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Prostate stem cell antigen (PSCA) is expressed in all stages of prostate cancer, including in advanced androgen-independent tumors and bone metastasis. PSCA may associate with prostate carcinogenesis and lineage plasticity in prostate cancer. PSCA is also a promising theranostic marker for a variety of other solid tumors, including pancreatic adenocarcinoma and renal cell carcinoma. Here, we identified a novel fully human PSCA antibody using phage display methodology. The structure-based affinity maturation yielded a high-affinity binder, F12, which is highly specific and does not bind to 6,000 human membrane proteins based on a membrane proteome array assay. F12 targets PSCA amino acids 63-69 as tested by the peptide scanning microarray, and it cross-reacts with the murine PSCA. IgG1 F12 efficiently internalizes into PSCA-expressing tumor cells. The antimitotic reagent monomethyl auristatin E (MMAE)-conjugated IgG1 F12 (ADC, F12-MMAE) exhibits dose-dependent efficacy and specificity in a human prostate cancer PC-3-PSCA xenograft NSG mouse model. This is a first reported ADC based on a fully human PSCA antibody and MMAE that is characterized in a xenograft murine model, which warrants further optimizations and investigations in additional preclinical tumor models, including prostate and other solid tumors.
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Antígenos de Neoplasias , Proteínas Ligadas por GPI , Imunoconjugados , Proteínas de Neoplasias , Neoplasias da Próstata , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Neoplasias da Próstata/imunologia , Imunoconjugados/farmacologia , Animais , Antígenos de Neoplasias/imunologia , Camundongos , Proteínas Ligadas por GPI/imunologia , Proteínas de Neoplasias/imunologia , Proteínas de Neoplasias/antagonistas & inibidores , Linhagem Celular Tumoral , Oligopeptídeos/imunologia , Oligopeptídeos/farmacologia , Imunoglobulina G/imunologia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/farmacologiaRESUMO
Plasma metabolites offer insights into aging processes and aging-related biomarkers. Here, the dietary effects of various functional foods on older adult mice were evaluated using metabolomic techniques. Fifty-week-old mice were divided into four groups (n = 4 each) and fed either a normal diet (AC) or the diets from Triticum aestivum sprout (TA), Schisandra chinensis (SZ), or Pisum sativum sprout (PS) extracts. Additionally, a group of 8-week-old mice fed a normal diet (YC; n = 5) was included for the comparison. The PS group had a significantly lower free fatty acid content and higher ornithine, proline, citric acid, and oxalic acid contents than the AC group. The PS group also showed reduced oxidative stress and muscle damage, suggesting the higher anti-aging efficacy of P. sativum sprouts than the other diets. These findings suggest plasma metabolite profiling is an effective tool to assess the anti-aging effects of functional foods. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01479-8.
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Intricate ecosystem of the human gut microbiome is affected by various environmental factors, genetic makeup of the individual, and diet. Specifically, resistant starch (RS) is indigestible in the small intestine but nourishes the gut microbiota in the colon. Degradation of RS in the gut begins with primary degraders, such as Bifidobacterium adolescentis and Ruminococcus bromii. Recently, new RS degraders, such as Ruminococcoides bili, have been reported. These microorganisms play crucial roles in the transformation of RS into short-chain fatty acids (SCFAs), such as acetate, propionate, and butyrate. SCFAs are necessary to maintain optimal intestinal health, regulate inflammation, and protect against various illnesses. This review discusses the effects of RS on gut and highlights its complex interactions with gut flora, especially the Ruminococcaceae family.
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The fecal microbiota of two healthy adults was cultivated in a medium containing commercial fructooligosaccharides [FOS; 1-kestose (GF2), nystose (GF3), and 1F-fructofuranosylnystose (GF4)]. Initially, the proportions of lactobacilli in the two feces samples were only 0.42% and 0.17%; however, they significantly increased to 7.2% and 4.8%, respectively, after cultivation on FOS. Most FOS-utilizing isolates could utilize only GF2; however, Lacticaseibacillus paracasei strain Lp02 could fully consume GF3 and GF4 too. The FOS operon (fosRABCDXE) was present in Lc. paracasei Lp02 and another Lc. paracasei strain, KCTC 3510T, but fosE was only partially present in the non-FOS-degrading strain KCTC 3510T. In addition, the top six upregulated genes in the presence of FOS were fosABCDXE, particularly fosE. FosE is a ß-fructosidase that hydrolyzes both sucrose and all three FOS. Finally, a genome-based analysis suggested that fosE is mainly observed in Lc. paracasei, and only 13.5% (61/452) of their reported genomes were confirmed to include it. In conclusion, FosE allows the utilization of FOS, including GF3 and GF4 as well as GF2, by some Lc. paracasei strains, suggesting that this species plays a pivotal role in FOS utilization in the human gut.
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Fezes , Microbioma Gastrointestinal , Lacticaseibacillus paracasei , Oligossacarídeos , beta-Frutofuranosidase , Humanos , Oligossacarídeos/metabolismo , Fezes/microbiologia , Lacticaseibacillus paracasei/metabolismo , Lacticaseibacillus paracasei/genética , beta-Frutofuranosidase/metabolismo , beta-Frutofuranosidase/genética , Adulto , Óperon , Trissacarídeos/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismoRESUMO
Osteoarthritis (OA) is a chronic degenerative joint disease that causes chronic pain, swelling, stiffness, disability, and significantly reduces the quality of life. Typically, OA is treated using painkillers and non-steroidal anti-inflammatory drugs (NSAIDs). While current pharmacologic treatments are common, their potential side effects have prompted exploration into functional dietary supplements. Recently, eggshell membrane (ESM) has emerged as a potential functional ingredient for joint and connective tissue disorders due to its clinical efficacy in relieving joint pain and stiffness. Despite promising clinical evidence, the effects of ESM on OA progression and its mechanism of action remain poorly understood. This study evaluated the efficacy of Ovomet®, a powdered natural ESM, against joint pain and disease progression in a monosodium iodoacetate (MIA)-induced rodent model of OA in mice and rats. The results demonstrate that ESM significantly alleviates joint pain and attenuates articular cartilage destruction in both mice and rats that received oral supplementation for 5 days prior to OA induction and for 28 days thereafter. Interestingly, ESM significantly inhibited mRNA expression levels of pro-inflammatory cytokines including tumor necrosis factor alpha (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6), as well as inflammatory mediators, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase in the knee joint cartilage at the early stage of OA, within 7 days after OA induction. However, this effect was not observed in the late stage at 28 days after OA induction. ESM further attenuates the induction of protein expression for cartilage-degrading enzymes like matrix metalloproteinase (MMPs) 3 and 13, and a disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5), in the late-stage. In addition, MIA-induced reduction of the protein expression levels of cartilage components, cartilage oligomeric matrix protein (COMP), aggrecan (ACAN) and collagen type II α-1 chain (COL2α1), and cartilage extracellular matrix (ECM) synthesis promoting transcriptional factor SRY-Box 9 (SOX-9) were increased via ESM treatment in the cartilage tissue. Our findings suggest that Ovomet®, a natural ESM powder, is a promising dietary functional ingredient that can alleviate pain, inflammatory response, and cartilage degradation associated with the progression of OA.
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Cartilagem Articular , Casca de Ovo , Osteoartrite , Animais , Cartilagem Articular/efeitos dos fármacos , Cartilagem Articular/metabolismo , Cartilagem Articular/patologia , Osteoartrite/tratamento farmacológico , Osteoartrite/induzido quimicamente , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ratos , Inflamação/tratamento farmacológico , Suplementos Nutricionais , Citocinas/metabolismo , Modelos Animais de Doenças , Ratos Sprague-Dawley , Artralgia/tratamento farmacológico , Artralgia/induzido quimicamente , Fatores de Tempo , Ácido Iodoacético , Anti-Inflamatórios/farmacologiaRESUMO
Motivated by the increasing cost, environmental concerns, and limited availability of Co, researchers are actively seeking alternative cathode materials for lithium-ion batteries. A promising strategy involves structure-modified materials, such as a NiMn core/shell system. This design leverages the high energy density of a Ni-rich core while employing an Mn-rich shell to enhance interfacial stability by suppressing unwanted reactions with the electrolyte. This approach offers improved cycling stability and reduced reliance on Co. However, the interdiffusion of Mn ions between the core and shell remains a significant challenge during synthesis. This work presents a facile approach to address the issue of Mn interdiffusion in core/shell cathode materials. The study demonstrates that partial oxidation of the precursor during the drying stage effectively enhances the Mn oxidation state. This strategy successfully suppresses Mn interdiffusion during subsequent calcination, leading to the preservation of the core/shell architecture in the final cathode material. This optimized structure mitigates interfacial reactions, enhances chemomechanical properties, and reduces crosstalk, a major contributor to rollover failure. This work presents a novel approach for synthesizing high-performance core/shell cathode materials for next-generation lithium-ion batteries.
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17ß-Estradiol is an ovarian hormone that regulates energy circulation and storage by acting on the central nervous system. However, the metabolic differences between the blood and brain when stimulated by 17ß-estradiol are poorly understood. Moreover, research using menopause-induced models to investigate primary metabolites in the blood and brain is limited. Thus, this study aimed to identify metabolic changes in the plasma and brain resulting from 17ß-estradiol supplementation in an estrogen-deficient mouse model. Three groups of mice were utilized: sham-operated mice (Sham), ovariectomized mice (OVX), and ovariectomized mice that received a weekly supplementation of 17ß-estradiol (E2). Plasma and brain samples from these mice were subjected to metabolic analysis using gas chromatography-time-of-flight-mass spectrometry. Compared with the plasma samples from the Sham and OVX groups, the plasma samples from the E2 group contained higher contents of branched-chain amino acids (BCAAs), such as valine, isoleucine, and leucine. Meanwhile, the brain samples from the E2 group contained higher contents of most metabolites, including BCAAs, neurotransmitters, tricarboxylic acid cycle intermediates, and fatty acids, than those from the two other groups. This study is the first to reveal differences in energy metabolism induced by 17ß-estradiol supplementation through brain metabolic profiling of ovariectomized mice, emphasizing the importance of brain metabolic profiling in menopausal hormone research.
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Polarons are prevalent in condensed matter systems with strong electron-phonon coupling. The adiabaticity of the polaron relates to its transport properties and spatial extent. To date, only adiabatic small polaron formation has been measured following photoexcitation. The lattice reorganization energy is large enough that the first electron-optical phonon scattering event creates a small polaron without requiring substantial carrier thermalization. We measure that frustrating the iron-centered octahedra in the rare-earth orthoferrite ErFeO3 leads to antiadiabatic polaron formation. Coherent charge hopping between neighboring Fe3+âFe2+ sites is measured with transient extreme ultraviolet spectroscopy and lasts several picoseconds before the polaron forms. The resulting small polaron formation time is an order of magnitude longer than previous measurements and indicates a shallow potential well, even in the excited state. The results emphasize the importance of considering dynamic electron-electron correlations, not just electron-phonon-induced lattice changes, for small polarons for transport, catalysis, and photoexcited applications.
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α-Glucan microparticles (GMPs) have significant potential as high-value biomaterials in various industries. This study proposes a bottom-up approach for producing GMPs using four amylosucrases from Bifidobacterium sp. (BASs). The physicochemical characteristics of these GMPs were analyzed, and the results showed that the properties of the GMPs varied depending on the type of enzymes used in their synthesis. As common properties, all GMPs exhibited typical B-type crystal patterns and poor colloidal dispersion stability. Interestingly, differences in the physicochemical properties of GMPs were generated depending on the synthesis rate of linear α-glucan by the enzymes and the degree of polymerization (DP) distribution. Consequently, we found differences in the properties of GMPs depending on the DP distribution of linear glucans prepared with four BASs. Furthermore, we suggest that precise control of the type and characteristics of the enzymes provides the possibility of producing GMPs with tailored physicochemical properties for various industrial applications.
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Bifidobacterium , Glucanos , Guanosina Monofosfato , Tionucleotídeos , Glucanos/química , GlucosiltransferasesRESUMO
Assessing the ergodicity of graphene liquid cell electron microscope measurements, we report that loop states of circular DNA interconvert reversibly and that loop numbers follow the Boltzmann distribution expected for this molecule in bulk solution, provided that the electron dose is low (80-keV electron energy and electron dose rate 1-20 e- Å-2 s-1). This imaging technique appears to act as a "slow motion" camera that reveals equilibrated distributions by imaging the time average of a few molecules without the need to image a spatial ensemble.
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Elétrons , Grafite , Microscopia Eletrônica , Movimento (Física) , Conformação de Ácido NucleicoRESUMO
When navigated by the available energy of a system, often provided in the form of heat, physical processes or chemical reactions fleet on a free-energy landscape, thus changing the structure. In in situ transmission electron microscopy (TEM), where material structures are measured and manipulated inside the microscope while being subjected to external stimuli such as electrical fields, laser irradiation, or mechanical stress, it is necessary to precisely determine the local temperature of the specimen to provide a comprehensive understanding of material behavior and to establish the relationship among energy, structure, and properties at the nanoscale. Here, we propose using cathodoluminescence (CL) spectroscopy in TEM for in situ measurement of the local temperature. Gadolinium oxide particles doped with emissive europium ions present an opportunity to utilize them as a temperature probe in CL measurements via a ratiometric approach. We show the thermometric performance of the probe and demonstrate a precision of ±5 K in the temperature range from 113 to 323 K with the spatial resolution limited by the size of the particles, which surpasses other methods for temperature determination. With the CL-based thermometry, we further demonstrate measuring local temperature under laser irradiation.
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Seed longevity is a critical characteristic in agriculture, yet the specific genes/proteins responsible for this trait and the molecular mechanisms underlying reduced longevity during seed aging remain largely elusive. Here we report the comparative proteome and metabolome profiling of three rice cultivars exhibiting varying degrees of aging tolerance: Dharial, an aging-tolerant cultivar; Ilmi, an aging-sensitive cultivar; and A2, a moderately aging-tolerant cultivar developed from the crossbreeding of Dharial and Ilmi. Artificial aging treatment (AAT) markedly reduced the germination percentage and enhanced the activities of antioxidant enzymes in all the cultivars. Further, proteomics results showed a key role of the ubiquitin (Ub)-proteasome pathway in the degradation of damaged proteins during AAT while other proteases were majorly reduced. In addition, proteins associated with energy production and protein synthesis were strongly reduced in Ilmi while these were majorly increased in A2 and Dharial. These, along with metabolomics results, suggest that Ub-proteasome mediated protein degradation during AAT results in the accumulation of free amino acids in Ilmi while tolerant cultivars potentially utilize those for energy production and synthesis of stress-related proteins, especially hsp20/alpha-crystallin family protein. Additionally, both Dharial and A2 seem to activate brassinosteroid signaling and suppress jasmonate signaling which initiates a signaling cascade that allows accumulation of enzymatic and non-enzymatic antioxidants for efficient detoxification of aging-induced ROS. Taken together, these results provide an in-depth understanding of the aging-induced changes in rice seeds and highlight key pathways responsible for maintaining seed longevity during AAT.
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Antioxidantes , Oryza , Antioxidantes/metabolismo , Brassinosteroides/metabolismo , Germinação , Oryza/metabolismo , Complexo de Endopeptidases do Proteassoma/metabolismo , Sementes/metabolismoRESUMO
PURPOSE AND METHOD: The purpose of this study was to determine the changes in the Blood Oxygen Level Dependent signal of Primary somatosensory area (S1) and Brodmann area 3 (BA3) per finger and phalanx in comparison to the activation voxel when 250 Hz vibratory stimulation with high sensitivity for the Pacinian corpuscle was given to the four fingers and three phalanges. RESULTS: The result of analyzing the activation voxel showed a significant difference for S1 per finger and phalanx, but for BA3, no significant difference was observed despite a similar trend to S1. In contrast, the activation intensity (BOLD) displayed a significant difference for S1 per finger and phalanx and for BA3, where the activation voxel had no significant variation. In addition, while the result of S1 did not indicate whether the index or the little fingers had the highest sensitivity based on the BOLD signal per finger, the result of BA3 marked the strongest BOLD signal for the little finger as a response to 250 Hz vibratory stimulation. The activation intensity per phalanx was the highest for the intermediate phalanx for S1 and BA3, which was in line with a previous study comparing the activation voxel. CONCLUSIONS: The method based on the intensity of the nerve activation is presumed to have high sensitivity as the signal intensity is monitored within a specific, defined area. Thus, for the extraction of brain activation patterns of micro-domains, such as BA3, monitoring the BOLD signal that reflects the nerve activation intensity more sensitively is likely to be advantageous.
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Imageamento por Ressonância Magnética , Córtex Somatossensorial , Córtex Somatossensorial/fisiologia , Imageamento por Ressonância Magnética/métodos , Dedos/inervação , Mapeamento Encefálico/métodosRESUMO
OBJECTIVE: We aimed to compare the image quality and focal lesion detection ability of hepatobiliary phase (HBP) images obtained using compressed sensing (CS) and controlled aliasing in parallel imaging results in higher acceleration (CAIPIRINHA) in patients with liver cirrhosis. MATERIALS AND METHODS: We retrospectively included 244 gadoxetic acid-enhanced liver MRI from 244 patients with cirrhosis obtained by two HBP images using CS and CAIPIRINHA from July 2020 to December 2020. The optimized resolution and scan time for CS-HBP and CAIPIRINHA-HBP were 0.9 × 0.9 × 1.5 mm3 and 15 s and 1.3 × 1.3 × 3 mm3 and 16 s, respectively. We compared the image quality between the two sets of images in 244 patients and focal lesion (n = 294) analyses for 112 patients. RESULTS: CS-HBP showed comparable overall image quality (3.7 ± 0.9 vs. 3.6 ± 0.8, p = 0.680), superior liver edge sharpness (3.9 ± 0.6 vs. 3.6 ± 0.5, p < 0.001), and fewer respiratory motion artifacts (4.0 ± 0.7 vs. 3.8 ± 0.5, p < 0.001), but higher non-respiratory artifacts (3.4 ± 0.7 vs. 3.6 ± 0.6, p < 0.001) and subjective image noise (3.5 ± 0.8 vs. 3.6 ± 0.7, p = 0.014) than CAIPIRINHA-HBP. CS-HBP showed a higher signal-to-noise ratio in the liver than CAIPIRINHA-HBP (20.9 ± 9.0 vs. 18.9 ± 7.1, p = 0.008). The pooled sensitivity, specificity, and AUC were 90.0%, 77.5%, and 0.84 for CS-HBP and 73.5%, 82.4%, and 0.78 for CAIPIRINHA-HBP, respectively. CONCLUSIONS: CS-HBP showed better focal lesion detection ability, comparable overall image quality, and fewer respiratory motion artifacts, but higher non-respiratory artifacts and noise compared to CAIPIRINHA-HBP. Thus, CS-HBP could be recommended for liver MRI in patients with cirrhosis to improve diagnostic performance. CLINICAL RELEVANCE STATEMENT: Thin-slice CS-HBP may be useful for detecting sub-centimeter hepatocellular carcinoma in cirrhotic patients with Child-Pugh classification A while maintaining comparable subjective image quality. KEY POINTS: ⢠Compared with controlled aliasing in parallel imaging results in higher acceleration, compressed sensing hepatobiliary phase yielded thinner slices and shorter scan time at a higher accelerating factor. ⢠Compressed sensing hepatobiliary phase showed comparable overall image quality, superior liver edge sharpness, and fewer respiratory motion artifacts, but higher non-respiratory artifacts and subjective image noise than controlled aliasing in parallel imaging results in higher acceleration-hepatobiliary phase. ⢠Compressed sensing hepatobiliary phase can detect sub-centimeter hepatocellular carcinoma in cirrhotic patients with Child-Pugh classification A.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Meios de Contraste , Estudos Retrospectivos , Imageamento Tridimensional/métodos , Gadolínio DTPA , Imageamento por Ressonância Magnética/métodos , Aceleração , Cirrose Hepática/complicações , Cirrose Hepática/diagnóstico por imagem , Neoplasias Hepáticas/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/patologia , Artefatos , Aumento da Imagem/métodosRESUMO
Although soybean (Glycine max) leaves generate building blocks to produce seeds, a comprehensive understanding of the metabolic changes in soybean leaves during the entire growth stages is limited. Here, we investigated the metabolite changes in soybean leaves from five cultivars among four vegetative (V) and eight reproductive (R) stages using metabolite profiling coupled with chemometrics. Principal component analysis (PCA) of all samples showed a clear separation by growth stage. The total amount of monosaccharides and organic acids for energy production were highly detected in the V stage samples, accumulating in concentrations 2.5 and 1.7 times higher than in the R stage samples, respectively. The results of partial least-squares-discriminant analysis (PLS-DA) revealed a clear separation from R1 to R5 by the first PLS, suggesting significant alterations in the metabolic networks up to R5. After flowering, the stage of seed formation, R5, was associated with lower levels of most amino acids and an accumulation of phytosterols. The negative correlation observed between amino acids and phytosterol levels suggests a sophisticated coordination between carbon and nitrogen metabolism in plant, ensuring and supporting optimal growth (r = -0.50085, P = 0.0001). In addition, R-stage samples had decreased monosaccharide levels, indicating redistribution to seeds and senescence-related metabolite changes. Thus, metabolite profiling coupled with chemometrics could be a useful tool for investigating alterations in metabolic networks during various plant growth and development stages. Furthermore, we observed variations in flavonoid contents among the different cultivars. The results could be a basis of further studies on the source-sink interactions in the plant system.
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BACKGROUND: Virtual reality (VR)-based physical exercise is an innovative and effective intervention strategy for healthcare in older adults. OBJECTIVE: This meta-analysis aimed to clarify the effects of VR-based balance exercise programs on various balancing abilities of older adults. In addition, the effect size of each variable was computed by total exercise time, sensor type, avatar presence, and feedback type to determine influencing factors that lead to the success of VR-based rehabilitation programs. METHODS: The databases searched were PubMed/Medline, CINAHL, NDSL, and Google Scholar. Inclusion criteria were: (1) independent older adults; (2) non-immersive VR exercise; (3) randomized controlled design; (4) both balance and gait data; and (5) written in English and Korean. The studies without information to compute effect sizes were excluded. Standardized mean difference was used to analyze the effect size (d). RESULTS: Twenty-five studies were finally included in this study. The main findings of this meta-analysis were as follows: (1) Non-immersive VR-based balance exercises are moderately and largely effective for improving overall balance function, (2) VR balance exercise was more effective for static balance than for gait, (3) VR exercise is more effective when avatars are presented and KP is provided as feedback. CONCLUSION: Total exercise time and mode of feedback are influencing factors that affect the effectiveness of VR-based balance exercises.
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The protein extract of Ulva australis hydrolyzed with Alcalase and Flavourzyme was found to have multi-functional properties, including total antioxidant capacity (TAC), collagenase inhibitory, and antibacterial activities. The #5 fraction (SP5) and #7 fraction (SP7) of U. australis hydrolysate from cation-exchange chromatography displayed significantly high TAC, collagenase inhibitory, and antibacterial effects against Propionibacterium acnes, and only the Q3 fraction from anion-exchange chromatography displayed high multi-functional activities. Eight of 42 peptides identified by MALDI-TOF/MS and Q-TOF/MS/MS were selected from the results for screening with molecular docking on target proteins and were then synthesized. Thr-Gly-Thr-Trp (TGTW) displayed ABTS [2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)] radical scavenging activity. The effect of TAC as Trolox equivalence was dependent on the concentration of TGTW. Asn-Arg-Asp-Tyr (NRDY) and Arg-Asp-Arg-Phe (RDRF) exhibited collagenase inhibitory activity, which increased according to the increase in concentration, and their IC50 values were 0.95 mM and 0.84 mM, respectively. Peptides RDRF and His-Ala-Val-Tyr (HAVY) displayed anti-P. Acnes effects, with IC50 values of 8.57 mM and 13.23 mM, respectively. These results suggest that the U. australis hydrolysate could be a resource for the application of effective nutraceuticals and cosmetics.
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BACKGROUND: Classically activated M1 macrophages, characterized by aberrant glycolysis and secretion of inflammatory cytokines, play pivotal roles in inflammatory diseases, including inflammatory bowel disease (IBD). Recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors were shown to suppress Na+/H+ exchanger 1 (NHE1) and Na+/Ca2+ exchanger 1 (NCX1) activity, regulating downstream intracellular Ca2+ concentrations in cardiomyocytes. However, whether SGLT2 inhibitors regulate M1 macrophage polarization by downregulating NHE1 and NCX1 remains unknown. METHODS: We analyzed cellular responses to SGLT2 inhibitors using mouse bone marrow-derived macrophages and peritoneal macrophages treated with lipopolysaccharide (LPS). To induce IBD, we used a dextran sulfate sodium salt-induced colitis mouse model. RESULTS: We observed that NHE1 and NCX1 were overexpressed in LPS-treated macrophages, leading to M1 macrophage polarization. Mechanistically, NHE1 and NCX1-mediated Ca2+ accumulation in the macrophage resulted in enhanced glycolysis by promoting PI3K/AKT/mTORC1 signaling. SGLT2 inhibitors suppressed both the expression levels and activities of NHE1 and NCX1, and consequently downregulated PI3K/AKT/mTORC1 signaling and glycolysis in LPS-treated macrophages. We observed inhibition of LPS-stimulated M1 polarization and cytokine production by SGLT2 inhibitors in vitro, ex vivo, and in an IBD mouse model. CONCLUSIONS: NHE1 promotes M1 macrophage polarization and SGLT2 inhibitors are a novel strategy to treat M1 macrophage-mediated inflammatory diseases, including IBD.
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Doenças Inflamatórias Intestinais , Inibidores do Transportador 2 de Sódio-Glicose , Animais , Camundongos , Lipopolissacarídeos/farmacologia , Lipopolissacarídeos/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/metabolismo , Macrófagos/metabolismo , Modelos Animais de Doenças , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismoRESUMO
BACKGROUND: Unlike gestational diabetic mellitus (GDM), which is strictly managed by most patients and physicians, obesity does not have proper management guidelines, and the importance of its management during pregnancy is often ignored. The aim of this study was to compare maternal and neonatal outcomes according to obesity and GDM, alone or in combination. METHODS: This was a retrospective cohort study of 3,078 consecutive pregnant women who experienced prenatal care and delivery of a live singleton neonate between January 2016 and December 2020 at our institution. Study participants were categorized into 4 mutually exclusive groups, as follows: group 1, no GDM without obesity; group 2, GDM without obesity; group 3, no GDM with obesity; and group 4, GDM with obesity. RESULTS: Compared to group 2, group 3 had higher rates of pre-eclampsia, cesarean section including emergent cesarean section rate. Also, neonates in group 3 were heavier and had lower glucose levels compared to those in group 2. Of note, there was no significant difference in maternal or neonatal outcomes except the rate of large-for-gestational-age (LGA) between group 1 and group 2. Among the GDM groups, group 4 had higher risks for pre-eclampsia, cesarean section, and LGA infant status than group 2. CONCLUSION: Our data showed that obese women without GDM face higher risk of adverse pregnancy outcomes than women with supervised GDM and non-obese women. We also confirmed that adverse pregnancy outcomes associated with GDM were mainly attributable to obesity among women receiving GDM education.
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Diabetes Gestacional , Pré-Eclâmpsia , Gravidez , Lactente , Recém-Nascido , Feminino , Humanos , Diabetes Gestacional/epidemiologia , Cesárea , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Estudos Retrospectivos , Obesidade/complicaçõesRESUMO
Background: The sepsis screening tool is essential because it enables the rapid identification of high-risk patients and facilitates prompt treatment. Quick Sequential Organ Failure Assessment (qSOFA) is a widely used screening tool for sepsis. However, it has limitations in predicting patient prognosis. We developed the S-S.M.A.R.T (sepsis evaluation with shock index, mental status, age, and ROX index on triage) and aimed at evaluating it as a screening tool for patients with suspected sepsis in the emergency department. Methods: We conducted a single-center retrospective chart review of patients with suspected sepsis in the emergency department. We compared the prognosis prediction abilities of the S-S.M.A.R.T and qSOFA scores in patients with suspected sepsis. The primary outcome was 7-day mortality, and the secondary outcomes included 30-day mortality and ICU admission. The receiver operating characteristic (ROC) curve analysis and the chi-square test were used. Results: In total, 401 patients were enrolled. The mean age of the patients was 72.2 ± 15.6 years, and 213 (53.1%) of them were female. The S-S.M.A.R.T had superior predictive ability for prognosis of patients with suspected sepsis compared to qSOFA (area under the ROC curve (AUC) of 0.789 vs. 0.699; p=0.02 for 7-day mortality, AUC of 0.786 vs. 0.681; p < 0.001 for 30-day mortality, AUC 0.758 vs 0.717; p=0.05 for ICU admission). Conclusion: The S-S.M.A.R.T can be useful in predicting the prognosis of patients with suspected sepsis in the emergency department.