood samples, brachial and popliteal artery flow-mediated dilation (FMD), peripheral and central pulse-wave velocity (PWV), blood pressure (BP), maximal walking capacity, time to claudication (COT), and oxygen utility capacity were measured pre- and-post-MitoQ and placebo. There were significant group by time interactions (P < 0.05) for brachial and popliteal FMD that both increased by Δ2.6 and Δ3.3%, respectively, and increases superoxide dismutase (Δ0.03 U/mL), maximal walking time (Δ73.8 s), maximal walking distance (Δ49.3 m), and COT (Δ44.2 s). There were no changes in resting heart rate, BP, malondialdehyde, total antioxidant capacity, PWV, or oxygen utility capacity (P > 0.05). MitoQ intake may be an effective strategy for targeting the vascular mitochondrial environment, which may be useful for restoring endothelial function, leg pain, and walking time in patients with PAD.NEW & NOTEWORTHY The results of this study reveal for the first time that acute oral intake of mitochondrial-targeted antioxidant (MitoQ, 80 mg) is effective for improving vascular endothelial function and superoxide dismutase in patients with peripheral artery disease (PAD). Acute MitoQ intake is also effective for improving maximal walking capacity and delaying the onset of claudication in patients with PAD. These findings suggest that the acute oral intake of MitoQ-mediated improvements in vascular mitochondria play a pivotal role for improving endothelial function, the redox environment, and skeletal muscle performance in PAD.
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Antioxidantes/uso terapêutico , Artéria Braquial/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Tolerância ao Exercício/efeitos dos fármacos , Hemodinâmica/efeitos dos fármacos , Claudicação Intermitente/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Compostos Organofosforados/uso terapêutico , Doença Arterial Periférica/tratamento farmacológico , Artéria Poplítea/efeitos dos fármacos , Ubiquinona/análogos & derivados , Idoso , Antioxidantes/metabolismo , Pressão Arterial/efeitos dos fármacos , Artéria Braquial/metabolismo , Artéria Braquial/fisiopatologia , Estudos Cross-Over , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Feminino , Humanos , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/metabolismo , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Contração Muscular/efeitos dos fármacos , Nebraska , Compostos Organofosforados/metabolismo , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/metabolismo , Doença Arterial Periférica/fisiopatologia , Artéria Poplítea/metabolismo , Artéria Poplítea/fisiopatologia , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Ubiquinona/metabolismo , Ubiquinona/uso terapêutico , Rigidez Vascular/efeitos dos fármacos , CaminhadaRESUMO
Differentiation of stem cells into functional replacement cells and tissues is a major goal of the regenerative medicine field. However, one limitation has been organization of differentiated cells into multi-cellular, three-dimensional assemblies. The islets of Langerhans contain many endocrine and non-endocrine cell types, such as insulin-producing ß cells and endothelial cells. Despite the potential importance of endothelial cells to islet function, facilitating interactions between endothelial cells and islet endocrine cell types already differentiated from human embryonic stem cells has been difficult in vitro. We have developed a strategy of assembling human embryonic stem cell-derived islet cells with endothelial cells into three-dimensional aggregates on a hydrogel. The resulting islet organoids express ß cell and other endocrine markers and are functional, capable of undergoing glucose-stimulated insulin secretion. This assembly was not observed on traditional tissue culture plastic and in aggregates generated in suspension culture, highlighting how physical culture conditions greatly influence the interactions among these cell types. These results provide a platform for evaluating the effects of the islet tissue microenvironment on human embryonic stem cell-derived ß cells and other islet endocrine cells to develop tissue engineered islets. STATEMENT OF SIGNIFICANCE: Differentiation of insulin-producing cells and tissues from human pluripotent stem cells is being investigated for diabetes cell replacement therapies. Despite successes generating ß cells, the cell type responsible for glucose-stimulated insulin secretion within the islets of Langerhans found in the pancreas, successful assembly with other non-endocrine cell types, particularly endothelial cells, has been technically challenging. The present study provides a platform for the assembly of endothelial cells with SC-ß and other endocrine cells, producing islet organoids that are functional and express ß cell markers, that can be used to study the islet microenvironment and islet tissue engineering.
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Células Imobilizadas/metabolismo , Células Endoteliais/metabolismo , Hidrogéis/química , Células Secretoras de Insulina/metabolismo , Organoides/metabolismo , Células-Tronco/metabolismo , Linhagem Celular , Células Imobilizadas/citologia , Células Endoteliais/citologia , Humanos , Células Secretoras de Insulina/citologia , Organoides/citologia , Células-Tronco/citologiaRESUMO
Recent advances in human pluripotent stem cell (hPSC) differentiation protocols have generated insulin-producing cells resembling pancreatic ß cells. While these stem cell-derived ß (SC-ß) cells are capable of undergoing glucose-stimulated insulin secretion (GSIS), insulin secretion per cell remains low compared with islets and cells lack dynamic insulin release. Herein, we report a differentiation strategy focused on modulating transforming growth factor ß (TGF-ß) signaling, controlling cellular cluster size, and using an enriched serum-free media to generate SC-ß cells that express ß cell markers and undergo GSIS with first- and second-phase dynamic insulin secretion. Transplantation of these cells into mice greatly improves glucose tolerance. These results reveal that specific time frames for inhibiting and permitting TGF-ß signaling are required during SC-ß cell differentiation to achieve dynamic function. The capacity of these cells to undergo GSIS with dynamic insulin release makes them a promising cell source for diabetes cellular therapy.
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Células-Tronco Embrionárias/fisiologia , Células Secretoras de Insulina/fisiologia , Células-Tronco Pluripotentes/fisiologia , Animais , Diferenciação Celular/fisiologia , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Células Secretoras de Insulina/metabolismo , Camundongos , Pâncreas/metabolismo , Pâncreas/fisiologia , Células-Tronco Pluripotentes/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Fatty acids have a low permeability through the cell membrane. Therefore, the intracellular biotransformation of fatty acids can be slow due to supply limitations. The effects of expression level of the fatty acid transporter FadL in Escherichia coli on the biotransformations were investigated. The enhanced expression of FadL led to 5.5-fold increase of the maximum reaction rate Vmax (i.e., 200 µmol/min per g dry cells (200 U/g dry cells)) of the recombinant E. coli expressing a hydratase of Stenotrophomonas maltophilia in the periplasm with respect to hydration of oleic acid. The FadL expression level was also critical for oxidation of 12- and 10- hydroxyoctadecanoic acid by the recombinant E. coli expressing an alcohol dehydrogenase (ADH) of Micrococcus luteus. In addition, the multistep biotransformation of ricinoleic acid into the ester (i.e., (Z)-11-(heptanoyloxy)undec-9-enoic acid) by the recombinant E. coli expressing the ADH of M. luteus and a Baeyer-Villiger monooxygenase of Pseudomonas putida KT2440 was 2-fold increased to 40 U/g dry cells with expression of FadL to an appropriate level. The FadL expression level is one of the critical factors to determine whole-cell biotransformation rates of not only long chain fatty acids but also hydroxy fatty acids. This study may contribute to whole-cell biocatalyst engineering for biotransformation of hydrophobic substances.
Assuntos
Proteínas da Membrana Bacteriana Externa/metabolismo , Membrana Celular/metabolismo , Proteínas de Escherichia coli/metabolismo , Proteínas de Transporte de Ácido Graxo/metabolismo , Ácidos Graxos/metabolismo , Álcool Desidrogenase/genética , Bactérias/genética , Bactérias/metabolismo , Proteínas da Membrana Bacteriana Externa/genética , Biotransformação , Proteínas de Escherichia coli/genética , Proteínas de Transporte de Ácido Graxo/genética , Hidroliases/genética , Oxigenases de Função Mista/genética , Ácido Oleico/metabolismoRESUMO
OBJECTIVE: To investigate the correlation between bladder wall thickness (BWT) measured by ultrasonography and lower urinary tract dysfunction (LUTD) in patients with lower urinary tract symptoms (LUTS). METHODS: Forty-eight women with LUTS who underwent urodynamic study and BWT by ultrasonography as outpatients were studied. We assessed LUTS during a medical examination by interview. The thinnest part of the bladder wall was measured by a transabdominal ultrasonography. We excluded patients who had visited another hospital previously because we did not know what treatment they had received, including medications, behavioral therapy, or other treatments. We constructed receiver operating characteristic (ROC) curves for diagnosis of LUTD and also determined reliable BWT criteria by calculating the area under the curve. Statistical analyses were performed using the Kolmogorov-Smirnov method and Student's t-test. RESULTS: The mean age, body mass index, and duration of symptoms were 59.9±9.7 years, 26.06±3.4 kg/m2, and 53.4±38.2 months, respectively. Urodynamic study parameters (Valsalva leak point pressure, maximal urethral closure pressure, functional length, and postvoid residual volume) were lower in patients with BWT <3 mm; however, these differences were not significant. Patients with BWT ≥3 mm developed a hypoactive bladder (P=0.009) and intrinsic sphincter deficiency (ISD) (P=0.001) at a significantly higher rate. According to the ROC analysis, the best BWT cut-off value was 3 mm for overactive bladder diagnosis. CONCLUSIONS: Women with LUTD showed higher BWT values (≥3 mm), especially patients with hypoactive bladder and ISD. Sonographic evaluation of BWT is an easy, fast, and noninvasive method for possible diagnostic tool for LUTD.
RESUMO
Cardiovascular diseases (CVDs) have become prominent in mortality and morbidity rates. Prevalent cardiovascular conditions, such as hypertension, atherosclerosis and oxidative stress, are increasing at an alarming rate. Conventional drugs have been associated with adverse effects, suggesting a need for an alternative measure to ameliorate CVD. A number of plant- and herb-derived preventative food and therapeutic drugs for cardiovascular conditions are progressively used for their various benefits. Naturally derived food and drugs have fewer side effects because they come from natural elements; preventative food, such as grape seed, inhibits changes of histopathology and biomarkers in vital organs whereas therapeutic drugs, for instance Xanthone, improve heart functions by suppressing oxidative stress of myocyte. This review closely examines the various plant- and herb-derived drugs that have assumed an essential role in treating inflammation and oxidative stress for prevalent cardiovascular conditions. Furthermore, the use of plant-derived medicine with other synthetic particles, such as nanoparticles, for targeted therapy is investigated for its effective clinical use in the future.
RESUMO
Quisqualis indica (QI) has been used for treating disorders such as stomach pain, constipation, and digestion problem. This study was aimed to evaluate the therapeutic efficacy of QI extract on treating benign prostatic hyperplasia (BPH) in LNCaP human prostate cancer cell line and a testosterone-induced BPH rat model. LNCaP cells were treated with QI plus testosterone propionate (TP), and androgen receptor (AR) and prostate specific antigen (PSA) expression levels were assessed by Western blotting. To induce BPH, the rats were subjected to a daily subcutaneous injection of TP (3 mg/kg) for 4 weeks. The rats in treatment group were orally gavaged with QI (150 mg/kg) together with the TP injection. In-vitro studies showed that TP-induced increases in AR and PSA expression in LNCaP cells were reduced by QI treatment. In BPH-model rats, the prostate weight, testosterone in serum, dihydrotestosterone (DHT) concentration and 5α-reductase type 2 mRNA expression in prostate tissue were significantly reduced following the treatment with QI. TP-induced prostatic hyperplasia and the expression of proliferating cell nuclear antigen (PCNA) and cyclin D1 were significantly attenuated in QI-treated rats. In addition, QI induced apoptosis by up-regulating caspase-3 and -9 activity and decreasing the B-cell lymphoma 2 (Bcl-2)/Bcl-2-associated X protein (Bax) ratio in prostate tissues of BPH rats. Further investigation showed that TP-induced activation of AKT and glycogen synthase kinase 3ß (GSK3ß) was reduced by QI administration. Therefore, our findings suggest that QI attenuates the BPH state in rats through anti-proliferative and pro-apoptotic activities and might be useful in the clinical treatment of BPH.