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AIMS: Heart failure (HF) is one of the most devastating consequences of cardiovascular diseases. Regardless of etiology, cardiac fibrosis is present and promotes the loss of heart function in HF patients. Cardiac resident fibroblasts, in response to a host of pro-fibrogenic stimuli, trans-differentiate into myofibroblasts to mediate cardiac fibrosis, the underlying mechanism of which remains incompletely understood. METHODS: Fibroblast-myofibroblast transition was induced in vitro by exposure to transforming growth factor (TGF-ß). Cardiac fibrosis was induced in mice by either transverse aortic constriction (TAC) or by chronic infusion with angiotensin II (Ang II). RESULTS: Through bioinformatic screening, we identified Kruppel-like factor 6 (KLF6) as a transcription factor preferentially up-regulated in cardiac fibroblasts from individuals with non-ischemic cardiomyopathy (NICM) compared to the healthy donors. Further analysis showed that nuclear factor kappa B (NF-κB) bound to the KLF6 promoter and mediated KLF6 trans-activation by pro-fibrogenic stimuli. KLF6 knockdown attenuated whereas KLF6 over-expression enhanced TGF-ß induced fibroblast-myofibroblast transition in vitro. More importantly, myofibroblast-specific KLF6 depletion ameliorated cardiac fibrosis and rescued heart function in mice subjected to the TAC procedure or chronic Ang II infusion. SIGNIFICANCE: In conclusion, our data support a role for KLF6 in cardiac fibrosis.
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Fibroblastos , Fibrosis , Factor 6 Similar a Kruppel , Ratones Endogámicos C57BL , Miofibroblastos , Animales , Factor 6 Similar a Kruppel/metabolismo , Factor 6 Similar a Kruppel/genética , Fibrosis/metabolismo , Ratones , Humanos , Masculino , Fibroblastos/metabolismo , Miofibroblastos/metabolismo , Miofibroblastos/patología , Angiotensina II/farmacología , Miocardio/metabolismo , Miocardio/patología , Factor de Crecimiento Transformador beta/metabolismo , FN-kappa B/metabolismo , Células Cultivadas , Factores de Transcripción de Tipo Kruppel/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/genéticaRESUMEN
Constructing an artificial solid electrolyte interphase (ASEI) on Li metal anodes (LMAs) is a potential strategy for addressing the dendrite issues. However, the mechanical fatigue of the ASEI caused by stress accumulation under the repeated deformation from the Li plating/stripping is not taken seriously. Herein, this work introduces a mechanically interlocked [an]daisy chain network (DCMIN) into the ASEI to stabilize the Li metal/ASEI interface by combining the functions of energy dissipation and fast Li-ion transport. The DCMIN featured by large-range molecular motions is cross-linked via efficient thiol-ene click chemistry; thus, the DCMIN has flexibility and excellent mechanical properties. As an ASEI, the crown ether units in DCMIN not only interact with the dialkylammonium of a flexible chain, forming the energy dissipation behavior but also coordinate with Li ion to support the fast Li-ion transport in DCMIN. Therefore, a stable 2800 h-symmetrical cycling (1 mA cm-2) and an excellent 5 C-rate (full cell with LiFePO4) performance are achieved by DCMIN-based ASEI. Furthermore, the 1-Ah pouch cell (LiNi0.88Co0.09Mn0.03O2 cathode) with DCMIN-coated LMA exhibits improved capacity retention (88%) relative to the Control. The molecular design of DCMIN provides new insights into the optimization of an ASEI for high-energy LMAs.
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Reasonably elevating the working voltage (≥4.4â V vs. Li/Li+ ) of the cathode is one of the efficient approaches to maximize the energy density of lithium-ion batteries (LIBs). As a preferred partner for high-voltage LIB systems, localized high-concentration electrolyte (LHCE), characterized by a stronger Li solvation structure, less free solvent, and robust electrode/electrolyte interphase has attracted much attention in academic circles. Herein, we systematically studied the role of the diluent in LHCE on the formation of the cathode electrolyte interphase (CEI) and elucidated that the existing anion-diluent pairing in the inner Helmholtz plane (IHP) results in an uneven CEI and subsequent battery degradation under high voltage. A m-fluorotoluene (mFT) diluent was further employed in the LHCE containing lithium difluoro(oxalato)borate (LiDFOB) to facilitate a uniform and rich-anion-derived CEI, since the weaker interaction of HmFT -BDFOB - , as compared to the HHhydrofluoroether -BDFOB - , reduces the influence of mFT in IHP or initial CEI formation. Consequently, the mFT-dominated LHCE propels the high-voltage performance of LIBs one step forward, endowing a 4.6â V-class 1.2-Ah graphite||LiNi0.8 Co0.1 Mn0.1 O2 pouch cells a 90.4 % capacity retention after 130â cycles. Our study thus describes a new index affecting the CEI formation and proposes novel strategies to deeply optimize the high-voltage LIBs.
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Effect of fuel injection pressure on organic carbon (OC), elemental carbon (EC) and particulate semivolatile organic compounds (SVOCs), i.e., n-alkanes and polycyclic aromatic hydrocarbons (PAHs), emissions from a common-rail diesel engine was analyzed comprehensively. EC emission rate evidently decreased with increasing injection pressure at low fuel injection pressure ranges (80-120 MPa), while engine load effect on the EC emission was insignificant at high injection pressure ranges (140-160 MPa). The higher fraction of EC2 in the total EC emission appeared at the highest injection pressure ranges (140-160 MPa) under middle and high loads, suggesting the spontaneous carbonization process from soot precursor to ordered soot during the high temperature process. Low injection pressure provided poor combustion condition and caused unburned diesel fuel to volatilize more 2-3 ring PAHs. The percentage of 4-ring PAHs exhibited a rise-then-fall trend with increasing injection pressure, while the maximum percentage of 5-7 ring PAHs appeared at the highest injection pressure ranges (140-160 MPa) under high load condition, suggesting that higher combustion temperature and larger pyrolysis zone under the high injection pressure promoted the formation of lager and more stable PAHs. The fractions of fuel-derived short chain (C16-C21) and oil-derived long chain (C22-C33) in the total n-alkanes exhibited obvious load and injection pressure dependence.
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Liver ischemia and reperfusion (IR) injury is the major complication of liver-related operations. Macrophage polarization has an essential effect on the mechanism of liver IR injury. Vitamin D receptor (VDR) has been found to regulate macrophage polarization and alleviate IR injury. Nevertheless, the correlation between VDR and macrophage polarization in liver IR injury has not been clearly elucidated. VDR knockout mice and wild-type littermates underwent partial liver ischemia for 90 min and reperfusion for 6 h. RAW264.7 cells were also used to verify the influence of VDR on macrophage polarization in vitro. VDR activation could promote M2 macrophage polarization and then reduce liver injury. In contrast, VDR deficiency aggravated the liver injury by disturbing M2 macrophage polarization. Moreover, autophagy participated in the effect of VDR on M2 macrophage polarization through mediating suppressor of cytokine signaling. Therefore, VDR plays a vital influence in liver IR injury. The protective role of VDR activation in liver IR injury is related to regulate M2 macrophage polarization by autophagy.
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Radiation enteritis is a kind of intestinal radiation injury in patients with pelvic and retroperitoneal malignancies after radiotherapy, and its occurrence and development process are very complicated. At present, studies have confirmed that intestinal microecological imbalance is an important factor in the formation of this disease. Abdominal radiation causes changes in the composition of the flora and a decrease in its diversity, which is mainly manifested by a decrease in beneficial bacterial species such as Lactobacilli and Bifidobacteria. Intestinal dysbacteriosis aggravates radiation enteritis, weakens the function of the intestinal epithelial barrier, and promotes the expression of inflammatory factors, thereby aggravating the occurrence of enteritis. Given the role of the microbiome in radiation enteritis, we suggest that the gut microbiota may be a potential biomarker for the disease. Treatment methods such as probiotics, antibiotics, and fecal microbiota transplantation are ways to correct the microbiota and may be an effective way to prevent and treat radiation enteritis. Based on a review of the relevant literature, this paper reviews the mechanism and treatment of intestinal microbes in radiation enteritis.
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BACKGROUND: Oxidative stress is an important mechanism in liver ischemia/reperfusion (I/R) injury. Hepatocyte apoptosis and proliferation occur in parallel with liver I/R injury, and the degree of apoptosis and proliferation determines the effects on hepatocytes. Vitamin D receptor (VDR) can lessen liver I/R injury, but previous studies focused mostly on inflammation and immunity. METHODS: H2O2 was used to induce hepatocyte injury. Before treatment with H2O2, Hep-3B cells were pretreated with paricalcitol (PC) and siRNA-VDR. Rapamycin and chloroquine were also applied in the study. RESULTS: The number of apoptotic cells was measured with an annexin V (AV) -fluorescein isothiocyanate apoptosis detection kit. Expression of proteins was measured by western blotting. As compared with the H2O2+Hep-3B group, levels of AV/PI, cleaved caspase-3, and p62 were lower, and expression levels of Bcl-2, proliferating cell nuclear antigen, and VDR were higher, in the PC+H2O2+Hep-3B group. When the VDR gene was silenced by siRNA-VDR in the siRNA-VDR+H2O2+Hep-3B group, expressions of AV/PI, cleaved caspase-3, and p62 were upregulated, and expressions of Bcl-2, proliferating cell nuclear antigen, and VDR were downregulated, as compared with values for the siRNA-NC+H2O2+Hep-3B group. Treatment with rapamycin or chloroquine partially reversed the effect of PC and siRNA-VDR on apoptosis and proliferation. CONCLUSIONS: VDR mediates hepatocyte apoptosis and proliferation through autophagy.
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Peróxido de Hidrógeno , Receptores de Calcitriol , Humanos , Apoptosis , Autofagia/fisiología , Caspasa 3/farmacología , Proliferación Celular , Cloroquina/farmacología , Hepatocitos/metabolismo , Peróxido de Hidrógeno/farmacología , Antígeno Nuclear de Célula en Proliferación/farmacología , Proteínas Proto-Oncogénicas c-bcl-2/farmacología , Receptores de Calcitriol/metabolismo , ARN Interferente Pequeño/farmacología , Sirolimus/farmacologíaRESUMEN
Cardiac fibrosis is a key pathophysiological process that contributes to heart failure. Cardiac resident fibroblasts, exposed to various stimuli, are able to trans-differentiate into myofibroblasts and mediate the pro-fibrogenic response in the heart. The present study aims to investigate the mechanism whereby transcription of chloride channel accessory 2 (Clca2) is regulated in cardiac fibroblast and its potential implication in fibroblast-myofibroblast transition (FMyT). We report that Clca2 expression was down-regulated in activated cardiac fibroblasts (myofibroblasts) compared to quiescent cardiac fibroblasts in two different animal models of cardiac fibrosis. Clca2 expression was also down-regulated by TGF-ß, a potent inducer of FMyT. TGF-ß repressed Clca2 expression at the transcriptional level likely via the E-box element between -516 and -224 of the Clca2 promoter. Further analysis revealed that Twist1 bound directly to the E-box element whereas Twist1 depletion abrogated TGF-ß induced Clca2 trans-repression. Twist1-mediated Clca2 repression was accompanied by erasure of histone H3/H4 acetylation from the Clca2 promoter. Mechanistically Twist1 interacted with HDAC1 and recruited HDAC1 to the Clca2 promoter to repress Clca2 transcription. Finally, it was observed that Clca2 over-expression attenuated whereas Clca2 knockdown enhanced FMyT. In conclusion, our data demonstrate that a Twist1-HDAC1 complex represses Clca2 transcription in cardiac fibroblasts, which may contribute to FMyT and cardiac fibrosis.
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BACKGROUND We aimed to evaluate the value of prophylactic extended-field intensity-modulated radiation therapy (IMRT) in the treatment of locally advanced cervical cancer with multiple pelvic lymph node metastases (≥2) and negative common iliac and paraaortic lymph nodes. MATERIAL AND METHODS Thirty-four patient with newly diagnosed cervical cancer (IB1-IVA) and multiple pelvic lymph node metastases (≥2) confirmed by computed tomography and magnetic resonance imaging were randomly divided into an extended-field group (17 patients) and a pelvic-field group (17 patients). In the extended-field group, we added the drainage area of paraaortic lymph nodes on the pelvic field. The pelvic field was administered Dt 45.0 to 50.4 Gy, while the drainage area of paraaortic lymph nodes was administered Dt 40.0 to 45.0 Gy. Both groups were given Irl92 intracavitary radiotherapy after 3 weeks of external irradiation. The total dose of point A was 25.0 to 30.0 Gy, fractional 6.0 to 7.0 Gy. All patients had concurrent platinum-based chemotherapy once weekly until the end of radiotherapy. RESULTS No paraaortic lymph node metastasis was found in the extended-field group (P=0.0184), and disease-free survival (DFS) was prolonged (P=0.0286). Adverse effects in patients with III-IV degree myelosuppression were increased in the extended-field group (P=0.0324). However, all patients recovered after symptomatic treatment. CONCLUSIONS Prophylactic extended-field IMRT with chemotherapy reduced the metastasis rate of paraaortic lymph nodes and prolonged the DFS in patients with locally advanced cervical cancer and multiple pelvic lymph node metastases (≥2), while the toxic adverse effects were tolerated.
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Radioterapia de Intensidad Modulada , Neoplasias del Cuello Uterino/radioterapia , Femenino , Humanos , Metástasis Linfática , Persona de Mediana Edad , Radioterapia de Intensidad Modulada/efectos adversos , Neoplasias del Cuello Uterino/patologíaRESUMEN
[This corrects the article DOI: 10.3389/fcell.2020.00839.].
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The operating temperatures of commercial lithium-ion batteries (LIBs) are generally restricted to a narrow range of -20 to 55 °C because the electrolyte is composed of highly volatile and flammable organic solvents and thermally unstable salts. Herein, the use of concentrated electrolytes is proposed to widen the operating temperature to -20 to 100 °C. It is demonstrated that a 4.0 mol L-1 LiN(SO2 F)2 /dimethyl carbonate electrolyte enables the stable charge-discharge cycling of a graphite anode and a high-capacity LiNi0.6 Co0.2 Mn0.2 O2 cathode and the corresponding full cell in a wide temperature range from -20 to 100 °C owing to the highly thermal stable solvation structure of the concentrated electrolyte together with the robust and Li+ -conductive passivation interphase it offered that alleviate various challenges at high temperatures. This work demonstrates the potential for the development of safe LIBs without the need for bulky and heavy thermal management systems, thus significantly increasing the overall energy density.
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[This corrects the article DOI: 10.3389/fcell.2020.00794.].
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[This corrects the article DOI: 10.3389/fcell.2020.00484.].
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[This corrects the article DOI: 10.3389/fcell.2020.00484.].
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Cardiac hypertrophy is a critical intermediate step in the pathogenesis of heart failure. A myriad of signaling networks converge on cardiomyocytes to elicit hypertrophic growth in response to various injurious stimuli. In the present study, we investigated the cardiomyocyte-specific role of myocardin-related transcription factor A (MRTF-A) in angiotensin-II (Ang-II)-induced cardiac hypertrophy and the underlying mechanism. We report that conditional MRTF-A deletion in cardiomyocytes attenuated Ang-II-induced cardiac hypertrophy in mice. Similarly, MRTF-A knockdown or inhibition suppressed Ang-II-induced prohypertrophic response in cultured cardiomyocytes. Of note, Ang II treatment upregulated expression of phosphodiesterase 5 (PDE5), a known mediator of cardiac hypertrophy and heart failure, in cardiomyocytes, which was blocked by MRTF-A depletion or inhibition. Mechanistically, MRTF-A activated expression of specificity protein 1 (Sp1), which in turn bound to the PDE5 promoter and upregulated PDE5 transcription to promote hypertrophy of cardiomyocytes in response to Ang II stimulation. Therefore, our data unveil a novel MRTF-A-Sp1-PDE5 axis that mediates Ang-II-induced hypertrophic response in cardiomyocytes. Targeting this newly identified MRTF-A-Sp1-PDE5 axis may yield novel interventional solutions against heart failure.
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The matricellular protein SPON2 plays diverse roles in the development of cardiovascular diseases. SPON2 is expressed in endothelial cells, but its transcription regulation in the context of atherogenesis remains incompletely appreciated. Here we report that SPON2 expression was up-regulated by pro-atherogenic stimuli (oxLDL and TNF-α) in vascular endothelia cells. In addition, endothelial SPON2 was elevated in Apoe -/- mice fed on a Western diet compared to the control mice. Induction of SPON2 in endothelial cells by pro-atherogenic stimuli was mediated by BRG1, a chromatin remodeling protein, both in vitro and in vivo. Further analysis revealed that BRG1 interacted with the sequence-specific transcription factor Egr-1 to activate SPON2 transcription. BRG1 contributed to SPON2 trans-activation by modulating chromatin structure surrounding the SPON2 promoter. Functionally, activation of SPON2 transcription by the Egr-1/BRG1 complex provided chemoattractive cues for macrophage trafficking. SPON2 depletion abrogated the ability of BRG1 or Egr-1 to stimulate endothelial derived chemoattractive cue for macrophage migration. On the contrary, recombinant SPON2 rescued endothelial chemo-attractability in the absence of BRG1 or Egr-1. In conclusion, our data have identified a novel transcriptional cascade in endothelial cells that may potentially promote macrophage recruitment and vascular inflammation leading to atherogenesis.
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Cardiac ischemia-reperfusion injury (IRI) represents a major pathophysiological event associated with permanent loss of heart function. Several inter-dependent processes contribute to cardiac IRI that include accumulation of reactive oxygen species (ROS), aberrant inflammatory response, and depletion of energy supply. Inducible nitric oxide synthase (iNOS) is a pro-inflammatory mediator and a major catalyst of ROS generation. In the present study we investigated the epigenetic mechanism whereby iNOS transcription is up-regulated in macrophages in the context of cardiac IRI. We report that germline deletion or systemic inhibition of myocardin-related transcription factor A (MRTF-A) in mice attenuated up-regulation of iNOS following cardiac IRI in the heart. In cultured macrophages, depletion or inhibition of MRTF-A suppressed iNOS induction by hypoxia-reoxygenation (HR). In contrast, MRTF-A over-expression potentiated activation of the iNOS promoter by HR. MRTF-A directly binds to the iNOS promoter in response to HR stimulation. MRTF-A binding to the iNOS promoter was synonymous with active histone modifications including trimethylated H3K4, acetylated H3K9, H3K27, and H4K16. Further analysis revealed that MRTF-A interacted with H4K16 acetyltransferase TIP60 to synergistically activate iNOS transcription. TIP60 depletion or inhibition achieved equivalent effects as MRTF-A depletion/inhibition in terms of iNOS repression. Of interest, TIP60 appeared to form a crosstalk with the H3K4 trimethyltransferase complex to promote iNOS trans-activation. In conclusion, we data suggest that the MRTF-A-TIP60 axis may play a critical role in iNOS transcription in macrophages and as such be considered as a potential target for the intervention of cardiac IRI.
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Liver sinusoidal endothelial cells play a key role maintaining the hepatic homeostasis, the disruption of which is associated with such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. In the present study we investigated the role of brahma-related gene 1 (BRG1), a chromatin remodeling protein, in regulating endothelial transcription and the implication in liver fibrosis. We report that endothelial-specific deletion of BRG1 in mice attenuated liver fibrosis induced by injection with thioacetamide (TAA). Coincidently, alleviation of liver fibrosis as a result of endothelial BRG1 deletion was accompanied by an up-regulation of eNOS activity and NO bioavailability. In cultured endothelial cells, exposure to lipopolysaccharide (LPS) suppressed eNOS activity whereas BRG1 depletion with small interfering RNA restored eNOS-dependent NO production. Further analysis revealed that BRG1 was recruited to the caveolin-1 (CAV1) promoter by Sp1 and activated transcription of CAV1, which in turn inhibited eNOS activity. Mechanistically, BRG1 interacted with the H3K4 trimethyltransferase MLL1 to modulate H3K4 trimethylation surrounding the CAV1 promoter thereby contributing to LPS-induced CAV1 activation. In conclusion, our data unveil a novel role for BRG1 in the regulation of endothelial function and liver fibrosis.
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ADN Helicasas/metabolismo , Células Endoteliales/metabolismo , Fibrosis/metabolismo , Hígado/metabolismo , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Animales , Células Cultivadas , ADN Helicasas/deficiencia , ADN Helicasas/aislamiento & purificación , Fibrosis/inducido químicamente , Humanos , Hígado/efectos de los fármacos , Ratones , Óxido Nítrico/análisis , Proteínas Nucleares/deficiencia , Proteínas Nucleares/aislamiento & purificación , Tioacetamida , Factores de Transcripción/deficiencia , Factores de Transcripción/aislamiento & purificaciónRESUMEN
Galectin-3 (encoded by LGALS3) is a glycan-binding protein that regulates a diverse range of pathophysiological processes contributing to the pathogenesis of human diseases. Previous studies have found that galectin-3 levels are up-regulated in the liver by a host of different injurious stimuli. The underlying epigenetic mechanism, however, is unclear. Here we report that conditional knockout of Brahma related gene (BRG1), a chromatin remodeling protein, in hepatocytes attenuated induction of galectin-3 expression in several different animal models of liver injury. Similarly, BRG1 depletion or pharmaceutical inhibition in cultured hepatocytes suppressed the induction of galectin-3 expression by treatment with LPS plus free fatty acid (palmitate). Further analysis revealed that BRG1 interacted with AP-1 to bind to the proximal galectin-3 promoter and activate transcription. Mechanistically, DNA demethylation surrounding the galectin-3 promoter appeared to be a rate-limiting step in BRG1-mediated activation of galectin-3 transcription. BRG1 recruited the DNA 5-methylcytosine dioxygenase TET1 to the galectin-3 to promote active DNA demethylation thereby activating galectin-3 transcription. Finally, TET1 silencing abrogated induction of galectin-3 expression by LPS plus palmitate in cultured hepatocytes. In conclusion, our data unveil a novel epigenetic pathway that contributes to injury-associated activation of galectin-3 transcription in hepatocytes.
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BACKGROUND: Accumulating evidences suggest that microRNAs (miRNAs) play key roles in mediating glioblastoma progression. Decreased expression of miR-152-3p was reported in several cancer types including glioblastoma. METHODS: The sensitivity of glioblastoma cells to cisplatin was assessed by the cell counting kit-8 assay and flow cytometry analysis. The expression of miR-152-3p was determined by RT-qPCR method. Bioinformatic analysis, dual luciferase reporter assay and Western blot were used to explore the target gene of miR-152-3p. The association between miR-152-3p and SOS1 was confirmed in glioblastoma tissues by Pearson correlation analysis. RESULTS: In the current study, we discovered that overexpression of miR-152-3p increased cisplatin sensitivity while inhibition of miR-152-3p decreased cisplatin sensitivity in glioblastoma cells (T98G and U87). In addition, miR-152-3p augmented cell apoptosis induced by cisplatin treatment. It was further predicted and validated that SOS1, a protein involved in regulating chemotherapy sensitivity, was a direct target gene of miR-152-3p. SOS1 was proven to suppress the cytotoxic effect of cisplatin in glioblastoma. Transfection of recombinant SOS1 could effectively reverse the increased cisplatin sensitivity induced by miR-152-3p overexpression in T98G. Furthermore, overexpression of SOS1 reduced the percentage of apoptotic cells increased by miR-152-3p mimic in the presence of cisplatin in T98G. More importantly, a significant negative correlation between miR-152-3p levels and SOS1 levels was observed in glioblastoma tissues collected from 40 patients. CONCLUSION: Our study identified miR-152-3p as a chemotherapy sensitizer in glioblastoma.