Comprehensive transcriptomics and metabolomics analyses reveal that hyperhomocysteinemia is a high risk factor for coronary artery disease in a chinese obese population aged 40-65: a prospective cross-sectional study.

BACKGROUND: Clinical observations suggest a complex relationship between obesity and coronary artery disease (CAD). This study aimed to characterize the intermediate metabolism phenotypes among obese patients with CAD and without CAD. METHODS: Sixty-two participants who consecutively underwent coronary angiography were enrolled in the discovery cohort. Transcriptional and untargeted metabolomics analyses were carried out to screen for key molecular changes between obese patients with CAD (CAD obese), without CAD (Non-CAD obese), and Non-CAD leans. A targeted GC-MS metabolomics approach was used to further identify differentially expressed metabolites in the validation cohorts. Regression and receiver operator curve analysis were performed to validate the risk model. RESULTS: We found common aberrantly expressed pathways both at the transcriptional and metabolomics levels. These pathways included cysteine and methionine metabolism and arginine and proline metabolism. Untargeted metabolomics revealed that S-adenosylhomocysteine (SAH), 3-hydroxybenzoic acid, 2-hydroxyhippuric acid, nicotinuric acid, and 2-arachidonoyl glycerol were significantly elevated in the CAD obese group compared to the other two groups. In the validation study, targeted cysteine and methionine metabolomics analyses showed that homocysteine (Hcy), SAH, and choline were significantly increased in the CAD obese group compared with the Non-CAD obese group, while betaine, 5-methylpropanedioic acid, S-adenosylmethionine, 4-PA, and vitamin B2 (VB2) showed no significant differences. Multivariate analyses showed that Hcy was an independent predictor of obesity with CAD (hazard ratio 1.7; 95%CI 1.2-2.6). The area under the curve based on the Hcy metabolomic (HCY-Mtb) index was 0.819, and up to 0.877 for the HCY-Mtb.index plus clinical variables. CONCLUSION: This is the first study to propose that obesity with hyperhomocysteinemia is a useful intermediate metabolism phenotype that could be used to identify obese patients at high risk for developing CAD.

Adipose-derived mesenchymal stem cells therapy for acute kidney injury induced by ischemia-reperfusion in a rat model.

Acute kidney injury (AKI) represents a group of complicated syndromes with a high mortality rate. The administration of adipose-derived mesenchymal stem cells (ADMSCs) has been tested as a possible treatment method for AKI. The long-term evaluation of AKI induced by ischemia/reperfusion (IR) and the probable renal protection of ADMSCs are limited. In this study we have established a rat AKI model induced by IR and investigated the possible protective effects of ADMSCs. Adult Sprague-Dawley (SD) rats were divided into three groups (n = 6/each group). The MOCK group was as the normal control. Rats in the IR-AKI and IR-AKI+ADMSCs groups were subjected to IR injury by clamping both renal pedicles for 40 minutes. Rats in the MOCK and IR-AKI groups were injected with PBS via the tail vein as negative treatment controls. Rats in the IR-AKI+ADMSCs group received ADMSCs therapy (2 × 106 cells were injected into the rats via the tail vein). We found that ADMSC transplantation restored the pathologic morphology induced by IR-AKI to normal compared with the MOCK group, suggesting the reparative function of ADMSCs in kidney tissues. Compared with IR-induced AKI alone, ADMSC treatment significantly decreased the number of apoptotic cells, the level of total urinary protein and serum creatinine, the expression of pro-inflammatory cytokines (IL-6, TNF-α, IL-1ß, IFN-γ, TNF-α, IFN-γ, and TGF-ß), and the inflammation-associated proteins (HGF and SDF1), but increased the expression of the anti-inflammatory cytokine, IL-10, and the anti-apoptotic regulator, Bcl-2. Our data have indicated that ADMSC transplantation may protect against IR-induced AKI by anti-apoptotic and anti-inflammatory effects.

Multifunctional Hydrogels with Temperature, Ion, and Magnetocaloric Stimuli-Responsive Performances.

In this work, multifunctional hydrogels with vivid color change and shrinking-swelling response to temperature, ion strength, and alternating magnetic field are fabricated via magnetic assembly. The hydrogels show gradual shift colors from yellowish green to green, cyan, blue, purple, and even reddish violet in response to temperature or ion strength. In the response process, the whole color modulation process is fully reversible and transferable along with a relative short response time. Especially, the magnetism and porous structure of the hybrid hydrogel enable it to be a potential carrier for hydrophobic molecules. Taking advantage of the magnetocaloric responsiveness, the dyed oil loaded hydrogel exhibits a controllable release behavior in each reversible shrinking-swelling cycle under an alternating magnetic field. This multi-responsive hydrogel can hold promise for practical engineering applications, including sensors, displays, and controlled release.

[Multifractal Analysis of Rapeseed Spectrum for Chlorophyll Diagnosis Modeling].

One of the most important topics in crop information science is how to make use of the crop's information for non-destructive nutrient diagnosis which can be solved with spectrum analysis. The canopy's spectrum feature is a key indicator to describe the nutritional status for the rapeseeds. The original spectrum is to be disturbed with external factors such as environment and climate; however, it is difficult to be directly used for rapeseed biomass diagnosis due to its huge fluctuation. However, the multifractal feature of the spectra remains stable relatively. In order to study the relationship between the canopy's spectrum of the rapeseed and its chlorophyll, based on the multifractal theory, a quantitative model of chlorophyll prediction and a qualitative model of planting pattern identification were proposed in this paper to study the high oleic acid rapeseed samples in 24 transplanting regions and 24 direct planting regions. At first, the generalized Hurst exponent and mass exponents together with other relevant multifractal parameters of the spectra were extracted with popular multifractal detrended fluctuation analysis (MF-DFA) in different six considered wavelength ranges. It shows that all of them possess representative multifractal nature. However, there are some differences of the multifractal characteristics between the two kinds of regions with different planting pattern in some bands. In addition, by correlation analysis and detection between the multifractal parameters of the spectra and the SPAD values in six considered ranges of bands, it demonstrates that there is some difference of the effective information content in the different ranges of bands. In the quantitative model of chlorophyll prediction, for each groups of samples in transplanting regions and direct planting regions and mixed together in each significant bands, a selected multifractal parameter was used to establish the univariate model for predicting the rapeseed leaf's SPAD values, respectively. The results of all the relative root mean square errors are small than 5%. Finally, the qualitative model was proposed to distinguish the samples by the two planting pattern. Youden index, as the identification accuracy was calculated for the six considered ranges of bands by the Fisher's linear discriminant analysis. The best Youden index is 0.902 5 and the corresponding band range is 350~1 350 nm. The significant work provides a theoretical and practical method for predicting rapeseed leaf's SPAD and also provides effective way to find the sensitive bands of the spectra for identification diagnosis.

Atorvastatin Attenuates TNF-alpha Production via Heme Oxygenase-1 Pathway in LPS-stimulated RAW264.7 Macrophages.

OBJECTIVE: To assess the effect of atorvastatin on lipopolysaccharide (LPS)-induced TNF-α production in RAW264.7 macrophages. METHODS: RAW264.7 macrophages were treated in different LPS concentrations or at different time points with or without atorvastatin. TNF-α level in supernatant was measured. Expressions of TNF-α mRNA and protein and heme oxygenase-1 (HO-1) were detected by ELISA, PCR, and Western blot, respectively. HO activity was assayed. RESULTS: LPS significantly increased the TNF-α expression and secretion in a dose- and time-dependent manner. The HO-1 activity and HO-1 expression level were significantly higher after atorvastatin treatment than before atorvastatin treatment and attenuated by SB203580 and PD98059 but not by SP600125, suggesting that the ERK and p38 mitogen-activated protein kinase (MAPK) pathways participate in regulating the above-mentioned effects of atorvastatin. Moreover, the HO-1 activity suppressed by SnPP or the HO-1 expression inhibited by siRNA significantly attenuated the effect of atorvastatin on TNF-α expression and production in LPS-stimulated macrophages. CONCLUSION: Atorvastatin can attenuate LPS-induced TNF-α expression and production by activating HO-1 via the ERK and p38 MAPK pathways, suggesting that atorvastatin can be used in treatment of inflammatory diseases such as sepsis, especially in those with atherosclerotic diseases.

Structuring and Shaping of Mechanically Robust and Functional Hydrogels toward Wearable and Implantable Applications.

Hydrogels possess unique features such as softness, wetness, responsiveness, and biocompatibility, making them highly suitable for biointegrated applications that have close interactions with living organisms. However, conventional man-made hydrogels are usually soft and brittle, making them inferior to the mechanically robust biological hydrogels. To ensure reliable and durable operation of biointegrated wearable and implantable devices, mechanical matching and shape adaptivity of hydrogels to tissues and organs are essential. Recent advances in polymer science and processing technologies have enabled mechanical engineering and shaping of hydrogels for various biointegrated applications. In this review, polymer network structuring strategies at micro/nanoscales for toughening hydrogels are summarized, and representative mechanical functionalities that exist in biological materials but are not easily achieved in synthetic hydrogels are further discussed. Three categories of processing technologies, namely, 3D printing, spinning, and coating for fabrication of tough hydrogel constructs with complex shapes are reviewed, and the corresponding hydrogel toughening strategies are also highlighted. These developments enable adaptive fabrication of mechanically robust and functional hydrogel devices, and promote application of hydrogels in the fields of biomedical engineering, bioelectronics, and soft robotics.

Giant polarization ripple in transverse pyroelectricity.

Pyroelectricity originates from spontaneous polarization variation, promising in omnipresent non-static thermodynamic energy harvesting. Particularly, changing spontaneous polarization via out-of-plane uniform heat perturbations has been shown in solar pyroelectrics. However, these approaches present unequivocal inefficiency due to spatially coupled low temperature change and duration along the longitudinal direction. Here we demonstrate unconventional giant polarization ripples in transverse pyroelectrics, without increasing the total energy input, into electricity with an efficiency of 5-fold of conventional longitudinal counterparts. The non-uniform graded temperature variation arises from decoupled heat localization and propagation, leading to anomalous in-plane heat perturbation (29-fold) and enhanced thermal disequilibrium effects. This in turn triggers an augmented polarization ripple, fundamentally enabling unprecedented electricity generation performance. Notably, the device generates a power density of 38 mW m-2 at 1 sun illumination, which is competitive with solar thermoelectrics and ferrophotovoltaics. Our findings provide a viable paradigm, not only for universal practical pyroelectric heat harvesting but for flexible manipulation of transverse heat transfer towards sustainable energy harvesting and management.

An Elastic and Damage-Tolerant Dry Epidermal Patch with Robust Skin Adhesion for Bioelectronic Interfacing.

On-skin patches that record biopotential and biomechanical signals are essential for wearable healthcare monitoring, clinical treatment, and human-machine interaction. To acquire wearing comfort and high-quality signals, patches with tissue-like softness, elastic recovery, damage tolerance, and robust bioelectronic interface are highly desired yet challenging to achieve. Here, we report a dry epidermal patch made from a supramolecular polymer (SESA) and an in situ transferred carbon nanotubes' percolation network. The polymer possesses a hybrid structure of copolymerized permanent scaffold permeated by multiple dynamic interactions, which imparts a desired mechanical response transition from elastic recoil to energy dissipation with increased elongation. Such SESA-based patches are soft (Young's modulus ∼0.1 MPa) and elastic within physiologically relevant strain levels (97% elastic recovery at 50% tensile strain), intrinsically mechanical-electrical damage-resilient (∼90% restoration from damage after 5 min), and interference-immune in dynamic signal acquisition (stretch, underwater, sweat). We demonstrate its versatile physiological sensing applications, including electrocardiogram recording under various disturbances, machine-learning-enabled hand-gesture recognition through electromyogram measurement, subtle radial artery pulse, and drastic knee kinematics sensing. This epidermal patch offers a promising noninvasive, long-duration, and ambulant bioelectronic interfacing with anti-interference robustness.

Macromolecule conformational shaping for extreme mechanical programming of polymorphic hydrogel fibers.

Mechanical properties of hydrogels are crucial to emerging devices and machines for wearables, robotics and energy harvesters. Various polymer network architectures and interactions have been explored for achieving specific mechanical characteristics, however, extreme mechanical property tuning of single-composition hydrogel material and deployment in integrated devices remain challenging. Here, we introduce a macromolecule conformational shaping strategy that enables mechanical programming of polymorphic hydrogel fiber based devices. Conformation of the single-composition polyelectrolyte macromolecule is controlled to evolve from coiling to extending states via a pH-dependent antisolvent phase separation process. The resulting structured hydrogel microfibers reveal extreme mechanical integrity, including modulus spanning four orders of magnitude, brittleness to ultrastretchability, and plasticity to anelasticity and elasticity. Our approach yields hydrogel microfibers of varied macromolecule conformations that can be built-in layered formats, enabling the translation of extraordinary, realistic hydrogel electronic applications, i.e., large strain (1000%) and ultrafast responsive (~30 ms) fiber sensors in a robotic bird, large deformations (6000%) and antifreezing helical electronic conductors, and large strain (700%) capable Janus springs energy harvesters in wearables.

Dynamic thermal trapping enables cross-species smart nanoparticle swarms.

Bioinspired nano/microswarm enables fascinating collective controllability beyond the abilities of the constituent individuals, yet almost invariably, the composed units are of single species. Advancing such swarm technologies poses a grand challenge in synchronous mass manipulation of multimaterials that hold different physiochemical identities. Here, we present a dynamic thermal trapping strategy using thermoresponsive-based magnetic smart nanoparticles as host species to reversibly trap and couple given nonmagnetic entities in aqueous surroundings, enabling cross-species smart nanoparticle swarms (SMARS). Such trapping process endows unaddressable nonmagnetic species with efficient thermo-switchable magnetic response, which determines SMARS' cross-species synchronized maneuverability. Benefiting from collective merits of hybrid components, SMARS can be configured into specific smart modules spanning from chain, vesicle, droplet, to ionic module, which can implement localized or distributed functions that are single-species unachievable. Our methodology allows dynamic multimaterials integration despite the odds of their intrinsic identities to conceive distinctive structures and functions.

Scalable thermoelectric fibers for multifunctional textile-electronics.

Textile electronics are poised to revolutionize future wearable applications due to their wearing comfort and programmable nature. Many promising thermoelectric wearables have been extensively investigated for green energy harvesting and pervasive sensors connectivity. However, the practical applications of the TE textile are still hindered by the current laborious p/n junctions assembly of limited scale and mechanical compliance. Here we develop a gelation extrusion strategy that demonstrates the viability of digitalized manufacturing of continuous p/n TE fibers at high scalability and process efficiency. With such alternating p/n-type TE fibers, multifunctional textiles are successfully woven to realize energy harvesting on curved surface, multi-pixel touch panel for writing and communication. Moreover, modularized TE garments are worn on a robotic arm to fulfill diverse active and localized tasks. Such scalable TE fiber fabrication not only brings new inspiration for flexible devices, but also sets the stage for a wide implementation of multifunctional textile-electronics.

Somatosensory, Light-Driven, Thin-Film Robots Capable of Integrated Perception and Motility.

Living organisms are capable of sensing and responding to their environment through reflex-driven pathways. The grand challenge for mimicking such natural intelligence in miniature robots lies in achieving highly integrated body functionality, actuation, and sensing mechanisms. Here, somatosensory light-driven robots (SLiRs) based on a smart thin-film composite tightly integrating actuation and multisensing are presented. The SLiR subsumes pyro/piezoelectric responses and piezoresistive strain sensation under a photoactuator transducer, enabling simultaneous yet non-interfering perception of its body temperature and actuation deformation states. The compact thin film, when combined with kirigami, facilitates rapid customization of low-profile structures for morphable, mobile, and multiple robotic functionality. For example, an SLiR walker can move forward on different surfaces, while providing feedback on its detailed locomotive gaits and subtle terrain textures, and an SLiR anthropomorphic hand shows bodily senses arising from concerted mechanoreception, thermoreception, proprioception, and photoreception. Untethered operation with an SLiR centipede is also demonstrated, which can execute distinct, localized body functions from directional motility, multisensing, to wireless human and environment interactions. This SLiR, which is capable of integrated perception and motility, offers new opportunities for developing diverse intelligent behaviors in soft robots.

EZH2-inhibitor DZNep enhances apoptosis of renal tubular epithelial cells in presence and absence of cisplatin.

BACKGROUND: The enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase and induces the trimethylation of histone H3 lysine 27 (H3K27me3) in the promoter of many key genes; EZH2 acts as a transcriptional repressor and is an epigenetic regulator for several cancers. However, the role of EZH2 in nonneoplastic diseases, such as kidney diseases, is unknown and has been investigated. MATERIALS AND METHOD: NRK-52E cells were treated with DZNep, a potent inhibitor of EZH2, with different concentrations and for different times to evaluate the apoptosis level of NRK-52E cells by Western blot and Flow cytometry analysis. The binding of EZH2 to the Deptor promoter was determined by ChIP assay. RESULTS: The inhibition of EZH2 with 3-deazaneplanocin A (DZNep), a specific inhibitor of EZH2, led to the apoptosis of NRK-52E cells and the inhibition of mTORC1 and mTORC2 activity. A ChIP assay demonstrated that EZH2 bound the promoter region of Deptor, an endogenous inhibitor of mTORC1 and mTORC2, and regulated the transcription of Deptor by modulating H3K27me3 in its promoter region. Further experiments were performed to examine the effects of EZH2 inhibition on cisplatin-induced injured cells. Cisplatin induced the activation of mTORC1 and mTORC2 and apoptosis in NRK-52E cells, and DZNep inhibited mTORC1 and mTORC2 activity and aggravated cell apoptosis. CONCLUSIONS: These data suggested that EZH2 inhibition increased the transcription of Deptor by modifying H3K27me3 in its promoter region, subsequently inhibited mTORC1 and mTORC2 activities, downregulated the expression of apoptosis suppressor genes, and finally led to apoptosis in renal tubular cells. The inhibition of EZH2 aggravated the cisplatin-induced injury in renal tubular cells by inactivating the mTOR complexes. The present study provides new insight into renal protection and suggests that EZH2 might be a target.

Direct-Ink-Write 3D Printing of Hydrogels into Biomimetic Soft Robots.

Hydrogels are promising starting materials for biomimetic soft robots as they are intrinsically soft and hold properties analogous to nature's organic parts. However, the restrictive mold-casting and post-assembly fabrication alongside mechanical fragility impedes the development of hydrogel-based soft robots. Herein, we harness biocompatible alginate as a rheological modifier to manufacture 3D freeform architectures of both chemically and physically cross-linked hydrogels using the direct-ink-write (DIW) printing. The intrinsically hydrophilic polymer network of alginate allows the preservation of the targeted functions of the host hydrogels, accompanied by enhanced mechanical toughness. The integration of free structures and available functionalities from diversified hydrogel family renders an enriched design platform for bioinspired fluidic and stimulus-activated robotic prototypes from an artificial mobile tentacle, a bioengineered robotic heart with beating-transporting functions, and an artificial tendril with phototropic motion. The design strategy expands the capabilities of hydrogels in realizing geometrical versatility, mechanical tunability, and actuation complexity for biocompatible soft robots.

Value of BNP and tumour marker CA125 in patients with heart failure.

OBJECTIVE: The objective was to study the association between B-type natriuretic peptide (BNP) and tumour markers and heart failure (HF) to evaluate the value of BNP and carbohydrate antigen 125 (CA125) in HF patients. DESIGN AND SETTING: A university hospital-based cross-over study of 285 subjects (157 men and 128 women) in HF, chronic obstructive pulmonary disease (COPD), mild-mid pulmonary hypertension patients and control subjects. RESULTS: CA125 and BNP were significantly higher in the HF group than in the non-HF group and in severe HF than in mild HF (P < 0.01). No changes were observed in other tumour markers. CA125 and BNP decreased obviously after clinical improvement by aggressive treatment (P < 0.01). Left ventricular ejection fraction correlated positively with CA125 (r = 0.789, P < 0.01) and BNP (r = 0.730, P < 0.01) in left heart failure patients, but not in other patients. BNP and CA125 had better accuracy and positive predictive value in diagnosing HF from the characteristic receiver-operator curve. CONCLUSIONS: CA125 and BNP are markedly elevated in heart failure and closely reflect heart function. They are better markers in evaluating the efficiency of short-term therapy. Detecting BNP combined with CA125 may be more valuable than only detecting BNP or CA125 for diagnosing HF and evaluating the efficiency of treatment.

In-built thermo-mechanical cooperative feedback mechanism for self-propelled multimodal locomotion and electricity generation.

Utilization of ubiquitous low-grade waste heat constitutes a possible avenue towards soft matter actuation and energy recovery opportunities. While most soft materials are not all that smart relying on power input of some kind for continuous response, we conceptualize a self-locked thermo-mechano feedback for autonomous motility and energy generation functions. Here, the low-grade heat usually dismissed as 'not useful' is used to fuel a soft thermo-mechano-electrical system to perform perpetual and untethered multimodal locomotions. The innately resilient locomotion synchronizes self-governed and auto-sustained temperature fluctuations and mechanical mobility without external stimulus change, enabling simultaneous harvesting of thermo-mechanical energy at the pyro/piezoelectric mechanistic intersection. The untethered soft material showcases deterministic motions (translational oscillation, directional rolling, and clockwise/anticlockwise rotation), rapid transitions and dynamic responses without needing power input, on the contrary extracting power from ambient. This work may open opportunities for thermo-mechano-electrical transduction, multigait soft energy robotics and waste heat harvesting technologies.

Hypochlorite modified albumins promote cell death in the tubule interstitium in rats via mitochondrial damage in obstructive nephropathy and the protective effects of antioxidant peptides.

A major feature of the injury sustained by the kidney during obstructive nephropathy is a profound induction of apoptosis in the tubular epithelium. In this study, we explored the central roles of mitochondria and the mechanism of the protective effect of the mitochondrial targeted peptides in tubular cell apoptosis and interstitial fibrosis during obstructive nephropathy. Unilateral ureter obstruction (UUO) was performed on rats, and the animals were randomly assigned to intravenous treatment with normal saline, rat serum albumin (RSA), or HOCl-rat serum albumin (HOCl-RSA) in the presence or absence of SS-31. A sham-operation control group was set up by left ureteral dissociation but not ligation. Compared with the control group, UUO animals displayed fibrotic abnormalities, accompanied by increased expression of collagen-I, fibronectin, α-SMA protein and mRNA in the renal interstitium. They also displayed oxidative stress, as evidenced by increased levels of HOCl-alb, TBARS, and mitochondrial reactive oxygen species (ROS) and a decrease in MnSOD activity in the renal homogenate. Damage to mitochondrial structure and functions was observed, as evidenced by a decrease in the mitochondrial membrane potential (MMP), ATP production, mtDNA copy number alterations and release of cytochrome C (cyto C) from the mitochondria to the cytoplasm. These changes were accompanied by activation of caspase-3, caspase-7, caspase-9, and PARP-1 and increased apoptotic cells in the proximal tubules. HOCl-RSA challenge further exacerbated the above biological effects in UUO animals, but these effects were prevented by administration of SS-31. These data suggested that accumulation of HOCl-alb may promote tubular cell apoptosis and interstitial fibrosis, probably related to mitochondrial oxidative stress and damage, and that SS-31 might contribute to apoptotic pathway suppression via scavenging of ROS in the mitochondria.

Nanophotonic-Engineered Photothermal Harnessing for Waste Heat Management and Pyroelectric Generation.

At present, there are various limitations to harvesting ambient waste heat which include the lack of economically viable material and innovative design features that can efficiently recover low grade heat for useful energy conversion. In this work, a thermal nanophotonic-pyroelectric (TNPh-pyro) scheme consisting of a metamaterial multilayer and pyroelectric material, which performs synergistic waste heat rejection and photothermal heat-to-electricity conversion, is presented. Unlike any other pyroelectric configuration, this conceptual design deviates from the conventional by deliberately employing back-reflecting NIR to enable waste heat reutilization/recuperation to enhance pyroelectric generation, avoiding excessive solar heat uptake and also retaining high visual transparency of the device. Passive solar reflective cooling up to 4.1 °C is demonstrated. Meanwhile, the photothermal pyroelectric performance capitalizing on the back-reflecting effect shows an open circuit voltage (Voc) and short circuit current (Isc) enhancement of 152 and 146%, respectively. In addition, the designed photoactive component (TiO2/Cu) within the metamaterial multilayer provides the TNPh-pyro system with an effective air pollutant photodegradation functionality. Finally, proof-of-concept for concurrent photothermal management and enhanced solar pyroelectric generation under a real outdoor environment is demonstrated.

Macrophage-derived foam cells impair endothelial barrier function by inducing endothelial-mesenchymal transition via CCL-4.

Recently, endothelial-mesenchymal transition (EndMT) has been demonstrated to play an important role in the development of atherosclerosis, the molecular mechanisms of which remain unclear. In the present study, scanning electron microscopy directly revealed a widened endothelial space and immunohistofluorescence demonstrated that EndMT was increased in human aorta atherosclerotic plaques. M1 macrophage-derived foam cell (M1-FC) supernatants, but not M2 macrophage-derived foam cell (M2-FC) supernatants, induced EndMT. A protein array and enzyme-linked immunosorbent assay identified that the levels of several cytokines, including C-C motif chemokine ligand 4 (CCL-4) were increased in M1-FC supernatants, in which EndMT was promoted, accompanied by increased endothelial permeability and monocyte adhesion. Furthermore, anti-CCL-4 antibody abolished the effects of M1-FC supernatants on EndMT. At the same time, CCL-4 activated its receptor, C-C motif chemokine receptor-5 (CCR-5), and upregulated transforming growth factor-ß (TGF-ß) expression. Further experiments revealed that EndMT induced by CCL-4 was reversed by treatment with CCR-5 antagonist and the RNA-mediated knockdown of TGF-ß. On the whole, the data of the present study suggest that M1-FCs induce EndMT by upregulating CCL-4, and increase endothelial permeability and monocyte adhesion. These data may help to elucidate the important role of EndMT in the development of atherosclerosis.

Hydrogen sulfide suppresses endoplasmic reticulum stress-induced endothelial-to-mesenchymal transition through Src pathway.

AIMS: Hydrogen sulfide (H2S) ameliorates cardiac fibrosis in several models by suppressing endoplasmic reticulum (ER) stress. Endothelial-to-mesenchymal transition (EndMT) is implicated in the development of cardiac fibrosis. Therefore, we investigated whether H2S could attenuate EndMT by suppressing ER stress. MAIN METHODS: ER stress was induced by tunicamycin (TM) and thapsigargin (TG) and inhibited by 4-phenylbutyrate (4-PBA) in human umbilical vein endothelial cells (HUVECs). ER stress and EndMT were measured by Western blot, Real-Time PCR and immunofluorescence staining. Inhibition Smad2 and Src pathway were performed by specific inhibitors and siRNA. Ultrastructural examination was detected by transmission electron microscope. The functions of HUVECs were investigated by cell migration assay and tube formation in vitro. KEY FINDINGS: Under ER stress, the expression of endothelial marker CD31 significantly decreased while mesenchymal markers α-SMA, vimentin and collagen 1 increased which could be inhibited by 4-PBA. Moreover, HUVECs changed into a fibroblast-like appearance with the activation of Smad2 and Src kinase pathway. After inhibiting Src pathway, EndMT would be significantly inhibited. TM reduced H2S levels in cell lysate and H2S pretreatment could preserve endothelial cell appearance with decreased ER stress and ameliorated dilation of ER. H2S could also downregulate the mesenchymal marker expression, and upregulate the endothelial markers expression, accompanied with the suppression of Src pathway. Moreover, H2S partially restored the capacity of migration and tube formation in HUVECs. SIGNIFICANCE: These results revealed that H2S could protect against ER stress-induced EndMT through Src pathway, which may be a novel role for the cardioprotection of H2S.