BRG1 Deficiency Promotes Cardiomyocyte Inflammation and Apoptosis by Activating the cGAS-STING Signaling in Diabetic Cardiomyopathy.

Brahma-related gene 1 (BRG1) has been implicated in the repair of DNA double-strand breaks (DSBs). Downregulation of BRG1 impairs DSBs repair leading to accumulation of double-stranded DNA (dsDNA). Currently, the role of BRG1 in diabetic cardiomyopathy (DCM) has not been clarified. In this study, we aimed to explore the function and molecular by which BRG1 regulates DCM using mice and cell models. We found that BRG1 was downregulated in the cardiac tissues of DCM mice and in cardiomyocytes cultured with high glucose and palmitic acid (HG/PA), which was accompanied by accumulation of dsDNA and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling pathway. shRNA-mediated Brg1 knockdown aggravated DCM mice cardiac functions, enhanced dsDNA accumulation, cGAS-STING signaling activation, which induced inflammation and apoptosis. In addition, the results were further verified in HG/PA-treated primary neonatal rat cardiomyocytes (NRCMs). Overexpression of BRG1 in NRCMs yielded opposite results. Furthermore, a selective cGAS inhibitor RU.521 or STING inhibitor C-176 partially reversed the BRG1 knockdown-induced inflammation and apoptosis in vitro. In conclusion, our results demonstrate that BRG1 is downregulated during DCM in vivo and in vitro, resulting in cardiomyocyte inflammation and apoptosis due to dsDNA accumulation and cGAS-STING signaling activation. Therefore, targeting the BRG1-cGAS-STING pathway may represent a novel therapeutic strategy for improving cardiac function of patients with DCM.

Molecular mechanisms of metabolic dysregulation in diabetic cardiomyopathy.

Diabetic cardiomyopathy (DCM), one of the most serious complications of diabetes mellitus, has become recognized as a cardiometabolic disease. In normoxic conditions, the majority of the ATP production (>95%) required for heart beating comes from mitochondrial oxidative phosphorylation of fatty acids (FAs) and glucose, with the remaining portion coming from a variety of sources, including fructose, lactate, ketone bodies (KB) and branched chain amino acids (BCAA). Increased FA intake and decreased utilization of glucose and lactic acid were observed in the diabetic hearts of animal models and diabetic patients. Moreover, the polyol pathway is activated, and fructose metabolism is enhanced. The use of ketones as energy sources in human diabetic hearts also increases significantly. Furthermore, elevated BCAA levels and impaired BCAA metabolism were observed in the hearts of diabetic mice and patients. The shift in energy substrate preference in diabetic hearts results in increased oxygen consumption and impaired oxidative phosphorylation, leading to diabetic cardiomyopathy. However, the precise mechanisms by which impaired myocardial metabolic alterations result in diabetes mellitus cardiac disease are not fully understood. Therefore, this review focuses on the molecular mechanisms involved in alterations of myocardial energy metabolism. It not only adds more molecular targets for the diagnosis and treatment, but also provides an experimental foundation for screening novel therapeutic agents for diabetic cardiomyopathy.

CcpA-Knockout Staphylococcus aureus Induces Abnormal Metabolic Phenotype via the Activation of Hepatic STAT5/PDK4 Signaling in Diabetic Mice.

Catabolite control protein A (CcpA), an important global regulatory protein, is extensively found in S. aureus. Many studies have reported that CcpA plays a pivotal role in regulating the tricarboxylic acid cycle and pathogenicity. Moreover, the CcpA-knockout Staphylococcus aureus (S. aureus) in diabetic mice, compared with the wild-type, showed a reduced colonization rate in the tissues and organs and decreased inflammatory factor expression. However, the effect of CcpA-knockout S. aureus on the host's energy metabolism in a high-glucose environment and its mechanism of action remain unclear. S. aureus, a common and major human pathogen, is increasingly found in patients with obesity and diabetes, as recent clinical data reveal. To address this issue, we generated CcpA-knockout S. aureus strains with different genetic backgrounds to conduct in-depth investigations. In vitro experiments with high-glucose-treated cells and an in vivo model study with type 1 diabetic mice were used to evaluate the unknown effect of CcpA-knockout strains on both the glucose and lipid metabolism phenotypes of the host. We found that the strains caused an abnormal metabolic phenotype in type 1 diabetic mice, particularly in reducing random and fasting blood glucose and increasing triglyceride and fatty acid contents in the serum. In a high-glucose environment, CcpA-knockout S. aureus may activate the hepatic STAT5/PDK4 pathway and affect pyruvate utilization. An abnormal metabolic phenotype was thus observed in diabetic mice. Our findings provide a better understanding of the molecular mechanism of glucose and lipid metabolism disorders in diabetic patients infected with S. aureus.

Interfacial Water Stability between Modified Phosphogypsum Asphalt Mortar and Aggregate Based on Molecular Dynamics.

The objective of this study is to unravel the modification mechanism of a coupling agent on the water sensitivity of phosphogypsum asphalt mortar. The adhesion process of phosphogypsum asphalt mastic modified with three kinds of coupling agents (KH-550, KH-570, and CS-101) and raw phosphogypsum to the aggregate minerals was simulated based on the molecular dynamics software, Materials Studio 2020, and the water film layer was considered along the simulation. When the three coupling agents were added, the interfacial adhesion work gradually increased with the increase of modified phosphogypsum dosage, and the trends of each model were relatively similar. With the increase of simulation time, the mean square displacement of water molecules of the three interfacial models showed different trends, and the increasing trend rank was unmodified phosphogypsum > KH-550 > KH-570 > CS-101. The diffusion coefficient of the water molecular layer of asphalt mastic modified with CS-101 coupling agent in phosphogypsum shows a significant decrease with the increase of CS-101-modified phosphogypsum (more than 5% mass ratio to asphalt). Compared to raw phosphogypsum asphalt mortar, the addition of coupling agents can significantly limit the diffusion of water molecules and effectively improve the interfacial adhesion work, in which CS-101 coupling agent has the best effect, followed by KH-570 and KH-550.

Methazolamide Attenuates the Development of Diabetic Cardiomyopathy by Promoting ß-Catenin Degradation in Type 1 Diabetic Mice.

Methazolamide (MTZ), a carbonic anhydrase inhibitor, has been shown to inhibit cardiomyocyte hypertrophy and exert a hypoglycemic effect in patients with type 2 diabetes and diabetic db/db mice. However, whether MTZ has a cardioprotective effect in the setting of diabetic cardiomyopathy is not clear. We investigated the effects of MTZ in a mouse model of streptozotocin-induced type 1 diabetes mellitus (T1DM). Diabetic mice received MTZ by intragastric gavage (10, 25, or 50 mg/kg, daily for 16 weeks). In the diabetic group, MTZ significantly reduced both random and fasting blood glucose levels and improved glucose tolerance in a dose-dependent manner. MTZ ameliorated T1DM-induced changes in cardiac morphology and dysfunction. Mechanistic analysis revealed that MTZ blunted T1DM-induced enhanced expression of ß-catenin. Similar results were observed in neonatal rat cardiomyocytes (NRCMs) and adult mouse cardiomyocytes treated with high glucose or Wnt3a (a ß-catenin activator). There was no significant change in ß-catenin mRNA levels in cardiac tissues or NRCMs. MTZ-mediated ß-catenin downregulation was recovered by MG132, a proteasome inhibitor. Immunoprecipitation and immunofluorescence analyses showed augmentation of AXIN1-ß-catenin interaction by MTZ in T1DM hearts and in NRCMs treated with Wnt3a; thus, MTZ may potentiate AXIN1-ß-catenin linkage to increase ß-catenin degradation. Overall, MTZ may alleviate cardiac hypertrophy by mediating AXIN1-ß-catenin interaction to promote degradation and inhibition of ß-catenin activity. These findings may help inform novel therapeutic strategy to prevent heart failure in patients with diabetes.

Bactericidal Effect of Pseudomonas oryziphila sp. nov., a Novel Pseudomonas Species Against Xanthomonas oryzae Reduces Disease Severity of Bacterial Leaf Streak of Rice.

Pseudomonas is a diverse genus of Gammaproteobacteria with increasing novel species exhibiting versatile trains including antimicrobial and insecticidal activity, as well as plant growth-promoting, which make them well suited as biocontrol agents of some pathogens. Here we isolated strain 1257 that exhibited strong antagonistic activity against two pathovars of Xanthomonas oryzae, especially X. oryzae pv. oryzicola (Xoc) responsible for the bacterial leaf streak (BLS) in rice. The phylogenetic, genomic, physiological, and biochemical characteristics support that strain 1257 is a representative of a novel Pseudomonas species that is most closely related to the entomopathogenic bacterium Pseudomonas entomophila. We propose to name it Pseudomonas oryziphila sp. nov. Comparative genomics analyses showed that P. oryziphila 1257 possesses most of the central metabolic genes of two closely related strains P. entomophila L48 and Pseudomonas mosselii CFML 90-83, as well as a set of genes encoding the type IV pilus system, suggesting its versatile metabolism and motility properties. Some features, such as insecticidal toxins, phosphate solubilization, indole-3-acetic acid, and phenylacetic acid degradation, were disclosed. Genome-wide random mutagenesis revealed that the non-ribosomal peptide catalyzed by LgrD may be a major active compound of P. oryziphila 1257 against Xoc RS105, as well as the critical role of the carbamoyl phosphate and the pentose phosphate pathway that control the biosynthesis of this target compound. Our findings demonstrate that 1257 could effectively inhibit the growth and migration of Xoc in rice tissue to prevent the BLS disease. To our knowledge, this is the first report of a novel Pseudomonas species that displays a strong antibacterial activity against Xoc. The results suggest that the P. oryziphila strain could be a promising biological control agent for BLS.

An improved, versatile and efficient modular plasmid assembly system for expression analyses of genes in Xanthomonas oryzae.

Xanthomonas oryzae pathovars oryzae (Xoo) and oryzicola (Xoc) infect rice, causing bacterial blight and bacterial leaf streak, respectively, which are two economically important bacterial diseases in paddy fields. The interactions of Xoo and Xoc with rice can be used as models for studying fundamental aspects of bacterial pathogenesis and host tissue specificity. However, an improved vector system for gene expression analysis is desired for Xoo and Xoc because some broad host range vectors that can replicate stably in X. oryzae pathovars are low-copy number plasmids. To overcome this limitation, we developed a modular plasmid assembly system to transfer the functional DNA modules from the entry vectors into the pHM1-derived backbone vectors on a high-copy number basis. We demonstrated the feasibility of our vector system for protein detection, and quantification of virulence gene expression under laboratory conditions and in association with host rice and nonhost tobacco cells. This system also allows execution of a mutant complementation equivalent to the single-copy chromosomal integration system and tracing of pathogens in rice leaf. Based on this assembly system, we constructed a series of protein expression and promoter-probe vectors suitable for classical double restriction enzyme cloning. These vector systems enable cloning of all genes or promoters of interest from Xoo and Xoc strains. Our modular assembly system represents a versatile and highly efficient toolkit for gene expression analysis that will accelerate studies on interactions of X. oryzae with rice.

Role of Hippo-YAP1/TAZ pathway and its crosstalk in cardiac biology.

The Hippo pathway undertakes a pivotal role in organ size control and the process of physiology and pathology in tissue. Its downstream effectors YAP1 and TAZ receive upstream stimuli and exert transcription activity to produce biological output. Studies have demonstrated that the Hippo pathway contributes to maintenance of cardiac homeostasis and occurrence of cardiac disease. And these cardiac biological events are affected by crosstalk among Hippo-YAP1/TAZ, Wnt/ß-catenin, Bone morphogenetic protein (BMP) and G-protein-coupled receptor (GPCR) signaling, which provides new insights into the Hippo pathway in heart. This review delineates the interaction among Hippo, Wnt, BMP and GPCR pathways and discusses the effects of these pathways in cardiac biology.

Effect of long-term treatment of Carvacrol on glucose metabolism in Streptozotocin-induced diabetic mice.

BACKGROUND: Carvacrol is a food additive with various bioactivities, including reducing the blood glucose level as well as improvement of heart function, in diabetic mice. We explored the antihyperglycemic effect of carvacrol and its effect on the key hepatic enzymes accounting for glucose metabolism. METHODS: A streptozotocin (STZ)-induced diabetes-mellitus model in mice was used. Mice were divided randomly into a control group, diabetic group, low dose carvacrol-treated diabetic group (10 mg/kg body weight [BW]), and high dose carvacrol-treated diabetic group (20 mg/kg BW). Carvacrol was injected intraperitoneally (i.p.) in each carvacrol-treated group daily for 4 weeks and 6 weeks, respectively. The level of random plasma glucose, fasting plasma glucose, and plasma insulin was determined at 4 weeks and 6 weeks after carvacrol administration. The plasma level of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and the activity of hepatic key enzymes related to glucose metabolism were determined. RESULTS: Carvacrol treatment decreased the levels of random plasma glucose and fasting plasma glucose, significantly in a dose-dependent manner. A significant improvement in glucose tolerance and a significant decrease in the plasma level of TG were observed in carvacrol-treated diabetic mice at a dose of 20 mg/kg BW compared with that in vehicle-treated diabetic mice. There was no significant difference in the plasma level of TC and insulin between vehicle-treated diabetic mice and carvacrol-treated diabetic mice. Carvacrol treatment at a dose of 20 mg/kg BW significantly reduced the plasma level of LDH but not AST, ALT, or ALP, compared with that in the vehicle-treated diabetic group. The activity of hexokinase (HK), 6-phosphofructokinase (PFK), and citrate synthetase (CS) was increased by carvacrol treatment in diabetic mice. CONCLUSIONS: Carvacrol exerted an anti-hyperglycemic effect in STZ-induced diabetic mice. This was achieved through regulating glucose metabolism by increasing the activity of the hepatic enzymes HK, PFK, and CS.

Molecular Mechanism of Hippo-YAP1/TAZ Pathway in Heart Development, Disease, and Regeneration.

The Hippo-YAP1/TAZ pathway is a highly conserved central mechanism that controls organ size through the regulation of cell proliferation and other physical attributes of cells. The transcriptional factors Yes-associated protein 1 (YAP1) and PDZ-binding motif (TAZ) act as downstream effectors of the Hippo pathway, and their subcellular location and transcriptional activities are affected by multiple post-translational modifications (PTMs). Studies have conclusively demonstrated a pivotal role of the Hippo-YAP1/TAZ pathway in cardiac development, disease, and regeneration. Targeted therapeutics for the YAP1/TAZ could be an effective treatment option for cardiac regeneration and disease. This review article provides an overview of the Hippo-YAP1/TAZ pathway and the increasing impact of PTMs in fine-tuning YAP1/TAZ activation; in addition, we discuss the potential contributions of the Hippo-YAP1/TAZ pathway in cardiac development, disease, and regeneration.

Idea Generation and New Direction for Exploitation Technologies of Coal-Seam Gas through Recombinative Innovation and Patent Analysis.

Coal-seam gas (CSG), as an alternative energy, has the characteristics of resource scarcity and technological exploitation complexity. The generation of ideas is vital to develop more efficient exploitation technologies for CSG. Innovative ideas originate from the recombination of existing knowledge elements according to recombinative innovation. The previous literature has focused on exploring an abundance of combinations, which leads to blindness towards idea generation. For this reason, it is critical to search for more valuable matching patterns among the redundant combinations of elements. In line with this concept, this paper proposes a method that consists of three phases: the collection of knowledge elements, the analysis of knowledge element depth and diversity, and the analysis of knowledge element relationships. In this process, we take the patent document as the carrier of knowledge recombination and identify the optimization method in the reorganization process by means of latent Dirichlet allocation (LDA) and association rules. This method is expected to assist in sparking better ideas for CSG exploitation technologies.

Carvacrol Attenuates Diabetic Cardiomyopathy by Modulating the PI3K/AKT/GLUT4 Pathway in Diabetic Mice.

Background: Diabetic cardiomyopathy (DCM), a common complication of diabetes mellitus, eventually leads to heart failure. Carvacrol is a food additive with diverse bioactivities. We aimed to study the protective effects and mechanisms of carvacrol in DCM. Methods: We used a streptozotocin-induced and db/db mouse model of types 1 and 2 diabetes mellitus (T1DM and T2DM), respectively. Both study groups received daily intraperitoneal injections of carvacrol for 6 weeks. Cardiac remodeling was evaluated by histological analysis. We determined gene expression of cardiac remodeling markers (Nppa and Myh7) by quantitative real-time PCR and cardiac function by echocardiography. Changes of PI3K/AKT signaling were determined with Western blotting. GLUT4 translocation was evaluated by Western blotting and immunofluorescence staining. Results: Compared with control mice, both T1DM and T2DM mice showed cardiac remodeling and left ventricular dysfunction. Carvacrol significantly reduced blood glucose levels and suppressed cardiac remodeling in mice with T1DM and T2DM. At the end of the treatment period, both T1DM and T2DM mice showed lesser cardiac hypertrophy, Nppa and Myh7 mRNA expressions, and cardiac fibrosis, compared to mice administered only the vehicle. Moreover, carvacrol significantly restored PI3K/AKT signaling, which was impaired in mice with T1DM and T2DM. Carvacrol increased levels of phosphorylated PI3K, PDK1, AKT, and AS160 and inhibited PTEN phosphorylation in mice with T1DM and T2DM. Carvacrol treatment promoted GLUT4 membrane translocation in mice with T1DM and T2DM. Metformin was used as the positive drug control in T2DM mice, and carvacrol showed comparable effects to that of metformin on cardiac remodeling and modulation of signaling pathways. Conclusion: Carvacrol protected against DCM in mice with T1DM and T2DM by restoring PI3K/AKT signaling-mediated GLUT4 membrane translocation and is a potential treatment of DCM.

Construction of N-halamine labeled silica/zinc oxide hybrid nanoparticles for enhancing antibacterial ability of Ti implants.

The traditional antibiotic treatment for bacterial infections often induces antibiotic resistance in bacteria. In this work, we developed hybrid nanoparticles (NPs) with a self-antibacterial ability on Ti implants using monodispersed polystyrene-acrylic acid (PSA) nanoparticles as colloidal templates followed by the electrostatic adsorption of zinc oxide (ZnO) and the subsequent deposition of silica (SiO2) membrane on the outside. These synthesized PSA-ZnO-SiO2 NPs were pretreated by 5,5-dimethylhydantoin (DMH) before chlorination in a diluted NaClO solution. These nanoparticles (PSA-ZnO-SiO2-DMH) were subsequently labeled by N-halamines and then immobilized on the surface of titanium plates through hydrogen bonding. Field emission scanning electron microscopy (FE-SEM) and X-ray photoelectron spectroscopy (XPS) were utilized to characterize the modified surface. Antibacterial tests disclosed that the PSA-ZnO-SiO2-DMH-Cl NPs modified surface exhibited excellent antibacterial activity against both Pseudomonas aeruginosa (P.au), Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). In vitro cell culture results revealed that PSA-ZnO-SiO2-DMH-Cl had no obvious cytotoxicity for an MC3T3-E1 preosteoblast. This novel surface system provides a promising self-antibacterial bioplatform for metallic implants without using antibiotics.

Towards highly efficient red thermally activated delayed fluorescence materials by the control of intra-molecular π-π stacking interactions.

Thermally activated delayed fluorescence (TADF) materials have attracted much attention as they can achieve 100% theoretical internal quantum efficiency without using expensive noble metals. However, efficient red TADF emitters are hard to realize according to the energy gap law. Here, three donor-acceptor-donor type TADF emitters with the same acceptor of o-phthalodinitrile (PN) but different donors (9, 9-dimethyl-9, 10-dihydroacridine (DMAC), phenoxazine (PXZ), and phenothiazine (PTZ) for DMAC-PN, PXZ-PN, and PTZ-PN, respectively) have been synthesized, and it is observed that the performance of the emitters can be improved by reducing the intra-molecular π-π stacking. DMAC-PN with reduced intra-molecular π-π stacking shows a photoluminescence quantum yield (PLQY) of 20.2% in degassed toluene solution, much higher than those of PXZ-PN, and PTZ-PN (0.8%, 0.2%, respectively). An organic light-emitting diode (OLED) employing DMAC-PN doped into 4,4'-bis(9H-carbazol-9-yl)biphenyl (CBP) as the emitting layer exhibits a maximum external quantum efficiency (EQE) of 10.2% with the emission peak at 564 nm. Moreover, when DMAC-PN is doped into a polar host, bis[2-(diphenylphosphino)phenyl] ether oxide (DPEPO), the OLED shows a large redshift of the emission maximum to 594 nm, while maintaining a peak EQE as high as 7.2%, indicating that efficient red TADF OLEDs can be fabricated by doping orange TADF emitters into hosts with proper polarity.

High-efficiency fluorescent organic light-emitting devices using sensitizing hosts with a small singlet-triplet exchange energy.

Materials with small singlet-triplet splits (ΔEST s) are introduced as sensitizing hosts to excite fluorescent dopants, breaking the trade-off between small ΔEST and high radiative decay rates. A highly efficient orange-fluorescent organic light-emitting diode (OLED) is prepared, showing a maximum external quantum efficiency of 12.2%.