Co-exposure of decabromodiphenyl ethane and cadmium increases toxicity to earthworms: Enrichment, oxidative stress, damage and molecular binding mechanisms.

The increase of electronic waste worldwide has resulted in the exacerbation of combined decabromodiphenyl ethane (DBDPE) and cadmium (Cd) pollution in soil, posing a serious threat to the safety of soil organisms. However, whether combined exposure increases toxicity remains unclear. Therefore, this study primarily investigated the toxic effects of DBDPE and Cd on earthworms at the individual, tissue, and cellular levels under single and combined exposure. The results showed that the combined exposure significantly increased the enrichment of Cd in earthworms by 50.32-90.42 %. The toxicity to earthworms increased with co-exposure, primarily resulting in enhanced oxidative stress, inhibition of growth and reproduction, intensified intestinal and epidermal damage, and amplified coelomocyte apoptosis. PLS-PM analysis revealed a significant and direct relationship between the accumulation of target pollutants in earthworms and oxidative stress, damage, as well as growth and reproduction of earthworms. Furthermore, IBR analysis indicated that SOD and POD were sensitive biomarkers in earthworms. Molecular docking elucidated that DBDPE and Cd induced oxidative stress responses in earthworms through the alteration of the conformation of the two enzymes. This study enhances understanding of the mechanisms behind the toxicity of combined pollution and provides important insights for assessing e-waste contaminated soils.

Five coexisting brominated flame retardants in a water-sediment-Vallisneria system: Bioaccumulation and effects on oxidative stress and photosynthesis.

The pollution of various brominated flame retardants (BFRs) is concurrence, while their environmental fate and toxicology in water-sediment-submerged plant systems remain unclear. In this study, Vallisneria natans plants were co-exposed to 2,3,4,5,6-pentabromotoluene (PBT), hexabromobenzene (HBB), 1,2-bis (2,4,6-tribromophenoxy) ethane (BTBPE), decabromodiphenyl ether (BDE209), and decabromodiphenyl ethane (DBDPE). The ∑BFRs concentration in the root was 2.15 times higher than that in the shoot. Vallisneria natans accumulated more BTBPE and HBB in 0.2, 1, and 5 mg/kg treatments, while they accumulated more DBDPE and BDE209 in 25 and 50 mg/kg treatments. The bioaccumulation factors in the shoot and root were 1.08-96.95 and 0.04-0.70, respectively. BFRs in sediments had a more pronounced effect on bioaccumulation levels than BFRs in water, and biotranslocation was another potential influence factor. The SOD activity, POD activity, and MDA content were significantly increased under co-exposure. The DBDPE separate exposure impacted the metabolism of substances and energy, inhibited mismatch repair, and disrupted ribosomal functions in Vallisneria natans. However, DBDPE enhanced their photosynthesis by upregulating the expression level of genes related to the light reaction. This study provides a broader understanding of the bioaccumulation and toxicity of BFRs in submerged plants, shedding light on the scientific management of products containing BFRs.

Failure evolution and instability prediction of fiber-reinforced polymer-confined cement mortar specimens under axial compression.

In geotechnical engineering, a large number of pillars are often left in underground space to support the overlying strata and protect the surface environment. To enhance pillar stability and prevent instability, this study proposes an innovative technology for pillar reinforcement. Specifically, local confinement of the pillar is achieved through fiber-reinforced polymer (FRP) strips, resulting in the formation of a more stable composite structure. In order to validate the effectiveness of this structural approach, acoustic emission characteristics and surface strain field characteristics were monitored during failure processes, while mathematical models were employed to predict specimen instability. The test results revealed that increasing FRP strip confinement width led to heightened activity in acoustic emission events during failure processes, accompanied by a decrease in shear cracks but an increase in tensile cracks. Moreover, ductility was improved and deformation resistance capacity was enhanced within specimens. Notably, initial crack generation occurred within unconfined regions of specimens during failures; however, both length and width as well as overall numbers of cracks significantly decreased due to implementation of FRP strips. Consequently, specimen failure speed was slowed down accordingly. Finally, the instability of the partial FRP-confined cement mortar could be more accurately predicted based on the model of FRP-confined concrete. It was verified by the test results.

Overexpressing of the GIPC1 protects against pathological cardiac remodelling.

OBJECTIVE: Pathological cardiac remodelling, including cardiac hypertrophy and fibrosis, is a key pathological process in the development of heart failure. However, effective therapeutic approaches are limited. The ß-adrenergic receptors are pivotal signalling molecules in regulating cardiac function. G-alpha interacting protein (GAIP)-interacting protein, C-terminus 1 (GIPC1) is a multifunctional scaffold protein that directly binds to the C-terminus of ß1-adrenergic receptor (ß1-adrenergic receptor). However, little is known about its roles in heart function. Therefore, we investigated the role of GIPC1 in cardiac remodelling and its underlying molecular mechanisms. METHODS: Pathological cardiac remodelling in mice was established via intraperitoneal injection of isoprenaline for 14 d or transverse aortic constriction surgery for 8 weeks. Myh6-driving cardiomyocyte-specific GIPC1 conditional knockout (GIPC1 cKO) mice and adeno-associated virus 9 (AAV9)-mediated GIPC1 overexpression mice were used. The effect of GIPC1 on cardiac remodelling was assessed using echocardiographic, histological, and biochemical analyses. RESULTS: GIPC1 expression was consistently reduced in the cardiac remodelling model. GIPC1 cKO mice exhibited spontaneous abnormalities, including cardiac hypertrophy, fibrosis, and systolic dysfunction. In contrast, AAV9-mediated GIPC1 overexpression in the heart attenuated isoproterenol-induced pathological cardiac remodelling in mice. Mechanistically, GIPC1 interacted with the ß1-adrenergic receptor and stabilised its expression by preventing its ubiquitination and degradation, maintaining the balance of ß1-adrenergic receptor/ß2-adrenergic receptor, and inhibiting hyperactivation of the mitogen-activated protein kinase signalling pathway. CONCLUSIONS: These results suggested that GIPC1 plays a cardioprotective role and is a promising therapeutic target for the treatment of cardiac remodelling and heart failure.

Toxicity of decabromodiphenyl ethane on lettuce: Evaluation through growth, oxidative defense, microstructure, and metabolism.

Decabromodiphenyl ethane (DBDPE) as the most widely used novel brominated flame retardants (NBFRs), has become a ubiquitous emerging pollutant in the environment. However, its toxic effects on vegetable growth during agricultural production have not been reported. In this study, we investigated the response mechanisms of hydroponic lettuce to DBDPE accumulation, antioxidant stress, cell structure damage, and metabolic pathways after exposure to DBDPE. The concentration of DBDPE in the root of lettuce was significantly higher than that in the aboveground part. DBDPE induced oxidative stress on lettuce, which stimulated the defense of the antioxidative system of lettuce cells, and the cell structure produced slight plasma-wall separation. In terms of metabolism, metabolic pathway disorders were caused, which are mainly manifested as inhibiting amino acid biosynthesis and metabolism-related pathways, interfering with the biosyntheses of amino acids, organic acids, fatty acids, carbohydrates, and other substances, and ultimately manifested as decreased total chlorophyll content and root activity. In turn, metabolic regulation alleviated antioxidant stress. The mechanisms of the antioxidative reaction of lettuce to DBDPE were elucidated by IBR, PLS-PM analysis, and molecular docking. Our results provide a theoretical basis and research necessity for the evaluation of emerging pollutants in agricultural production and the safety of vegetables.

Insight into Bioaccumulation of Decabromodiphenyl Ethane in Eisenia fetida Increased by Microplastics.

The rise of electronics inevitably induced the co-pollution of novel brominated flame retardants (NBFRs) and microplastics (MPs). However, studies on how they interact to influence their bioavailability are scarce. Here, we explored the influence mechanism of acrylonitrile butadiene styrene (ABS)-MPs on the bioaccumulation of decabromodiphenyl ethane (DBDPE) in soil-earthworm microcosms. The influence exhibited a temporal pattern characterized by short-term inhibition and long-term promotion. After 28 days of exposure, DBDPE bioaccumulation in a co-exposure (10 mg kg-1 DBDPE accompanied by 1000 mg kg-1 ABS-MPs) was 2.61 times higher than that in a separate exposure. The adsorption process in the soil, intestines, and mucus introduced DBDPE-carried MPs, which had a higher concentration of DBDPE than the surrounding soil and directly affected the bioavailability of DBDPE. MP-pre-exposure (100, 1000, and 10000 mg kg-1) reduced epidermal soundness, mucus secretion, and worm cast production. This eventually promoted the contact between earthworm and soil particles and enhanced the DBDPE of earthworm tissue by 6%-61% in the next DBDPE-postexposure period, confirming that MPs increased DBDPE bioaccumulation indirectly by impairing the earthworm health. This study indicates that MPs promoted DBDPE bioaccumulation via adsorption and self-toxicity, providing new insight into the combined risk of MPs and NBFRs.

Contamination characteristics and potential health risk of brominated flame retardants in paddy soils and rice plants around a typical e-waste recycling site in south China.

Brominated flame retardants (BFRs) are widely used in various productions. As typical BFRs, polybrominated diphenyl ethers (PBDEs) are prohibited because of their toxicity and persistence. Some of the alternatives to PBDEs, new brominated flame retardants (NBFRs), have also been found in the environment and some have assigned hazardous properties and were categorized as persistent. In this study, a typical e-waste dismantling area was chosen as the study area, and the soil and rice samples were collected from the paddy fields around the circular economy park in Guiyu, China. The contaminations of PBDEs and NBFRs in soils and rice plants were detected, and the health risks associated with consumption and exposure to the environment were calculated as well. The concentrations of ∑PBDEs and ∑NBFRs in soil ranged from 283 to 928 µg/kg and 54.7-437 µg/kg, respectively. In rice plants, the majority of BFRs were concentrated in the following order: root > leaf > stem > grain. Additionally, only the PBT exhibited a stronger bioaccumulation ability in rice with the bioconcentration factors more than 1.00. The results of the health quotient calculation shown that BDE-47 might have an impact on people's health that only the HQ of BDE-47 in the soil was higher than 1.00, while there had no significant health risk in grain of BFRs. We believe that our work could assist researchers in investigating and revealing the human health effects of BFRs in soil and rice.

Acrylonitrile butadiene styrene microplastics aggravate the threat of decabromodiphenyl ethane to Eisenia fetida: Bioaccumulation, tissue damage, and transcriptional responses.

Little is known about how brominated flame retardants (NBFRs) and microplastics (MPs) co-pollution influences soil organisms. Here, we investigated the impacts of acrylonitrile butadiene styrene (ABS)-MPs in soil on the 28-d dynamic bioaccumulation, tissue damage, and transcriptional responses of decabromodiphenyl ethane (DBDPE) in Eisenia fetida by simulating different pollution scenarios (10 mg kg-1 DBDPE, 10 mg kg-1 DBDPE accompanied by 0.1 % ABS-MPs, and 10 mg kg-1 DBDPE accompanied by 0.1 % ABS-resin). The results show ABS resin did not influence DBDPE bioaccumulation or distribution, but ABS-MPs, particularly 74-187 µm size of MPs, prolonged DBDPE equilibrium time and significantly promoted DBDPE bioaccumulation in tissue (1.76-2.38 folds) and epidermis (2.72-3.34 folds). However, ABS-MPs and ABS-resin reduced DBDPE concentrations of intestines by 22.2-30.6 % and 37.3 %, respectively. DBDPE-MPs caused more serious epidermis and intestines damages than DBDPE. Additionally, compared to the control, DBDPE significantly up-regulated 1957 genes and down-regulated 2203 genes; meanwhile, DBDPE-MPs up-regulated 1475 genes and down-regulated 2231 genes. DBDPE and DBDPE-MPs both regulated lysosome, phagosome, and apoptosis as the top 3 enriched pathways, while DBDPE-MPs specifically regulated signaling pathways and compound metabolism. This study demonstrated that the presence of ABS-MPs aggravated the biotoxicity of DBDPE, providing scientific information for assessing the ecological risks of MPs and additives from e-waste in soil.

miR-135 protects against atrial fibrillation by suppressing intracellular calcium-mediated NLRP3 inflammasome activation.

Atrial fibrillation (AF), one of the most common types of arrhythmias, is associated with high morbidity and mortality, seriously endangering human health. Inflammation is closely associated with AF development. Activation of the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in cardiomyocytes has been shown to promote AF progression. Here, we demonstrate the effect of miR-135 on NLRP3 inflammasome and study the cardioprotective role of miR-135 in AF. We observed that overexpression of miR-135 in mice reduced the AF incidence and duration, and inhibited both excessive activation of NLRP3 inflammasome and the increased intracellular calcium release during AF. However, the inhibitory effect of miR-135 on AF was partly abolished in the presence of a specific agonist of the calcium-sensing receptor (CaSR). We showed in the present study that miR-135 has a protective effect against AF by suppressing intracellular calcium-mediated NLRP3 inflammasome activation, suggesting the potential of miR-135 as a therapeutic agent in the treatment of AF.

Polylactic acid microplastics induce higher biotoxicity of decabromodiphenyl ethane on earthworms (Eisenia fetida) compared to polyethylene and polypropylene microplastics.

Decabromodiphenyl ethane (DBDPE) and microplastics (MPs), such as fossil-based polymers polyethylene (PE), polypropylene (PP), and bio-based plastics polylactic acid (PLA) are abundant in e-waste dismantling areas. However, the information on the effects of DBDPE combined with MPs (DBDPE-MPs) on earthworms is still limited. In this study, we explored the impacts of DBDPE-MPs on neurotoxic biomarkers, tissue damage, and transcriptomics of Eisenia fetida by simulating different exposure patterns of 10 mg kg-1 DBDPE and 10 mg kg-1 DBDPE-MPs (PLA, PP, and PE). Results showed that the activities of acetylcholinesterase, Na+/K+-ATPase, Ca2+/Mg2+-ATPase, carboxylate enzyme, and the contents of calcium and glutamate were significantly stimulated. DBDPE-MP co-exposure caused more severe damage to the epidermis, muscles, and tissues. Transcriptomic analysis revealed that differentially expressed genes (DEGs) of DBDPE-MPs were mainly related to inflammation, the immune system, digestive system, endocrine system, and metabolism. DBDPE and PP-MPs had similar influences on immunity and metabolism. However, DBDPE-PLA and DBDPE-PE further affected the endocrine system and signaling pathways. Specific DEGs showed that detoxification systems in the case of MPs were significantly upregulated. The study indicated that MPs exacerbated DBDPE toxicity in the nervous system, epidermis, and gene regulation of E. fetida, helping to assess the ecological risks of e-wastes and microplastics in soil.

Enrichment and removal of five brominated flame retardants in the presence of co-exposure in a soil-earthworm system.

Brominated flame retardants (BFRs) are widely used because of their excellent flame retardant performance and are frequently detected in the soil environment. Their adverse impacts on soil organisms cannot be ignored. The enrichment and removal dynamics of the five BFRs (pentabromotoluene (PBT), hexabromobenzene (HBB), 1,2-bis(2,4,6-tribromophenoxy) ethane (BTBPE), decabromodiphenyl ethane (DBDPE), and decabromodiphenyl ether (BDE209)) in earthworms and different tissues (epidermis, intestinal tract, and cast) in the presence of co-exposure were explored for the first time. The results showed that the enrichment of the five BFRs in earthworms increased with increasing exposure concentration and time. The distribution of these chemicals in different tissues of earthworms was different. The contents of HBB and PBT in the intestine and epidermis were the highest and were more than 60% during most of the time. Additionally, the contents of BTBPE, BDE209, and DBDPE were significantly increased while the contents of HBB and PBT were significantly decreased in the cast. The correlation analysis indicated that HBB and PBT had a significant relationship in all the tissues, but BDE209 and DBDPE only had a relationship in the cast, which might be attributed to the structure of the pollutants. Additionally, the experiments illustrated that earthworms had strong removal for HBB and PBT, but were weak for DBDPE and BDE209.

Daming capsule protects against myocardial infarction by promoting mitophagy via the SIRT1/AMPK signaling pathway.

Myocardial infarction (MI) is a myocardial injury caused by coronary thrombosis or persistent ischemia and hypoxia. Due to its high morbidity and mortality, a safer and more effective treatment strategy is urgently needed. Daming capsule (DMC), a hypolipidemic drug, reportedly exerts cardioprotective effects in clinical and basic research, although its protective mechanism remains unknown. To investigate the mechanism underlying DMC-mediated improvement of cardiac function post-MI, C57/BL6 mice subjected to coronary artery ligation were administered DMC for 4 weeks. Our data demonstrated that DMC significantly improved cardiac structure and function compared to the saline group. Moreover, DMC inhibited inflammatory response and oxidative stress and improved mitochondrial structure and function in MI mice and hypoxia-stressed cardiomyocytes. Next, our research proved that DMC increased the expression of mitophagy receptor NLRX1. Interestingly, with the administration of DMC and siNLRX1, NLRX1 expression, mitochondria and lysosome colocalization, and mitochondrial membrane potential decreased, while mitochondrial ROS accumulation increased, suggesting that DMC promoted mitophagy to improve mitochondrial function via NLRX1 regulation. Further analysis showed that DMC activated the SIRT1/AMPK signaling pathway in vivo and in vitro. Our data showed that SIRT1 knockdown downregulated NLRX1 expression, leading to structural damage and functional impairment in mitochondria, as well as increased oxidative stress, inflammatory response, and decreased cardiac function in MI mice. Collectively, our findings reveal that DMC improves cardiac function post-MI by increasing mitophagy and inhibiting oxidative stress and inflammotory response in cardiomyocytes through the SIRT1/AMPK signaling pathway.

In-situ synthesis of Cu2O on cotton fibers with antibacterial properties and reusable photocatalytic degradation of dyes.

In this study, the cotton fabrics/cuprous oxide-nanocellulose (Cu2O-NC) flexible and recyclable composite material (COCO) with highly efficient photocatalytic degradation of dyes and antibacterial properties was fabricated. Using flexible cotton fabrics as substrates, Cu2O were in-situ synthesized to make Cu2O uniformly grew on cotton fibers and were wrapped with NC. The photocatalytic degradation ability of COCO-5 was verified by use methylene blue (MB), the degradation rate was as high as 98.32%. The mechanism of COCO-5 photocatalysis and the process of dye degradation were analyzed by using electron paramagnetic resonance (EPR) spectrum, transient photocurrent response (TPR) spectrum, Fourier transform infrared (FTIR) spectroscopy and ion chromatography (IC). This study analyzed the complete path from electron excitation to dye degradation to harmless small molecules. Qualitative and quantitative experiments demonstrate that COCO-5 has high antibacterial activity against S. aureus and E. coli, the highest antibacterial rate can reach 93.25%. Finally, the stability of COCO-5 was verified by recycling and mechanical performance tests. The textile-based Cu2O functionalized material has photocatalytic degradation and antibacterial properties, and the preparation process is simple and convenient for repeated use, so it has great potential in wastewater treatment containing dyes and bacteria.

Knockdown of endogenous RNF4 exacerbates ischaemia-induced cardiomyocyte apoptosis in mice.

RNF4, a poly-SUMO-specific E3 ubiquitin ligase, is associated with protein degradation, DNA damage repair and tumour progression. However, the effect of RNF4 in cardiomyocytes remains to be explored. Here, we identified the alteration of RNF4 from ischaemic hearts and oxidative stress-induced apoptotic cardiomyocytes. Upon myocardial infarction (MI) or H2 O2 /ATO treatment, RNF4 increased rapidly and then decreased gradually. PML SUMOylation and PML nuclear body (PML-NB) formation first enhanced and then degraded upon oxidative stress. Reactive oxygen species (ROS) inhibitor was able to attenuate the elevation of RNF4 expression and PML SUMOylation. PML overexpression and RNF4 knockdown by small interfering RNA (siRNA) enhanced PML SUMOylation, promoted p53 recruitment and activation and exacerbated H2 O2 /ATO-induced cardiomyocyte apoptosis which could be partially reversed by knockdown of p53. In vivo, knockdown of endogenous RNF4 via in vivo adeno-associated virus infection deteriorated post-MI structure remodelling including more extensive interstitial fibrosis and severely fractured and disordered structure. Furthermore, knockdown of RNF4 worsened ischaemia-induced cardiac dysfunction of MI models. Our results reveal a novel myocardial apoptosis regulation model that is composed of RNF4, PML and p53. The modulation of these proteins may provide a new approach to tackling cardiac ischaemia.

In situ study on interactions between hydroxyl groups in kaolinite and re-adsorption water.

The interactions between O-H groups in kaolinite and re-adsorption water is an important aspect that should be considered in the hydraulic fracturing method for the production of shale gas, because the external water adsorbed by kaolinite in shale would significantly affect the desorption of methane. In this study, the interactions were investigated via changing the amount of O-H groups and re-adsorption water in kaolinite by heating treatment and water re-adsorption. To overcome the overlap of IR vibration bands of the O-H functional groups in H2O and those in parent kaolinite, kaolinite samples with D2O re-adsorption were prepared by drying the H2O from raw kaolinite and soaking the dried kaolinite in D2O. The interactions between O-H groups in kaolinite and D2O molecules were investigated by in situ DRIFT and TG-MS. The results demonstrated that the vibration at 3670 ± 4 cm-1 in the DRIFT spectra could be due to the outer O-H groups of the octahedral sheet on the upper surface of the kaolinite microcrystal structure, rather than a type of inner-surface O-H group. All types of O-H groups, including the inner O-H groups in kaolinite, could be transformed into O-D groups after D2O re-adsorption at room temperature. The inner-surface O-H groups in kaolinite are the most preferred sites for D2O re-adsorption; thus, they would be the key factor for studying the effect of re-adsorption water on methane desorption. When the temperature increased from 100 °C to 300 °C, two layers of kaolinite slipped away from each other, resulting in the transformation of inner-surface O-H groups into outer O-H groups. Thus, the temperature range of 100 to 300 °C was suggested for the heat treatment of kaolinite to decrease the content of inner-surface O-H groups; thereby, the amount of re-adsorption water was reduced. However, to thoroughly remove the re-adsorption water, a temperature higher than 650 °C should be used.

TGF-ß1-PML SUMOylation-peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) form a positive feedback loop to regulate cardiac fibrosis.

Transforming growth factor-ß (TGF-ß) signaling pathway is involved in fibrosis in most, if not all forms of cardiac diseases. Here, we evaluate a positive feedback signaling the loop of TGF-ß1/promyelocytic leukemia (PML) SUMOylation/Pin1 promoting the cardiac fibrosis. To test this hypothesis, the mice underwent transverse aortic constriction (3 weeks) were developed and the morphological evidence showed obvious interstitial fibrosis with TGF-ß1, Pin1 upregulation, and increase in PML SUMOylation. In neonatal mouse cardiac fibroblasts (NMCFs), we found that exogenous TGF-ß1 induced the upregulation of TGF-ß1 itself in a time- and dose-dependent manner, and also triggered the PML SUMOylation and the formation of PML nuclear bodies (PML-NBs), and consequently recruited Pin1 into nuclear to colocalize with PML. Pharmacological inhibition of TGF-ß signal or Pin1 with LY364947 (3 µM) or Juglone (3 µM), the TGF-ß1-induced PML SUMOylation was reduced significantly with downregulation of the messenger RNA and protein for TGF-ß1 and Pin1. To verify the cellular function of PML by means of gain- or loss-of-function, the positive feedback signaling loop was enhanced or declined, meanwhile, TGF-ß-Smad signaling pathway was activated or weakened, respectively. In summary, we uncovered a novel reciprocal loop of TGF-ß1/PML SUMOylation/Pin1 leading to myocardial fibrosis.

Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates cardiac fibrosis induced by myocardial infarction in mice.

BACKGROUND AND PURPOSE: Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). EXPERIMENTAL APPROACH: GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function. Expression of SUMO-1, PML, TGF-ß1 and Pin1 was measured with Western blot or Real-time PCR. Collagen content, cell viability and myofibroblast transformation were measured in neonatal mouse cardiac fibroblasts (NMCFs). Promyelocytic leukemia (PML) protein was over-expressed by plasmid transfection. KEY RESULTS: GA improved cardiac fibrosis and dysfunction, and decreased SUMO-1 expression in MI mice. GA (>20 µM) inhibited NMCF viability in a dose-dependent manner. Nontoxic GA (10 µM) restrained angiotensin II (Ang II)-induced myofibroblast transformation and collagen production. GA also inhibited expression of TGF-ß1 mRNA and protein in vitro and in vivo. GA suppressed PML SUMOylation and PML nuclear body (PML-NB) organization, and disrupted expression and recruitment of Pin1 (a positive regulator of TGF-ß1 mRNA), whereas over-expression of PML reversed that. CONCLUSIONS AND IMPLICATIONS: Inhibition of SUMO-1 by GA alleviated MI-induced heart dysfunction and fibrosis, and the SUMOylated PML/Pin1/TGF-ß1 pathway is crucial for GA-inhibited cardiac fibrosis.

Transforming Growth Factor-ß Receptor III is a Potential Regulator of Ischemia-Induced Cardiomyocyte Apoptosis.

BACKGROUND: Myocardial infarction (MI) is often accompanied by cardiomyocyte apoptosis, which decreases heart function and leads to an increased risk of heart failure. The aim of this study was to examine the effects of transforming growth factor-ß receptor III (TGFßR3) on cardiomyocyte apoptosis during MI. METHODS AND RESULTS: An MI mouse model was established by left anterior descending coronary artery ligation. Cell viability, apoptosis, TGFßR3, and mitogen-activated protein kinase signaling were assessed by methylthiazolyldiphenyl-tetrazolium bromide assay, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay, immunofluorescence, electron microscopy, and Western blotting. Our results demonstrated that TGFßR3 expression in the border region of the heart was dynamically changed during MI. After stimulation with H2O2, TGFßR3 overexpression in cardiomyocytes led to increased cell apoptosis and activation of p38 signaling, whereas TGFßR3 knockdown had the opposite effect. ERK1/2 and JNK1/2 signaling was not altered by TGFßR3 modulation, and p38 inhibitor (SB203580) reduced the effect of TGFßR3 on apoptosis, suggesting that p38 has a nonredundant function in activating apoptosis. Consistent with the in vitro observations, cardiac TGFßR3 transgenic mice showed augmented cardiomyocyte apoptosis, enlarged infarct size, increased injury, and enhanced p38 signaling upon MI. Conversely, cardiac loss of function of TGFßR3 by adeno-associated viral vector serotype 9-TGFßR3 short hairpin RNA attenuated the effects of MI in mice. CONCLUSIONS: TGFßR3 promotes apoptosis of cardiomyocytes via a p38 pathway-associated mechanism, and loss of TGFßR3 reduces MI injury, which suggests that TGFßR3 may serve as a novel therapeutic target for MI.