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Great progress has been made in identifying positive regulators that activate adipocyte thermogenesis, but negative regulatory signaling of thermogenesis remains poorly understood. Here, we found that cardiotrophin-like cytokine factor 1 (CLCF1) signaling led to loss of brown fat identity, which impaired thermogenic capacity. CLCF1 levels decreased during thermogenic stimulation but were considerably increased in obesity. Adipocyte-specific CLCF1 transgenic (CLCF1-ATG) mice showed impaired energy expenditure and severe cold intolerance. Elevated CLCF1 triggered whitening of brown adipose tissue by suppressing mitochondrial biogenesis. Mechanistically, CLCF1 bound and activated ciliary neurotrophic factor receptor (CNTFR) and augmented signal transducer and activator of transcription 3 (STAT3) signaling. STAT3 transcriptionally inhibited both peroxisome proliferator-activated receptor-γ coactivator (PGC) 1α and 1ß, which thereafter restrained mitochondrial biogenesis in adipocytes. Inhibition of CNTFR or STAT3 could diminish the inhibitory effects of CLCF1 on mitochondrial biogenesis and thermogenesis. As a result, CLCF1-TG mice were predisposed to develop metabolic dysfunction even without external metabolic stress. Our findings revealed a brake signal on nonshivering thermogenesis and suggested that targeting this pathway could be used to restore brown fat activity and systemic metabolic homeostasis in obesity.
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Adipocitos Marrones , Biogénesis de Organelos , Animales , Ratones , Adipocitos Marrones/metabolismo , Tejido Adiposo Pardo/metabolismo , Homeostasis , Obesidad/genética , Obesidad/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Termogénesis/fisiologíaRESUMEN
Cellular senescence associates with pathological aging and tissue dysfunctions. Studies utilizing mouse models for cell lineage tracings have emphasized the importance of senescence heterogeneity in different organs and cell types. Here, we constructed a p21- (Akaluc - tdTomato - Diphtheria Toxin Receptor [DTR]) (ATD) mouse model to specifically study the undefined mechanism for p21-expressing senescent cells in the aged and liver injury animals. The successful expressions of these genes enabled in vitro flow cytometric sorting, in vivo tracing, and elimination of p21-expressing senescent cells. During the natural aging process, p21-expressing cells were found in various tissues of p21-ATD mice. Eliminating p21-expressing cells in the aged p21-ATD mice recovered their multiple biological functions. p21-ATD/Fah-/- mice, bred from p21-ATD mice and fumarylacetoacetate hydrolase (Fah)-/- mice of liver injury, showed that the majority of their senescent hepatocytes were the phenotype of p21+ rather than p16+. Furthermore, eliminating the p21-expressing hepatocytes significantly promoted the engraftment of grafted hepatocytes and facilitated liver repopulation, resulting in significant recovery from liver injury. Our p21-ATD mouse model serves as an optimal model for studying the pattern and function of p21-expressing senescent cells under the physical and pathological conditions during aging.
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Surface ligand chemistry is vital to control the synthesis, diminish surface defects, and improve the electronic coupling of quantum dots (QDs) toward emerging applications in optoelectronic devices. Here, we successfully develop highly homogeneous and dispersed AgBiS2 QDs, focus on the control of interdot spacing, and substitute the long-chain ligands with ammonium iodide in solution. This results in improved electronic coupling of AgBiS2 QDs with excellent surface passivation, which greatly facilitates carrier transport within the QD films. Based on the stable AgBiS2 QD dispersion with the optimal ligand state, a homogeneous and densely packed QD film is prepared by a facile one-step coating process, delivering a champion power conversion efficiency of approximately 8% in the QD solar cells with outstanding shelf life stability. The proposed surface engineering strategy holds the potential to become a universal preprocessing step in the realm of high-performance QD optoelectronic devices.
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Open ankle fractures, especially Gustilo-Anderson type III fractures are challenging to manage with controversy over the "best" or "superior" treatment strategy. This study aimed to evaluate the treatment outcome of immediate internal fixation combined with primary wound closure in the management of Gustilo-Anderson type IIIA open ankle fractures. We retrospectively assessed the outcomes of thirty-two patients treated using immediate internal fixation combined with primary wound closure with a minimum follow-up of twenty-four months. At the median follow-up of 38 months, the mean American Orthopaedic Foot and Ankle Society scale score was 87.22 ± 4.05. The physical component summary score of Short-Form 36 Health Status Survey was 66.63 ± 11.42 and the mental component summary score was 67.31 ± 7.20. Range of motion of Ankle/Foot injured side was 64.56 ± 4.30 degrees, and range of motion of Ankle/Foot uninjured side was 72.31 ± 3.12 degrees. Visual analog pain scale score was 1.5 ± 0.88 at rest and 3.09 ± 1.17 during activity. According to American Orthopaedic Foot and Ankle Society scale score, the rate of excellent and good outcomes was 90.6%. Postoperative complications were documented, comprising 2 (6.4%) cases of infection, 5 (15.6%) cases of wound skin necrosis, 1 (3.2%) case of postoperative ankle traumatic arthritis, and 1 (3.2%) case requiring reoperation due to suboptimal fibula fracture reduction. The study results demonstrated that immediate internal fixation combined with primary wound closure for Gustilo-Anderson type IIIA open ankle fractures achieve good functional outcomes and lower complication rates.
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Additive engineering has emerged as one of the most promising strategies to improve the performance of perovskite solar cells (PSCs). Among additives, perovskite nanocrystals (NCs) have a similar chemical composition and matched lattice structure with the perovskite matrix, which can effectively enhance the efficiency and stability of PSCs. However, relevant studies remain limited, and most of them focus on bromide-involved perovskite NCs, which may undergo dissolution and ion exchange within the FAPbI3 host, potentially resulting in an enlarged band gap. In this work, we employ butylamine-capped CsPbI3 NCs (BPNCs) as additives in PSCs, which can be well maintained and serve as seeds for regulating the crystallization and growth of perovskite films. The resultant perovskite film exhibits larger domain sizes and fewer grain boundaries without compromising the band gap. Moreover, BPNCs can alleviate lattice strain and reduce defect densities within the active layer. The PSCs incorporating BPNCs show a champion power conversion efficiency (PCE) of up to 25.41 %, well over both Control of 22.09 % and oleic acid/oleylamine capped CsPbI3 NC (PNC)-based devices of 23.11 %. This work illustrates the key role of nanosized seed surfaces in achieving high-performance photovoltaic devices.
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Primordial germ cell 7 (PGC7)(Dppa3 or Stella) is a small inherently disordered protein that is mainly expressed in oocytes and plays a vital role in the regulation of DNA methylation reprogramming in imprinted loci through interaction with other proteins. Most of PGC7-deficient zygotes are blocked at two-cell stage with an increased tri-methylation at lysine 27 of histone H3 (H3K27me3) level in the nucleus. Our previous work has indicated that PGC7 interacts with yin-yang1 (YY1) that is essential for the recruitment of enhancer of zeste homolog 2 (EZH2)-containing Polycomb repressive complex 2 (PRC2) to H3K27me3 modification sites. Here, we found that the presence of PGC7 weakened the interaction between YY1 and PRC2 without disrupting the assembly of core subunits of the PRC2 complex. In addition, PGC7 promoted AKT to phosphorylate serine 21 of EZH2, resulting in inhibition of EZH2 activity and the dissociation of EZH2 from YY1, thereby decreasing H3K27me3 level. In zygotes, the PGC7-deficient and AKT inhibitor MK2206 both promoted EZH2 to enter the pronuclei but without disturbing the subcellular localization of YY1 and caused an increase in the level of H3K27me3 in the pronuclei, as well as inhibition of the expression of zygote-activating genes regulated by H3K27me3 in two-cell embryos. In summary, PGC7 could affect zygotic genome activation during early embryonic development by regulating the level of H3K27me3 through regulation of PRC2 recruitment, EZH2 activity, and subcellular localization.NEW & NOTEWORTHY PGC7 and YY1 interaction inhibits recruitment of PRC2 by YY1. PGC7 promotes AKT and EZH2 interaction to increase pEZH2-S21 level, which weakens YY1 and EZH2 interaction, thereby decreasing H3K27me3 level. In zygotes, the PGC7-deficient and AKT inhibitor MK2206 promote EZH2 to enter the pronuclei, and increase H3K27me3 level in the pronuclei, as well as inhibition of the expression of zygote-activating genes regulated by H3K27me3 in two-cell embryos, which ultimately affects early embryo development.
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Histonas , Complejo Represivo Polycomb 2 , Complejo Represivo Polycomb 2/genética , Complejo Represivo Polycomb 2/metabolismo , Histonas/genética , Histonas/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Metilación de ADN , Células Germinativas/metabolismoRESUMEN
Epitranscriptomic abnormalities, which are highly prevalent in primary central nervous system malignancies, have been identified as crucial contributors to the development and progression of gliomas. RNA epitranscriptomic modifications, particularly the reversible modification methylation, have been observed throughout the RNA cycle. Epitranscriptomic modifications, which regulate RNA transcription and translation, have profound biological implications. These modifications are associated with the development of several cancer types. Notably, three main protein types-writers, erasers, and readers, in conjunction with other related proteins, mediate these epitranscriptomic changes. This review primarily focuses on the role of recently identified RNA methylation modifications in gliomas, such as N6-methyladenosine (m6A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), and N1-methyladenosine (m1A). We delved into their corresponding writers, erasers, readers, and related binding proteins to propose new approaches and prognostic indicators for patients with glioma.
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Glioma , Transcriptoma , Humanos , Metilación , ARN/metabolismo , 5-Metilcitosina/metabolismo , Glioma/genéticaRESUMEN
BACKGROUND: We aimed to establish an osteosarcoma prognosis prediction model based on a signature of endoplasmic reticulum stress-related genes. METHODS: Differentially expressed genes (DEGs) between osteosarcoma with and without metastasis from The Cancer Genome Atlas (TCGA) database were mapped to ERS genes retrieved from Gene Set Enrichment Analysis to select endoplasmic reticulum stress-related DEGs. Subsequently, we constructed a risk score model based on survival-related endoplasmic reticulum stress DEGs and a nomogram of independent survival prognostic factors. Based on the median risk score, we stratified the samples into high- and low-risk groups. The ability of the model was assessed by Kaplan-Meier, receiver operating characteristic curve, and functional analyses. Additionally, the expression of the identified prognostic endoplasmic reticulum stress-related DEGs was verified using real-time quantitative PCR (RT-qPCR). RESULTS: In total, 41 endoplasmic reticulum stress-related DEGs were identified in patients with osteosarcoma with metastasis. A risk score model consisting of six prognostic endoplasmic reticulum stress-related DEGs (ATP2A3, ERMP1, FBXO6, ITPR1, NFE2L2, and USP13) was established, and the Kaplan-Meier and receiver operating characteristic curves validated their performance in the training and validation datasets. Age, tumor metastasis, and the risk score model were demonstrated to be independent prognostic clinical factors for osteosarcoma and were used to establish a nomogram survival model. The nomogram model showed similar performance of one, three, and five year-survival rate to the actual survival rates. Nine immune cell types in the high-risk group were found to be significantly different from those in the low-risk group. These survival-related genes were significantly enriched in nine Kyoto Encyclopedia of Genes and Genomes pathways, including cell adhesion molecule cascades, and chemokine signaling pathways. Further, RT-qPCR results demonstrated that the consistency rate of bioinformatics analysis was approximately 83.33%, suggesting the relatively high reliability of the bioinformatics analysis. CONCLUSION: We established an osteosarcoma prediction model based on six prognostic endoplasmic reticulum stress-related DEGs that could be helpful in directing personalized treatment.
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Neoplasias Óseas , Osteosarcoma , Humanos , Pronóstico , Reproducibilidad de los Resultados , Osteosarcoma/genética , Factores de Riesgo , Estrés del Retículo Endoplásmico/genética , Neoplasias Óseas/genética , Proteasas Ubiquitina-EspecíficasRESUMEN
A barbed suture has been demonstrated to be effective in shortening the stitching time and improving the aesthetic appearance of the stitches during the entire knee replacement. However, no meta-analyses have been conducted specifically to evaluate the effect of the barbed thread on wound complications relative to the conventional suture. A comprehensive search of the PubMed database, the Embase database, the Cochrane Library and the Web of Science was performed to obtain search data up to June 2023, and only randomised controlled trials were included in this meta-analysis. We used Review Manager 5.3 for data synthesis and analysis. This meta-analysis included eight studies. It was found that the use of barbed sutures did not improve the incidence of the disease, the infection of the wound, the closure of the abscess and the injury. However, because of the limited sample size of the randomised controlled trials for this meta-analysis, the data should be handled with caution. More high-quality, large-sample studies will be required to confirm the results.
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Artroplastia de Reemplazo de Rodilla , Humanos , Artroplastia de Reemplazo de Rodilla/efectos adversos , Artroplastia de Reemplazo de Rodilla/métodos , Técnicas de Sutura , Suturas , Bases de Datos Factuales , Tempo Operativo , Resultado del TratamientoRESUMEN
Neuropathic pain is a somatosensory nervous system dysfunction that remains a threatening health problem globally. Recent studies have highlighted the involvement of C-C motif chemokine receptor 1 (CCR1) in neuropathic pain. Herein, the current study set out to explore the modulatory role of CCR1 in spinal nerve ligation (SNL)-induced neuropathic pain and its underlying molecular mechanism. First, it was found that CCR1 was highly expressed in spinal cord tissues and microglial cells of SNL rats. On the other hand, CCR1 knockdown attenuated nerve pain in SNL rats and repressed microglial cell activation in SNL rats and also in the LPS-induced microglial cell model of nerve injury, as evidenced by elevated microglial cell markers OX-42 and IL-1ß, IL-6 and TNF-α. Mechanistically, CCR1 enhanced small ubiquitin-like modifier 1 (SUMO1) modification of DiGeorge syndrome critical region gene 8 (DGCR8) in LPS-treated microglial cells by phosphorylating ERK. Moreover, CCR1 silencing brought about elevations in mechanical withdrawal threshold and thermal withdrawal latency. To conclude, our findings indicated that CCR1 enhanced the modification of DGCR8 by SUMO1 through phosphorylation of ERK, thereby promoting the activation and inflammatory response of spinal cord microglial cells and increasing the sensitivity of SNL rats to pain. Thus, this study offers a promising therapeutic target for the management of neuropathic pain.
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Neuralgia , Proteínas de Unión al ARN , Receptores de Quimiocina , Animales , Modelos Animales de Enfermedad , Quinasas MAP Reguladas por Señal Extracelular , Lipopolisacáridos , Neuralgia/terapia , Fosforilación , Proteínas de Unión al ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores CCR1 , Receptores de Quimiocina/metabolismo , Médula Espinal , Nervios Espinales , SumoilaciónRESUMEN
Ulcerative colitis (UC) is a chronic inflammatory disease of the intestine. It is characterized with recurrent. The pathogenesis is mainly associated with environmental factors, genetic susceptibility, dysbiosis of the intestinal flora and autoimmunity. The role of intestinal flora disorders in the pathogenesis and progression of UC is becoming increasingly prominent. More and more studies have confirmed that fecal microbiota transplantation (FMT) could reshape the composition of UC intestinal flora and it is expected to be a new strategy for UC treatment. In this study, we used 2% Dextran sulfate sodium (DSS) for 7 days to induce acute colitis model in mice, and interfere with FMT and Enterotoxigenic Escherichia coli (ETEC). ELISA and immunohistochemistry were applied to detect the concentration and expression of NF-κB p65, STAT3 and IL-6. 16SrRNA high-throughput sequencing was performed to explore the composition of intestinal flora. The aim was to study the treatment effect of FMT on UC mice and explore its potential mechanism by observing the changes of intestinal flora composition and diversity, and its relationship with NF-κB p65, STAT3 and IL-6 expression. We conclude that FMT could improve intestinal flora disorder in mice with ulcerative colitis, regulate NF-κB signaling pathway, and significantly reduce intestinal inflammation in UC mice.
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Colitis Ulcerosa , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Animales , Ratones , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/terapia , Colon/patología , Sulfato de Dextran , Modelos Animales de Enfermedad , Inflamación/terapia , Inflamación/patología , Interleucina-6 , Ratones Endogámicos C57BL , FN-kappa B , Transducción de SeñalRESUMEN
Aseptic loosening of the prosthesis caused by wear-particle-induced osteolysis is a long-term complication and one of the most common reasons for the failure of joint implants. The primary cause of aseptic loosening of the prosthesis is overactive bone resorption caused by wear-particle-activated osteoclasts in both direct and indirect ways. Therefore, drugs that can inhibit differentiation and bone resorption of osteoclasts need investigation as a potential therapeutic strategy to prevent and treat peri-prosthetic osteolysis and thereby prolong the service life of the prosthesis. This study has verified the potential inhibitory effect of LY450139 on inflammatory osteolysis induced by titanium particles in a mice skull model. In addition, we found that LY450139 inhibited receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis, bone resorption, and podosomal actin belt formation in a dose-dependent manner without evidence of cytotoxicity in vitro. In addition, LY450139 significantly decreased the expression of osteoclast-specific markers, including TRAP, CTSK, V-ATPase d2, CTR, DC-STAMP, NFATc1, and the downstream target gene Hes1 in Notch signaling pathway. Further investigation of the molecular mechanism demonstrated that LY450139 inhibited the formation of osteoclasts via inhibition of the NF-κB and Notch signaling pathways. In summary, LY450139 inhibited the formation of RANKL-mediated osteoclasts via NF-κB and Notch signaling and inhibited Ti particle-induced inflammatory osteolysis in vivo. LY450139 is a potential targeted drug for the treatment of peri-prosthetic osteolysis and other osteolytic disease associated with overactive osteoclasts.
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Resorción Ósea , Osteólisis , Alanina/análogos & derivados , Animales , Azepinas , Resorción Ósea/inducido químicamente , Modelos Animales de Enfermedad , Ratones , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Osteoclastos/metabolismo , Osteogénesis , Osteólisis/tratamiento farmacológico , Ligando RANK/metabolismo , Transducción de Señal , Solubilidad , Titanio/efectos adversosRESUMEN
BACKGROUND AND OBJECTIVE: Bioprostheses are the most common prostheses used for valve replacement in the Western medicine. The major flaw of bioprostheses is the occurrence of structural valve deterioration (SVD). This study aimed to assess the pathological features of porcine aortic valve (PAV)-SVD based on histomorphological and immunopathological characteristics of a large cohort of patients. METHODS: Histopathological data of 109 cases with resected PAV were collected. The type and amount of infiltrated cells were evaluated in the different types of bioprosthetic SVD by immunohistochemical staining. RESULTS: The most common cause of SVD was calcification, leaflet tear, and dehiscence (23.9%, 19.3%, and 18.3%, respectively). Immunohistochemical staining demonstrated that macrophages were infiltrated in the calcified, lacerated and dehiscence PAV, in which both M1 and M2 macrophages were existed in the calcified PAV. Importantly, the higher content of M1 macrophages and less content of M2 macrophages were found in the lacerated and dehiscence PAV, and MMP-1 expression was mainly found in the lacerated PAV. The endothelialization rate of leaflet dehiscence was higher than that of calcified and lacerated leaflets. A large number of CD31+/CD11b+ cells was aggregated in the spongy layer in the lacerated and dehiscence PAV. CONCLUSION: Cell regeneration and infiltration is a double edged sword for the PAV deterioration. Macrophage infiltration is involved in the different types of SVD, while only MMP-1 expression is involved in lacerated leaflets. The macrophage subtype of circulating angiogenic cells in dehiscence and tear PAV could be identified, which could reserve macrophages in the PAV-SVD.
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Bioprótesis , Implantación de Prótesis de Válvulas Cardíacas , Prótesis Valvulares Cardíacas , Animales , Válvula Aórtica/cirugía , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Metaloproteinasa 1 de la Matriz , Diseño de Prótesis , Falla de Prótesis , Regeneración , PorcinosRESUMEN
The promoting roles of the transcriptional regulator SMAR1 have been revealed in several tumors, such as colorectal and breast cancer, however, its roles in osteosarcoma (OS) progression are still confusing. Here, we find that SMAR1 expression is positively correlated with the overall survival of OS patients and negatively correlated with the expression of stemness markers by analyzing the online datasets. Through analyzing different Gene Expression Omnibus (GEO) datasets, SMAR1 is found to be lowly expressed in OS tissues relative to that in adjacent tissues. Functional experiments indicate that SMAR1 overexpression attenuates the stemness of OS cells, characterized as the decrease of stemness marker expression, sphere-formation ability and ALDH activity. Mechanistically, it is shown that SMAR1 increases the deacetylation level of the drug efflux pump ABCG2 via recruiting HDAC2 to the promoter of the gene coding ABCG2, and thus decreases ABCG2 transcriptional activity. Additionally, overexpression of ABCG2 rescues the inhibition of SMAR1 overexpression on the stemness of OS cells. Moreover, this SMAR1/ABCG2 axis positively regulates the chemotherapeutic sensitivity of OS cells. This work indicates that SMAR1 is a critical suppressor for OS progression through transcriptionally regulating ABCG2 expression.
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Neoplasias Óseas , Osteosarcoma , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2/genética , Línea Celular Tumoral , Movimiento Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Proteínas de Neoplasias/genética , Osteosarcoma/genéticaRESUMEN
BACKGROUND: Alfalfa is a high-quality forage cultivated widely in northern China. Recently, the failure of alfalfa plants to survive the winter has caused substantial economic losses. Water management has attracted considerable attention as a method for the potential improvement of winter survival. The aim of this study was to determine whether and how changes in the water regime affect the freezing tolerance of alfalfa. RESULTS: The alfalfa variety WL353LH was cultivated under water regimes of 80 and 25% of water-holding capacity, and all the plants were subjected to low temperatures at 4/0 °C (light/dark) and then - 2/- 6 °C (light/dark). The semi-lethal temperatures were lower for water-stressed than well-watered alfalfa. The pool sizes of total soluble sugars, total amino acids, and proline changed substantially under water-deficit and low-temperature conditions. Metabolomics analyses revealed 72 subclasses of differential metabolites, among which lipid and lipid-like molecules (e.g., fatty acids, unsaturated fatty acids, and glycerophospholipids) and amino acids, peptides, and analogues (e.g., proline betaine) were upregulated under water-deficit conditions. Some carbohydrates (e.g., D-maltose and raffinose) and flavonoids were also upregulated at low temperatures. Finally, Kyoto Encyclopedia of Genes and Genomes analyses revealed 18 significantly enriched pathways involved in the biosynthesis and metabolism of carbohydrates, unsaturated fatty acids, amino acids, and glycerophospholipids. CONCLUSIONS: Water deficit significantly enhanced the alfalfa' freezing tolerance, and this was correlated with increased soluble sugar, amino acid, and lipid and lipid-like molecule contents. These substances are involved in osmotic regulation, cryoprotection, and the synthesis, fluidity, and stability of the cellular membrane. Our study provides a reference for improving alfalfa' winter survival through water management.
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Respuesta al Choque por Frío/fisiología , Medicago sativa/metabolismo , Metabolómica , Agua/metabolismo , Aminoácidos/metabolismo , Metabolismo de los Hidratos de Carbono/genética , China , Frío , Congelación , Perfilación de la Expresión Génica , Metabolismo de los Lípidos/genética , Medicago sativa/genética , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estrés Fisiológico/fisiologíaRESUMEN
BACKGROUND: Hepatic fibrosis is a pathological response of the liver to a variety of chronic stimuli. Hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. Follistatin like 1 (Fstl1) is a secreted glycoprotein induced by transforming growth factor-ß1 (TGF-ß1). However, the precise functions and regulation mechanisms of Fstl1 in liver fibrogenesis remains unclear. METHODS: Hepatic stellate cell (HSC) line LX-2 stimulated by TGF-ß1, primary culture of mouse HSCs and a model of liver fibrosis induced by CCl4 in mice was used to assess the effect of Fstl1 in vitro and in vivo. RESULTS: Here, we found that Fstl1 was significantly up regulated in human and mouse fibrotic livers, as well as activated HSCs. Haplodeficiency of Fstl1 or blockage of Fstl1 with a neutralizing antibody 22B6 attenuated CCl4-induced liver fibrosis in vivo. Fstl1 modulates TGF-ß1 classic Samd2 and non-classic JNK signaling pathways. Knockdown of Fstl1 in HSCs significantly ameliorated cell activation, cell migration, chemokines C-C Motif Chemokine Ligand 2 (CCL2) and C-X-C Motif Chemokine Ligand 8 (CXCL8) secretion and extracellular matrix (ECM) production, and also modulated microRNA-29a (miR29a) expression. Furthermore, we identified that Fstl1 was a target gene of miR29a. And TGF-ß1 induction of Fstl1 expression was partially through down regulation of miR29a in HSCs. CONCLUSIONS: Our data suggests TGF-ß1-miR29a-Fstl1 regulatory circuit plays a key role in regulation the HSC activation and ECM production, and targeting Fstl1 may be a strategy for the treatment of liver fibrosis. Video Abstract.
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Anticuerpos Neutralizantes/uso terapéutico , Proteínas Relacionadas con la Folistatina/antagonistas & inhibidores , Cirrosis Hepática/terapia , MicroARNs/genética , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Tetracloruro de Carbono , Células Cultivadas , Proteínas Relacionadas con la Folistatina/genética , Proteínas Relacionadas con la Folistatina/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Haploidia , Humanos , Cirrosis Hepática/inducido químicamente , Cirrosis Hepática/genética , Cirrosis Hepática/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , MicroARNs/metabolismoRESUMEN
BACKGROUND: The aim of the study was to investigate the relationship between post-myocardial infarction (MI) inflammation and left ventricular (LV) remodeling in a swine model by 18F-fluorodeoxyglucose (FDG) imaging. METHODS: MI was induced in swine by balloon occlusion of the left anterior descending coronary artery. A series of FDG positron emission tomography (PET) images were taken within 2 weeks post-MI, employing a comprehensive strategy to suppress the physiological uptake of cardiomyocytes. Echocardiography was applied to evaluate LV volume, global and regional function. CD68+ macrophage and glucose transporters (GLUT-1, -3 and -4) were investigated by immunostaining. RESULTS: The physiological uptake of myocardium was adequately suppressed in 92.3% of PET scans verified by visual analysis, which was further confirmed by the minimal expression of myocardial GLUT-4. Higher FDG uptake was observed in the infarct than in the remote area and persisted within the observational period of 2 weeks. The FDG uptake of infarcted myocardium on day 1 post-MI was correlated with LV global remodeling, and the FDG uptake of infarcted myocardium on days 1 and 8 post-MI had a trend of correlating with regional remodeling of the infarct area. CONCLUSIONS: We here report a feasible swine model for investigating post-MI inflammation. FDG signal in the infarct area of swine persisted for a longer duration than has been reported in small animals. FDG activity in the infarct area could predict LV remodeling.
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Fluorodesoxiglucosa F18 , Ventrículos Cardíacos/diagnóstico por imagen , Inflamación/diagnóstico por imagen , Infarto del Miocardio/diagnóstico por imagen , Imagen de Perfusión Miocárdica/métodos , Animales , Antígenos CD/biosíntesis , Antígenos de Diferenciación Mielomonocítica/biosíntesis , Vasos Coronarios/patología , Ecocardiografía , Transportador de Glucosa de Tipo 1/biosíntesis , Transportador de Glucosa de Tipo 3/biosíntesis , Transportador de Glucosa de Tipo 4/biosíntesis , Corazón/diagnóstico por imagen , Procesamiento de Imagen Asistido por Computador , Células Musculares/patología , Miocitos Cardíacos/metabolismo , Necrosis , Tomografía de Emisión de Positrones , Radiofármacos , PorcinosRESUMEN
BACKGROUND: The comparative efficacy of epidural bupivacaine alone and bupivacaine combined with magnesium sulfate in providing postoperative analgesia remains controversial. METHODS: We searched Mediline (OvidSP), EMBASE (OvidSP) and Cochrane Central Register of Controlled Trials (CENTRAL) to identify trials that compared epidural bupivacaine and magnesium sulfate combination (intervention) with bupivacaine alone (control). Grading of Recommendations, Assessment, Development and Evaluations (GRADE) framework was used to assess the quality of evidence. RESULTS: Eleven studies fulfilled our inclusion criteria after screening. We found that epidural bupivacaine combined with magnesium sulfate could prolong the time for first rescue analgesics (SMD 4.96; 95% CI [2.75, 7.17], P < 0.00001, I2 = 98%), reduce the number of patients who need rescue analgesics (RR 0.38; 95% CI [0.20, 0.74], P = 0.004, I2 = 75%) and requirement for rescue analgesics (SMD -2.65; 95% CI [- 4.23, - 1.06], P = 0.001, I2 = 96%). CONCLUSIONS: Magnesium suifate as an adjuvant of epidural bupivacaine improved postoperative analgesia. However, we rated the quality of evidence to be very low because of high heterogeneity, imprecise of results and small sample sizes. Furthermore, further large high-quality trials are still needed to confirm the effects of magnesium sulfate on postoperative analgesia.
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Analgesia Epidural/métodos , Analgésicos/uso terapéutico , Anestésicos Locales/uso terapéutico , Bupivacaína/uso terapéutico , Sulfato de Magnesio/uso terapéutico , Dolor Postoperatorio/tratamiento farmacológico , Analgesia/métodos , Quimioterapia Combinada , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Resultado del TratamientoRESUMEN
A series of sarisan analogs containing 1,3,4-oxadiazole moieties were synthesized by iodine-mediated oxidative cyclization and screened inâ vitro for their antifungal activities at 50â µg/mL against five phytopathogenic fungi such as Valsa mali, Curvularia lunata, Alternaria alternate, Fusarium solani and Fusarium graminearum. 1,3,4-Oxadiazole derivatives 7e, 7p, 7r, 7t and 7u exhibited potent and a broad spectrum of antifungal activities against at least three phytopathogenic fungi at the concentration of 50â µg/mL. Especially, compound 7r displayed more potent antifungal activities against five phytopathogenic fungi than the positive control hymexazol. The EC50 of 7r against V. mali, C. lunata and A. alternate were 12.6, 14.5 and 17.0â µg/mL, respectively. Additionally, some interesting results of structure-activity relationships (SARs) were also observed.
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Antifúngicos/síntesis química , Productos Biológicos/síntesis química , Dioxolanos/química , Diseño de Fármacos , Oxadiazoles/química , Alternaria/efectos de los fármacos , Antifúngicos/farmacología , Ascomicetos/efectos de los fármacos , Productos Biológicos/farmacología , Dioxolanos/farmacología , Fusarium/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Relación Estructura-ActividadRESUMEN
Chiral quasi-2D perovskite single crystals (SCs) were investigated for their circular polarized light (CPL) detecting capability. Quasi-2D chiral perovskites, [(R)-ß-MPA]2 MAPb2 I7 ((R)-ß-MPA=(R)-(+)-ß-methylphenethylamine, MA=methylammonium), have intrinsic chirality and the capability to distinguish different polarization states of CPL photons. Corresponding quasi-2D SCs CPL photodetector exhibit excellent detection performance. In particular, our device responsivity is almost one order of magnitude higher than the reported 2D perovskite CPL detectors to date. The crystallization dynamics of the film were modulated to facilitate its carrier transport. Parallel oriented perovskite films with a homogeneous energy landscape is crucial to maximize the carrier collection efficiency. The photodetector also exhibits superior mechanical flexibility and durability, representing a promising candidate for sensitive and robust CPL photodetectors.