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Rheumatoid arthritis has a significant impact on the life quality, but current pharmacological therapies have limitations. As a result, there is growing interest in exploring the potential of natural plant components to intervene in the development of rheumatoid arthritis. Resveratrol, a natural polyphenol and one of the main active components of the Chinese herbal medicine Polygonum cuspidatum, has emerged as a promising candidate for this purpose. In the present study, we investigated the role and mechanism of resveratrol in inhibiting inflammatory response in rat primary fibroblast-like synoviocytes. Tumor necrosis factor (TNF)-α was used to establish a model of inflammation, the Sirtuin1 selective inhibitor Selisistat (EX527) was used to inhibit Sirtuin1 activity, and small interfering RNA was used to silence cortistatin expression. The results showed that pre-treatment with resveratrol could time- and dose-dependently inhibit TNF-α induced cellular interleukin (IL)-1ß and IL-6 secretion, and upregulate Sirtuin1 and cortistatin mRNA and protein expression in the range of 48 h, 100 µM. Selisistat (EX527) could attenuate resveratrol inhibited inflammatory response and upregulated cortistatin expression. Silencing cortistatin expression attenuated the effect of resveratrol on inhibiting inflammatory response, but did not affect its effect on upregulating Sirtuin1 expression. In conclusion, resveratrol effectively inhibited the TNF-α induced inflammatory response in fibroblast-like synoviocytes by a mechanism involving the Sirtuin1/cortistatin pathway.
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Artrite Reumatoide , Sinoviócitos , Animais , Ratos , Artrite Reumatoide/patologia , Células Cultivadas , Fibroblastos , NF-kappa B/metabolismo , Resveratrol/farmacologia , Sirtuína 1/genética , Sirtuína 1/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
We previously reported that interleukin-1ß (IL-1ß) in the red nucleus (RN) is involved in pain modulation and exerts a facilitatory effect in the development of neuropathic pain. Here, we explored the actions of signaling pathways, including the Janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (p38 MAPK) and nuclear factor-κB (NF-κB) pathways, on RN IL-1ß-mediated pain modulation. After a single dose of recombinant rat IL-1ß (rrIL-1ß, 10 ng) injected into the RN in normal rats, a tactile allodynia was evoked in the contralateral but not ipsilateral hindpaw, commencing 75 min and peaking 120 min postinjection. Up-regulated protein levels of phospho-STAT3 (p-STAT3) and p-JNK were observed in the RN 120 min after rrIL-1ß injection, the increases of p-STAT3 and p-JNK were blocked by anti-IL-1ß antibody. However, the expression levels of p-ERK, p-p38 MAPK, and NF-κB in the RN were not affected by rrIL-1ß injection. RN neurons and astrocytes contributed to IL-1ß-evoked up-regulation of p-STAT3 and p-JNK. Further studies demonstrated that injection of the JAK2 antagonist AG490 or JNK antagonist SP600125 into the RN 30 min prior to the administration of rrIL-1ß could completely prevent IL-1ß-evoked tactile allodynia, while injection of the ERK antagonist PD98059, p38 MAPK antagonist SB203580, or NF-κB antagonist PDTC did not affect IL-1ß-evoked tactile allodynia. In conclusion, our data provide additional evidence that RN IL-1ß is involved in pain modulation, and that it exerts a facilitatory effect by activating the JAK/STAT3 and JNK signaling pathways.
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Hiperalgesia/induzido quimicamente , Interleucina-1beta/farmacologia , Janus Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/metabolismo , Núcleo Rubro/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Escala de Avaliação Comportamental , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Hiperalgesia/metabolismo , Interleucina-1beta/antagonistas & inibidores , Janus Quinase 2/antagonistas & inibidores , MAP Quinase Quinase 4/antagonistas & inibidores , MAP Quinase Quinase 4/metabolismo , Masculino , Microglia/efeitos dos fármacos , Microglia/metabolismo , NF-kappa B/antagonistas & inibidores , NF-kappa B/metabolismo , Neuralgia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Recombinantes/farmacologia , Núcleo Rubro/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Quinase Induzida por NF-kappaBRESUMO
BACKGROUND: Lung cancer is the major cause of cancer-related death worldwide, and 80% patients of lung cancer are non-small-cell lung cancer (NSCLC) cases. MicroRNAs are important gene regulators with critical roles in diverse biological processes, including tumorigenesis. Studies indicate that sphingosine kinase 2 (SphK2) promotes tumor progression in NSCLC, but how this occurs is unclear. Thus, we explored the effect of miR-338-3p targeting SphK2 on proliferation and apoptosis of NSCLC cells. METHODS: Expression of miR-338-3p and SphK2 in NSCLC A549 and H1299 cell lines was measured using qRT-PCR and Western blot. CCK-8 and colony formation assays were used to assess the effect of miR-338-3p on NSCLC cell line proliferation. Flow cytometry was used to study the effect of miR-338-3p on NSCLC apoptosis. Luciferase reporter assay and Western blot were used to confirm targeting of SphK2 by miR-338-3p. Finally, in vivo tumorigenesis studies were used to demonstrate subcutaneous tumor growth. RESULTS: miR-338-3p expression in 34 NSCLC clinical samples was downregulated and this was correlated with TNM stage. miR-338-3p significantly suppressed proliferation and induced apoptosis of NSCLC A549 and H1299 cells in vitro. SphK2 was a direct target of miR-338-3p. Overexpression of miR-338-3p significantly inhibited SphK2 expression and reduced luciferase reporter activity containing the SphK2 3'-untranslated region (3'-UTR) through the first binding site. SphK2 lacking 3'-UTR restored the effects of miR-338-3p on cell proliferation inhibition. miR-338-3p significantly inhibited tumorigenicity of NSCLC A549 and H1299 cells in a nude mouse xenograft model. CONCLUSIONS: Collectively, miR-338-3p inhibited cell proliferation and induced apoptosis of NSCLC cells by targeting and down-regulating SphK2, and miR-338-3p could inhibit NSCLC cells A549 and H1299 growth in vivo, suggesting a potential mechanism of NSCLC progression. Therapeutically, miR-338-3p may serve as a potential target in the treatment of human lung cancer.
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Previous studies have demonstrated that the red nucleus (RN) is involved in the regulation of neuropathic pain and plays both facilitated and inhibitory roles through different cytokines. Here, we aim to investigate the expression changes and roles of interleukin-6 (IL-6), a pleiotropic cytokine, as well as its receptor (IL-6R) in the RN of rats with neuropathic pain induced by spared nerve injury (SNI). Immunohistochemistry indicated that IL-6 and IL-6R were weakly expressed in the RN of normal rats, and were mainly co-localized with neurons and oligodendrocytes. Following SNI, the expression levels of IL-6 and IL-6R in the RN did not show obvious changes at 1 week and 2 weeks postinjury. However, both of them were significantly increased in the RN contralateral (but not ipsilateral) to the nerve ligation side at 3 weeks postinjury, and co-localized not only with neurons and oligodendrocytes, but also with numerous astrocytes. Injection of different doses of anti-IL-6 antibody (100, 250, 500 ng) into the RN contralateral to the nerve ligation side at 3 weeks postinjury dose-dependently increased the paw withdrawal threshold (PWT) of rats and alleviated SNI-induced mechanical allodynia. Conversely, injection of different doses of recombinant rat IL-6 (5.0, 10, 20 ng) into the unilateral RN of normal rats dose-dependently decreased the PWT of contralateral (but not ipsilateral) hind paw and evoked significant mechanical allodynia, which was similar to SNI-induced neuropathic allodynia. These results further support the conclusion that the RN is involved in the modulation of neuropathic pain, and suggest that IL-6 and IL-6R in the RN play a facilitated role in the later maintenance of SNI-induced neuropathic pain.
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Interleucina-6/farmacologia , Tecido Nervoso/lesões , Neuralgia/tratamento farmacológico , Neurônios/efeitos dos fármacos , Núcleo Rubro/efeitos dos fármacos , Animais , Hiperalgesia/metabolismo , Interleucina-6/administração & dosagem , Interleucina-6/metabolismo , Masculino , Fatores de Crescimento Neural/metabolismo , Neuralgia/metabolismo , Neurônios/metabolismo , Ratos Sprague-Dawley , Núcleo Rubro/metabolismoRESUMO
BACKGROUND: Streptococcus mutans forms biofilms as a resistance mechanism against antimicrobial agents in the human oral cavity. We recently showed that human cathelicidin LL-37 exhibits inhibitory effects on biofilm formation of S. mutans through interaction with lipoteichoic acid (LTA), but without antibacterial or biofilm dispersal abilities. (-)-Epigallocatechin gallate (EGCG) is the most abundant constituent of tea catechins that has the greatest anti-infective potential to inhibit the growth of various microorganisms and biofilm formation. Therefore, in this study, we evaluated whether LL-37 interacts with EGCG to enhance the antibiofilm effect of EGCG on S. mutans biofilm formation. METHODS: Clinical S. mutans strains (n = 10) isolated from children's saliva were tested in a biofilm formation assay. The antibiofilm effect of EGCG with and without LL-37 was analyzed by the minimum biofilm eradication concentration assay and confirmed using field emission-scanning electron microscopy. In addition, the interaction among EGCG, LL-37, and LTA of S. mutans was determined using quartz crystal microbalance analysis. RESULTS: EGCG killed 100 % of planktonic S. mutans within 5 h, inhibited biofilm formation within 24 h, and reduced bacteria cells in preformed biofilms within 3 h at a concentration of 0.2 mg/mL. However, EGCG did not appear to interact with LTA. LL-37 effectively enhanced the bactericidal activity of EGCG against biofilm formation and preformed biofilms as determined by quantitative crystal violet staining and field emission-scanning electron microscopy. In addition, quartz crystal microbalance analysis revealed that LL-37 interacted with EGCG and promoted binding between EGCG and LTA of S. mutans. CONCLUSIONS: We show that LL-37 enhances the antibiofilm effect of EGCG on S. mutans. This finding provides new knowledge for dental treatment by using LL-37 as a potential antibiofilm compound.
Assuntos
Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , Biofilmes/efeitos dos fármacos , Streptococcus mutans , Catequina/análogos & derivados , Catequina/farmacologia , Humanos , Testes de Sensibilidade Microbiana , CatelicidinasRESUMO
Leptospiral lipopolysaccharide (L-LPS) has shown potency in activating toll-like receptor 2 (TLR2) in pig fibroblasts (PEFs_NCC1), and causes the expression of proinflammatory cytokines. However, the stimulation by L-LPS was weak eliciting the function of TLR2 sufficiently in pig innate immunity responses during Leptospira infection. In this study, the immune response of pig embryonic fibroblast cell line (PEFs_SV40) was investigated and was found to be the high immune response, thus TLR2 is the predominate receptor of L-LPS in pig cells. Further, we found a strategy using the antibody against L-LPS, to prevent L-LPS interaction with TLR2 in pig cells which could impact on immune activation.
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This study aimed to explore the association between the dietary antioxidant quality scores (DAQS) and all-cause mortality in hypertensive adults. In this retrospective cohort study, participants aged ≥ 18 years with hypertension were extracted from the National Health and Nutrition Examination Survey (NAHNES) 2007-2018. Outcome was all-cause mortality of hypertensive participants. DAQS was the exposure variable calculated based on the intake of vitamin A, C, E, zinc, selenium, and magnesium. The weighted univariable and multivariable COX proportional hazards regression models were utilized to explore the association between the DAQS and the all-cause mortality in hypertensive patients and were described as hazard ratios (HRs) and 95% confidence intervals (CIs). Subgroup analyses based on different age, gender, diabetes, and cardiovascular disease (CVD) history were further assessed this association. A total of 16,240 participants were finally included in this study. Until 12 December 2019, 2710 (16.69%) all-cause deaths were documented. After adjustment for confounding variables, high DAQS was associated with the lower all-cause mortality (HR = 0.83, 95%CI: 0.72-0.96) in hypertensive patients. Subgroup analyses suggested that the association between DAQS and the all-cause mortality in hypertensive patients remain robust, especially in patients with female (HR = 0.77, 95%CI: 0.63-0.95), aged ≥ 60 years (HR = 0.81, 95%CI: 0.69-0.96). High DAQS was associated with the lower odds of all-cause mortality in adults with hypertension and are a promising intervention to be further explored in hypertensive patients.
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Here, we present a protocol for the quantitative assessment of rat and mouse cardiomyocyte proliferation both in vitro and in vivo. For the in vivo approach, we describe steps for the isolation of neonatal rat cardiomyocytes and the employment of various indicators to quantify cell proliferation. We then detail in vivo procedures that incorporate comprehensive assays and a genetic lineage tracing strategy to evaluate endogenous cardiomyocyte proliferation. This protocol can be modified to investigate other mammalian cardiomyocyte proliferation. For complete details on the use and execution of this protocol, please refer to Ji et al.1.
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Sphingosine-1-phosphate (S1P) is biologically active lipid, leading to neuroinflammation and macrophage invasion in central nervous system, plays an important role in the development of multiple sclerosis (MS) model in experimental allergic encephalomyelitis (EAE) rats. Vitamin D is observed to be a key factor in regulating cell S1P levels. We detected vitamin D can alleviate the symptoms of EAE rats, but the exact mechanism is unclear. In PC12 cells, vitamin D can reverse S1P-induced cell death, but the signaling pathway unclear. This study was aimed to investigate S1P regulation mechanism or signaling pathway mediated by vitamin D in EAE and PC12 model. In our experiments, S1P and Sphingosine kinase type 1 (SphK1) mRNA and protein expression in EAE rats group, control group, vitamin D feeding group were detected by HPLC, ELISA, RT-PCR and western blot. PC12 cell death was detected by Propidium (PI) staining. VDR plasmid overexpression and RNA interference, immunofluorescence, real-time cell analysis, protein immunoblotting was used to detect SphK1 transcriptional regulation, cell-substrate attachment quality, the signaling pathway of cell apoptosis and inflammation related gene expression (Bax/Bcl-2, Casepase-3, Il-6, TGF-ß, TNF-α). Our study showed vitamin D can reverse the elevation of S1P level in EAE rats, reduce the severity and shorten the course of EAE. 1,25-(OH) 2D3 coupled with vitamin D receptor (VDR) inhibited SphK1 transcription. 1,25-(OH)2D3 significantly reduced PC12 cell death rate induced by S1P, in addition improved the cell substrate attachment quality. 1,25-(OH) 2D3 can block S1P-induced p-ERK activation and PI3K /Akt signaling pathway reduced Il-6, TGF-ß, TNF-α cytokine release and Bax/Bcl-2, Casepase-3 apoptosis protein expression. On the other hand, immunofluorescence staining showed 1,25-(OH) 2D3 can increase the expression of neuronal perinuclear protein MAP2 in PC12 cells probably protect nerve cells further. In summary, the ameliorative effect of vitamin D was derived from its ability to reduce S1P levels, provides an idea for vitamin D as a combination therapy for disease.
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Encefalomielite Autoimune Experimental , Esclerose Múltipla , Fosfotransferases (Aceptor do Grupo Álcool) , Ratos , Animais , Vitamina D/farmacologia , Fator de Necrose Tumoral alfa/genética , Interleucina-6 , Proteína X Associada a bcl-2 , Vitaminas , Lisofosfolipídeos/metabolismo , Esfingosina/metabolismo , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fator de Crescimento Transformador betaRESUMO
The ectopic gut colonization by orally derived pathobionts has been implicated in the pathogenesis of various gastrointestinal diseases, including inflammatory bowel disease (IBD). For example, gut colonization by orally derived Klebsiella spp. has been linked to IBD in mice and humans. However, the mechanisms whereby oral pathobionts colonize extra-oral niches, such as the gut mucosa, remain largely unknown. Here, we performed a high-density transposon (Tn) screening to identify genes required for the adaptation of an oral Klebsiella strain to different mucosal sites - the oral and gut mucosae - at the steady state and during inflammation. We find that K. aerogenes, an oral pathobiont associated with both oral and gut inflammation in mice, harbors a newly identified genomic locus named "locus of colonization in the inflamed gut (LIG)" that encodes genes related to iron acquisition (Sit and Chu) and host adhesion (chaperon usher pili [CUP] system). The LIG locus is highly conserved among K. aerogenes strains, and these genes are also present in several other Klebsiella species. The Tn screening revealed that the LIG locus is required for the adaptation of K. aerogenes in its ectopic niche. In particular, we determined K. aerogenes employs a CUP system (CUP1) present in the LIG locus for colonization in the inflamed gut, but not in the oral mucosa. Thus, oral pathobionts likely exploit distinct adaptation mechanisms in their ectopically colonized intestinal niche compared to their native niche.
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Microbioma Gastrointestinal , Doenças Inflamatórias Intestinais , Humanos , Animais , Camundongos , Klebsiella/genética , Doenças Inflamatórias Intestinais/patologia , Inflamação , Mucosa BucalRESUMO
Utilization of lipids as energy substrates after birth causes cardiomyocyte (CM) cell-cycle arrest and loss of regenerative capacity in mammalian hearts. Beyond energy provision, proper management of lipid composition is crucial for cellular and organismal health, but its role in heart regeneration remains unclear. Here, we demonstrate widespread sphingolipid metabolism remodeling in neonatal hearts after injury and find that SphK1 and SphK2, isoenzymes producing the same sphingolipid metabolite sphingosine-1-phosphate (S1P), differently regulate cardiac regeneration. SphK2 is downregulated during heart development and determines CM proliferation via nuclear S1P-dependent modulation of histone acetylation. Reactivation of SphK2 induces adult CM cell-cycle re-entry and cytokinesis, thereby enhancing regeneration. Conversely, SphK1 is upregulated during development and promotes fibrosis through an S1P autocrine mechanism in cardiac fibroblasts. By fine-tuning the activity of each SphK isoform, we develop a therapy that simultaneously promotes myocardial repair and restricts fibrotic scarring to regenerate the infarcted adult hearts.
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Coração , Lisofosfolipídeos , Esfingolipídeos , Esfingosina/análogos & derivados , Animais , Esfingolipídeos/metabolismo , Isoenzimas , Mamíferos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismoRESUMO
Induced pluripotent stem (iPS) cells have proven to be an effective technology in regenerative medicine; however, the low efficiency of reprogramming is a major obstacle to the successful generation of iPS cell lines. One of the most important characteristics of a high-quality iPS cell line is the inactivation of transgenes driven by a retrovirus-derived long terminal repeat promoter. In this study, we established a novel marker system containing three kinds of proteins: secreted-type luciferase (MetLuc), copepod Pontellina plumata green fluorescent protein (copGFP), and an antibiotic-resistant gene product (Neo(r)). The introduction of MetLuc-copGFP-Neo(r) in mouse embryonic fibroblasts (MEFs) allowed us to monitor the reporter expression changes as an indicator of the state of silencing during reprogramming. Transformation of iPS cells induced a remarkable reduction in reporter activity, indicating that the retroviral silencing was detected successfully. Our system enables us to monitor the silencing status of transgenes and to efficiently select iPS cell lines that can be used for further applications.
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Inativação Gênica , Genes Reporter , Engenharia Genética/métodos , Células-Tronco Pluripotentes Induzidas/metabolismo , Lentivirus/genética , Animais , Diferenciação Celular , Reprogramação Celular/genética , Embrião de Mamíferos , Fibroblastos/citologia , Fibroblastos/metabolismo , Vetores Genéticos , Proteínas de Fluorescência Verde/antagonistas & inibidores , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Células HEK293 , Humanos , Células-Tronco Pluripotentes Induzidas/citologia , Luciferases/antagonistas & inibidores , Luciferases/genética , Luciferases/metabolismo , Camundongos , TransgenesRESUMO
Leptospires are a group of bacteria with a unique ultrastructure and a fascinating swimming behavior that cause a number of emerging and re-emerging diseases worldwide called leptospirosis. The unusual form of motility is thought to play a critical role in the infection process. However, the inhibition mechanism of antiserum on the motility of Leptospira to attenuate the infection efficiency is unknown. In this study, effect of antiserum on motility was quantitatively investigated by swimming speed. Relatively low concentration of antiserum was found to inhibit leptospiral motility, suggesting that the basic immunization can affect the infection efficiency. Recovery of motility a few hours later after the addition of antiserum was observed. This raises a hypothesis that Leptospira carries surface molecules bound with antibodies toward the cell end to escape and recovers the motility.
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Anticorpos Antibacterianos/imunologia , Leptospira/imunologia , Leptospira/fisiologia , Locomoção/efeitos dos fármacos , Fatores de TempoRESUMO
An experimental investigation was conducted to elucidate the auditory characteristics of the older adult population. The study involved 24 older adult and 24 young participants, with the aim of exploring their horizontal lateralization ability. This was achieved by presenting 1-kHz pure tones to the participants' right and left ears while introducing interaural time differences (ITDs). We examined the impact of four rise times (2, 5, 20, and 50 ms) on the onset of the test sound. The findings revealed that older adult participants exhibited lower levels of lateralization than young participants. Moreover, both older adult and young participants demonstrated diminished recognition of the onset portion as the rise time increased. Of particular significance was the conspicuous presence of a right ear advantage (REA) among young participants as the rise time was extended (statistically significant between the left and right ears at the 1% level, considering an ITD of 0.8 ms and a rise time of 50 ms). In contrast, older adult participants did not exhibit REA, even with a prolonged rise time (not significant at the 5% level at the same condition). These results indicate that the REA is not only present in language, as previously observed, but also extends to a pure tone in young participants. The older adult participants exhibited reduced performance in both left-and right-ear sound recognition. The influence of hearing threshold and preferred ear on sound lateralization performance was minimal. Therefore, it can be inferred that factors other than hearing threshold or preferred ear contribute to the presence of REA in young participants or its decline with age. The central and/or corpus callosum functions may also contribute to this phenomenon.
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Upon myocardial infarction (MI), activated cardiac fibroblasts (CFs) begin to remodel the myocardium, leading to cardiac fibrosis and even heart failure. No therapeutic approaches are currently available to prevent the development of MI-induced pathological fibrosis. Most pharmacological trials fail from poor local drug activity and side effects caused by systemic toxicity, largely due to the lack of a heart-targeted drug delivery system that is selective for activated CFs. Here, we developed a reduced glutathione (GSH)-responsive nanoparticle platform capable of targeted delivering of drugs to activated CFs within the infarct area of a post-MI heart. Compared with systemic drug administration, CF-targeted delivery of PF543, a sphingosine kinase 1 inhibitor identified in a high-throughput antifibrotic drug screening, had higher therapeutic efficacy and lower systemic toxicity in a MI mouse model. Our results provide a CF-targeted strategy to deliver therapeutic agents for pharmacological intervention of cardiac fibrosis.
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Cisteína , Infarto do Miocárdio , Camundongos , Animais , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miocárdio/patologia , Fibrose , Fibroblastos , Modelos Animais de DoençasRESUMO
OBJECTIVE: The aim of this study was to investigate whether the neuropeptide calcitonin gene related peptide (CGRP) contributes to nitroglycerin (GTN) response in patients with chronic heart failure (CHF) and the association with the mitochondrial aldehyde dehydrogenase-2 (ALDH2) Glu504Lys (ALDH2*2) polymorphism. METHODS: This is a 2-period, placebo-controlled clinical study. An intravenous infusion of saline followed by GTN (20 µg/min), each for 2 hours, respectively, was given to 49 stable CHF patients. Blood pressure (BP), heart rate (HR) and respiratory rate (RR) were measured at baseline, at 10 min, 30 min, 1.0 h, 1.5 h, and 2.0 h after initiation of saline infusion and initiation of GTN therapy. Blood samples were drawn for the determination of plasma CGRP for 49 patients at baseline, and at 2.0 h after initiation of saline and GTN infusion, respectively. Global clinical status of the patients was evaluated. Left ventricular ejection (LVEF), left ventricular end-diastolic volume (LVEDV), stroke volume (SV) and cardiac output (CO) were measured with 2D echocardiography with Simpson's biplane method (Pillip HP sonos 5500) by the same investigator at baseline and at 2.0 h after initiation of saline and GTN infusion. RESULTS: Systolic blood pressure (SBP), diastolic blood pressure (DBP), and left ventricular end-diastolic volume (LVEDV) were decreased, while left ventricular ejection fraction (LVEF) was increased at the end of GTN infusion (p < 0.001, respectively). Saline infusion showed no hemodynamic effects. At the end of GTN infusion, ALDH2*1/*1 homozygous patients showed higher degrees of both the absolute decrease in SBP (DSBP) (p < 0.001) and increase in LVEF (p < 0.001) than carriers of the ALDH2*2 allele. Mean plasma concentration of CGRP was increased after GTN infusion (p < 0.001), but not changed after saline infusion (p > 0.05). Changes in plasma concentration of CGRP correlated positively with the improvement in LVEF (r = 0.400, p = 0.004), while correlated negatively with changes in SBP (r = -0.300, p = 0.036) and LVEDV (r = -0.290, p = 0.043). CONCLUSIONS: ALDH2*2 polymorphism is associated with contributions of CGRP to GTN response in CHF patients.
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Aldeído Desidrogenase/genética , Peptídeo Relacionado com Gene de Calcitonina/fisiologia , Insuficiência Cardíaca/tratamento farmacológico , Nitroglicerina/uso terapêutico , Polimorfismo Genético , Vasodilatadores/uso terapêutico , Adulto , Idoso , Aldeído-Desidrogenase Mitocondrial , Peptídeo Relacionado com Gene de Calcitonina/sangue , Doença Crônica , Feminino , Genótipo , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Migraine is a neurovascular disease with a high disability rate. Acupuncture treatment has emerged as a safe and viable alternative prophylactic therapy that can effectively alleviate the duration and frequency of migraine attacks. However, the therapeutic mechanisms underlying the effects of acupuncture are yet to be systematically elucidated. In this study, we enrolled female patients with migraine without aura (n = 20) and healthy controls (n = 10). Patients received acupuncture treatment on DU20, DU24, bilateral GB13, GB8, and GB20, applied three times per week over the course of 4 weeks for 12 sessions in total. Blood samples were collected from the median cubital vein before and after acupuncture treatment. Proteomic and metabolomic profiling was performed using liquid chromatography-mass spectrometry to determine the characteristics of differentially expressed molecules and expression of their corresponding biological pathways as well as to elucidate the pathogenesis of migraine and the biological effects underlying the treatment of migraine with acupuncture. Proteomic and metabolomic profiling of plasma samples from patients with migraine without aura before and after acupuncture treatment revealed enrichment of immune-related pathway functions and the arginine synthesis pathway. Joint pathway analyses revealed significant enrichment of the pentose phosphate and glycolysis/gluconeogenesis pathways in patients with migraine. The glycolysis/gluconeogenesis and riboflavin metabolism pathways were significantly enriched after acupuncture treatment. The expression levels of various key proteins and metabolites, including α-D-glucose, flavin adenine dinucleotide, biliverdin reductase B, and L-glutamate, were significantly differentially expressed before and after acupuncture treatment in patients with migraine without aura. Treatment of migraine with acupuncture was associated with significant changes in key molecules and pathways, indicative of physiological changes in the trigeminovascular system, glutamate neurotoxicity, and other migraine-related physiological changes. Overall, our comprehensive analysis using proteomic and metabolomic profiling demonstrates that energy metabolism may serve as a key correlative link in the occurrence of migraine and the therapeutic effects of acupuncture treatment. Our findings may facilitate the identification of diagnostic and therapeutic modalities in the ongoing search for effective treatments for migraine attacks.
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Importance: Anemia is the most widespread nutritional deficiency among pregnant females in the world. Despite numerous studies on anemia, evidence is limited about the association of severity of anemia with maternal and fetal health. Objective: To investigate the association between severity of anemia during pregnancy and risk of maternal and fetal adverse outcomes. Design, Setting, and Participants: This retrospective cohort study used data from China's Hospital Quality Monitoring System from January 1, 2016, to December 31, 2019, for pregnant females aged 15 to 49 years with birth outcomes reported at 1508 hospitals with maternity services in mainland China. Exposures: Anemia of varying severity during pregnancy was identified from daily standardized electronic inpatient discharge records using corresponding codes of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Mild anemia was defined as a hemoglobin concentration of 100 to 109 g/L (to convert g/L to g/dL, divide by 10.0); moderate anemia, as 70 to 99 g/L; and severe anemia, as less than 70 g/L. Main Outcomes and Measures: The main outcomes included 6 maternal outcomes (placental abruption, preterm birth, severe postpartum hemorrhage, shock, admission to the intensive care unit [ICU], and maternal mortality) and 3 neonatal outcomes (fetal growth restriction, malformation, and stillbirth). Multivariable logistic regression models were used to estimate the odds ratios (ORs) and 95% CIs of these outcomes among pregnant females with varying severity of anemia. Results: Among 18â¯948â¯443 pregnant females aged 15 to 49 years (mean [SD] age, 29.42 [4.87] years), 17.78% were diagnosed with anemia during pregnancy, including 9.04% with mild anemia, 2.62% with moderate anemia, 0.21% with severe anemia, and 5.90% with anemia of unknown severity. Compared with no anemia, anemia severity during pregnancy was associated with increased risks of placental abruption (mild: adjusted OR [aOR], 1.36 [95% CI, 1.34-1.38]; moderate: aOR, 1.98 [95% CI, 1.93-2.02]; severe: aOR, 3.35 [95% CI, 3.17-3.54]), preterm birth (mild: aOR, 1.08 [95% CI, 1.07-1.08]; moderate: aOR, 1.18 [95% CI, 1.17-1.19]; severe: aOR, 1.36 [95% CI, 1.32-1.41]), severe postpartum hemorrhage (mild: aOR, 1.45 [95% CI, 1.43-1.47]; moderate: aOR, 3.53 [95% CI, 3.47-3.60]; severe: 15.65 [95% CI, 15.10-16.22]), and fetal malformation (mild: aOR, 1.15 [95% CI, 1.14-1.17]; moderate: aOR, 1.19 [95% CI, 1.16-1.21]; severe: aOR, 1.62 [95% CI, 1.52-1.73]). Compared with no anemia, moderate or severe anemia were associated with increased risks of maternal shock (moderate: aOR, 1.50 [95% CI, 1.41-1.60]; severe: aOR, 14.98 [95% CI, 13.91-16.13]), ICU admission (moderate: aOR, 1.08 [95% CI, 1.01-1.16]; severe: aOR, 2.88 [95% CI, 2.55-3.25]), maternal death (moderate: aOR, 0.45 [95% CI, 0.30-0.65]; severe: aOR, 1.56 [95% CI, 0.97-2.48], fetal growth restriction (moderate: aOR, 0.80 [95% CI, 0.78-0.82]; severe: aOR, 1.08 [95% CI, 1.00-1.17]), and stillbirth (moderate: aOR,0.79 [95% CI, 0.76-0.81]; severe: aOR, 1.86 [95% CI, 1.75-1.98]), and mild anemia was associated with decreased risks (maternal shock: aOR, 0.67 [95% CI, 0.63-0.71]; ICU admission: aOR, 0.80 [95% CI, 0.76-0.84]; maternal death: aOR, 0.37 [95% CI, 0.29-0.49]; fetal growth restriction: aOR, 0.79 [95% CI, 0.77-0.80]; stillbirth: aOR, 0.59 [95% CI, 0.58-0.61]) after adjusting for sociodemographic characteristics and other complications during pregnancy. Conclusions and Relevance: The findings suggest that anemia during pregnancy is associated with maternal and fetal health outcomes and that mild anemia is associated with improved maternal and fetal survival and fetal growth. Further work is needed to validate the concentration of hemoglobin at which optimal maternal and fetal health are achieved.
Assuntos
Anemia/patologia , Complicações Hematológicas na Gravidez/patologia , Resultado da Gravidez , Adolescente , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Gravidez , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de DoençaRESUMO
New approaches for the management of glioblastoma (GBM) are an urgent and unmet clinical need. Here, we illustrate that the efficacy of radiotherapy for GBM is strikingly potentiated by concomitant therapy with the arginine-depleting agent ADI-PEG20 in a non-arginine-auxotrophic cellular background (argininosuccinate synthetase 1 positive). Moreover, this combination led to durable and complete radiological and pathological response, with extended disease-free survival in an orthotopic immune-competent model of GBM, with no significant toxicity. ADI-PEG20 not only enhanced the cellular sensitivity of argininosuccinate synthetase 1-positive GBM to ionizing radiation by elevated production of nitric oxide (ËNO) and hence generation of cytotoxic peroxynitrites, but also promoted glioma-associated macrophage/microglial infiltration into tumors and turned their classical antiinflammatory (protumor) phenotype into a proinflammatory (antitumor) phenotype. Our results provide an effective, well-tolerated, and simple strategy to improve GBM treatment that merits consideration for early evaluation in clinical trials.