A Metabolic Basis for Endothelial-to-Mesenchymal Transition.

Endothelial-to-mesenchymal transition (EndoMT) is a cellular process often initiated by the transforming growth factor ß (TGF-ß) family of ligands. Although required for normal heart valve development, deregulated EndoMT is linked to a wide range of pathological conditions. Here, we demonstrate that endothelial fatty acid oxidation (FAO) is a critical in vitro and in vivo regulator of EndoMT. We further show that this FAO-dependent metabolic regulation of EndoMT occurs through alterations in intracellular acetyl-CoA levels. Disruption of FAO via conditional deletion of endothelial carnitine palmitoyltransferase II (Cpt2E-KO) augments the magnitude of embryonic EndoMT, resulting in thickening of cardiac valves. Consistent with the known pathological effects of EndoMT, adult Cpt2E-KO mice demonstrate increased permeability in multiple vascular beds. Taken together, these results demonstrate that endothelial FAO is required to maintain endothelial cell fate and that therapeutic manipulation of endothelial metabolism could provide the basis for treating a growing number of EndoMT-linked pathological conditions.

A Novel Non-Fullerene D-A Interface with Two Asymmetrical Electron Acceptors Facilitates Charge and Energy Transfer for Effective Carbon Dioxide Reduction.

Converting carbon dioxide (CO2 ) into high-value chemicals using solar energy remains a formidable challenge. In this study, the CSC@PM6:IDT6CN-M:IDT8CN-M non-fullerene small-molecule organic semiconductor is designed with highly efficient electron donor-acceptor (D-A) interface for photocatalytic reduction of CO2 . Atomic Force Microscope and Transmission Electron Microscope images confirmed the formation of an interpenetrating fibrillar network after combination of donor and acceptor. The CO yield from the CSC@PM6:IDT6CN-M:IDT8CN-M reached 1346 µmol g-1  h-1 , surpassing those of numerous reported inorganic photocatalysts. The D-A structure effectively facilitated charge separation to enable electrons transfer from the PM6 to IDT6CN-M:IDT8CN-M. Meanwhile, attributing to the dipole moments of the strong intermolecular interactions between IDT6CN-M and IDT8CN-M, the intermolecular forces are enhanced, and laminar stacking and π-π stacking are strengthened, thereby reinforcing energy transfer between acceptor molecules and significantly enhanced charge separation. Moreover, the strong internal electric field in the D-A interface enhanced the excited state lifetime of PM6:IDT6CN-M:IDT8CN-M. In situ diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analysis demonstrated that carboxylate (COOH*) is the predominant intermediate during CO2 reduction, and possible pathways of CO2 reduction to CO are deduced. This study presents a novel approach for designing materials with D-A interface to achieve high photocatalytic activity.

Comparison of the applicability of electromembrane extraction and liquid-phase microextraction for extraction of non-polar basic drugs from different biological samples: Using clozapine as the model analyte.

Understanding and comparing the applicability of electromembrane extraction (EME) and liquid-phase microextraction (LPME) is crucial for selecting an appropriate microextraction approach. In this work, EME and LPME based on supported liquid membranes were compared using biological samples, including whole blood, urine, saliva, and liver tissue. After optimization, efficient EME and LPME of clozapine from four biological samples were achieved. EME provided higher recovery and faster mass transfer for blood and liver tissue than LPME. These advantages were attributed to the electric field disrupting clozapine binding to interfering substances. For urine and saliva, EME demonstrated similar recoveries while achieving faster mass transfer rates. Finally, efficient EME and LPME were validated and evaluated combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS). The coefficient of determination of all methods was greater than 0.999, and all methods showed acceptable reproducibility (≤14%), accuracy (90%-110%), and matrix effect (85%-112%). For liver and blood with high viscosity and complex matrices, EME-LC-MS/MS provided better sensitivity than LPME-LC-MS/MS. The above results indicated that both EME and LPME could be used to isolate non-polar basic drugs from different biological samples, although EME demonstrated higher recovery rates for liver tissue and blood.

Development of a sensitive direct competitive chemiluminescent enzyme immunoassay for gentamicin based on the construction of a specific single-chain variable fragment-alkaline phosphatase fusion protein.

A sensitive chemiluminescent enzyme immunoassay (CLEIA) was established for the determination of gentamicin (GEN) residue levels in animal tissue. This assay is based on a fusion protein of single-chain variable fragment (scFv) and alkaline phosphatase (AP). Initially, VL and VH derived from anti-gentamicin monoclonal antibody were linked by a short peptide to construct a scFv. Subsequently, the constructed scFv sequence was accessed into the pLIP6/GN vector, and a soluble scFv-AP fusion protein was generated. The scFv-AP fusion protein was used to develop a direct competitive CLEIA (dcCLEIA) for the determination of gentamicin. In the dcCLEIA, the half inhibitory concentration (IC50) and limit of detection (LOD) were 1.073 ng/mL and 0.380 ng/mL, respectively. The average recoveries of gentamicin spiked in animal tissue samples ranged from 78% to 96%. These results showed a strong correlation with ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The above results suggest that the anti-GEN scFv-AP fusion protein is suitable for detecting gentamicin residues in edible animal tissues.

Biomass-assisted fabrication of rGO-AuNPs as surface-enhanced Raman scattering substrates for in-situ monitoring methylene blue degradation.

Reduced graphene oxide-gold nanoparticles nanocomposites (rGO-AuNPs) with high surface-enhanced Raman scattering (SERS) activity was created by biomass-assisted green synthesis with Lilium casa blanca petals biomass for the first time, and its application for methylene blue (MB) degradation was explored through in-situ monitoring. Lilium casa blanca petals biomass was used as a reducing agent to reduce GO and chloroauric acid successively when carrying out rGO-AuNPs in-situ synthesis while it also acted as a capping agent. The produced rGO had oxygen-containing functional groups which had an outstanding performance in enhancing the SERS effect. Characterization results confirmed that the AuNPs were grafted onto the rGO sheet, and the mechanism study showed that total flavonoids in Lilium casa blanca petals biomass were the main biological compounds involved in the reduction. rGO-AuNPs had a high Raman enhancement factor (EF) which could reach 3.88 × 107. The synthesized nanocomposite also had a good catalytic activity that could be employed as catalyst in MB degradation, and it could complete degradation within 15min. The reaction rate increased linearly with the amount of rGO-AuNPs, and the degradation could be in-situ monitored both by UV and SERS.

Cardiovascular aspects of the (pro)renin receptor: Function and significance.

Cardiovascular diseases (CVDs), including all types of disorders related to the heart or blood vessels, are the major public health problems and the leading causes of mortality globally. (Pro)renin receptor (PRR), a single transmembrane protein, is present in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. PRR plays an essential role in cardiovascular homeostasis by regulating the renin-angiotensin system and several intracellular signals such as mitogen-activated protein kinase signaling and wnt/ß-catenin signaling in various cardiovascular cells. This review discusses the current evidence for the pathophysiological roles of the cardiac and vascular PRR. Activation of PRR in cardiomyocytes may contribute to myocardial ischemia/reperfusion injury, cardiac hypertrophy, diabetic or alcoholic cardiomyopathy, salt-induced heart damage, and heart failure. Activation of PRR promotes vascular smooth muscle cell proliferation, endothelial cell dysfunction, neovascularization, and the progress of vascular diseases. In addition, phenotypes of animals transgenic for PRR and the hypertensive actions of PRR in the brain and kidney and the soluble PRR are also discussed. Targeting PRR in local tissues may offer benefits for patients with CVDs, including heart injury, atherosclerosis, and hypertension.

Direct start-up of aerobic granular sludge system with dewatered sludge granular particles as inoculant.

Aerobic granular sludge (AGS) is a promising technology for engineering applications in the biological treatment of sewage. New objective is to skip the conventional granulation step to integrate it into a continuous-flow reactor directly. This study proposed a method for integrating spherical pelletizing granular sludge (SPGS) into a new patented aerobic granular sludge bed (AGSB), a continuous up-flow reactor. AGSB system could be startup directly, and after 120 days of operation, the SPGS maintained a relatively intact spherical structure and stability. With an initial high chemical oxygen demand (COD) volume loading of over 2.0 kg/(m3·d), this system achieved the desired effect as the same as a mature AGS system. The final mixed liquid suspended solids, and the ratio of 30 min-5 min sludge volume index (SVI30/SVI5) were 20,000 mg/L, and 0.84, respectively. Although hydraulic elution and filamentous bacteria (FBs) had a slightly negative impact on initial phase pollutant removal, the final removal rates for COD, total nitrogen (TN), ammonia nitrogen (NH4+-H), and total phosphorus (TP) were 90%, 70%, 95%, and 85%, respectively. The presence of specific functional microorganisms promoted the secretion of extracellular polymeric substances (EPS), from 90.65 to 209.78 mg/gVSS. The maturation process of SPGS altered the microbial community structures and reduced the species abundance of microbes in sludge.

Visible-light photocatalytic degradation of water-soluble polyvinyl alcohol in aqueous solution by Cu2O@TiO2: Optimization of conditions, mechanisms and toxicity analysis.

Polyvinyl alcohol (PVA), a water-soluble synthetic polymer, is one of the most prevalent non-native polyvinyl alcohols found in the environment. Due to its inherent invisibility, its potential for causing severe environmental pollution is often underestimated. To achieve efficient degradation of PVA in wastewater, a Cu2O@TiO2 composite was synthesized through the modification of titanium dioxide with cuprous oxide, and its photocatalytic degradation of PVA was investigated. The Cu2O@TiO2 composite, supported by titanium dioxide, facilitated photocarrier separation and demonstrated high photocatalytic efficiency. Under alkaline conditions, the composite exhibited a 98% degradation efficiency for PVA solutions and a 58.7% PVA mineralization efficiency. Radical capture experiments and electron paramagnetic resonance (EPR) analyses revealed that superoxide radicals primarily drive the degradation process within the reaction system. Throughout the degradation process, PVA macromolecules are broken down into smaller molecules, including ethanol, and compounds containing aldehyde, ketone, and carboxylic acid functional groups. Although the intermediate products exhibit reduced toxicity compared to PVA, they still pose certain toxic hazards. Consequently, further research is necessary to minimize the environmental impact of these degradation products.

Exosomes from Adipose-Derived Mesenchymal Stem Cells Protect Against Cyclophosphamide-Induced Cardiotoxicity in Rats.

A certain dosage of cyclophosphamide (CYP) in clinical applications contributes to severe cardiotoxicity. Herein, this study explored the impact of adipose-derived mesenchymal stem cell (AdMSC)-exosomes (Exos) on CYP-induced cardiotoxicity.AdMSCs and AdMSCs-Exos were isolated and identified. CYP was utilized for developing a cardiotoxicity rat model, after which blood was collected and then the serum contents of cardiac injury-related indexes (creatine kinase-MB, lactate dehydrogenase, aspartate aminotransferase, and alkaline phosphatase) were detected with enzyme-linked immunosorbent assay kits. Oxidative stress (OS)-related indicators were measured with the corresponding kits. Myocardial pathological changes and collagen fibrosis were tested with hematoxylin-eosin and Masson staining, and apoptosis-related and autophagy-related proteins in rat cardiac tissues with immunohistochemistry and Western blot assays, respectively.AdMSCs and AdMSCs-Exos were successfully isolated. AdMSCs-Exos could target rat hearts. AdMSCs-Exos improved cardiac function and diminished the content of the cardiac injury-related indexes in CYP rats. In addition, AdMSCs-Exos reduced CYP-induced cardiac fibrosis, OS, apoptosis, and autophagy in rats.AdMSCs-Exos alleviated CYP-induced cardiotoxicity in rats via the repression of OS, apoptosis, and autophagy.

Effects of different doses glimepiride intake on the pharmacokinetics of benzbromarone in rats.

Benzbromarone (BNR) is prescribed for the management of hyperuricemia, whereas glimepiride (GLM) for the treatment of Type 2 Diabetes Mellitus. Both drugs are certified to be mainly metabolized via cytochrome P450 (CYP) 2C9 in vivo and may have the potential drug-drug interactions. This study aims to investigate the possible influence of orally administered low- and high-dose glimepiride (GLM) on pharmacokinetic characteristics (PK) of benzbromarone (BNR) in rats. Fifteen rats were randomly assigned to group A, B and C (n=5) and administered 0.5% sodium carboxymethyl cellulose (CMC), 0.5mg/kg GLM (low-dose) and 1.0 mg/kg GLM (high-dose) once daily for 8 days, respectively, which were all followed with a single oral dose of BNR (9.0 mg/kg) on the day 8th. Blood samples were obtained from retro orbital plexus at the time points of 0.25, 0.5, 1, 2, 4, 6, 8, 10, 12 and 24h and BNR in plasma was quantitated by HPLC-MS/MS assay. Resultantly a slight influence of GLM on PK of BNR could be found in rats. When compared with Group A, the half-life time (t1/2z) of BNR in Group B and C significantly decreased 52.39% and 73.49%, respectively, although other major PK parameters were negligibly changed by co-administration of GLM. On the whole, the combinational therapy of GLM at low or high dose would notably alter the elimination of BNR and the effect was dose-dependent.

Fatty Acid Oxidation in Cell Fate Determination.

Mitochondrial fatty acid ß-oxidation (FAO) is a major catabolic process that degrades long-chain fatty acids. Recent reports reveal a broad role for FAO in cell fate control in endothelial cells, immune cells, and cancer cells. Concurrently, unique molecular pathways influenced by FAO have been identified that alter cell fate decisions.

Intimately coupled photocatalysis and functional bacterial system enhance degradation of 1,2,3- and 1,3,5-trichlorobenzene.

Intimate coupling of photocatalysis and biodegradation (ICPB) is considered a promising approach for the degradation of recalcitrant organic compounds. In this work, using Trichoderma with benzene degradation ability coupled with activated sludge as a biological source and sugarcane bagasse cellulose composite as a carrier, the ICPB system showed excellent degradation and mineralization of trichlorobenzene under visible light induction. The biofilm inside the ICPB carrier can degrade and mineralize the photocatalytic products. ICPB increased the degradation efficiency of 1,2,3-TCB and 1,3,5-TCB by 12.43% and 4.67%, respectively, compared to photocatalysis alone. The biofilms inside the ICPB carriers can mineralize photocatalytic products, which increases the mineralization efficiency by 18.74%. According to the analysis of intermediates, the degradation of 1,2,3-TCB in this coupled system involved stepwise dechlorination and ring opening. The biofilm in ICPB carrier evolved to be enriched in Cutaneotrichosporon, Trichoderma, Apiotrichum, Zoogloea, Dechloromonas, Flavihumibacter and Cupriavidus, which are known for biodegradable aromatic hydrocarbon and halogenate. Novel microbial seeds supplemented with Trichoderma-based ICPB seem to provide a new potential strategy for effective degradation and mineralization of TCB.

Coupling of photocatalysis and biological treatment for elemental chlorine free bleaching wastewater: Application of factorial design methodology.

In this study, the visible-light-induced intimately coupled photocatalysis and biodegradation (ICPB) technology was fabricated using the TiO2/bagasse cellulose composite as the carrier and Phanerochaete mixed activated sludge as the biological source. The ICPB degradation effect of elemental chlorine free (ECF) bleaching wastewater was evaluated via the response surface design. Then, the wastewater was characterized, including absorbable organic halogen (AOX), dissolved organic carbon (DOC), chemical oxygen demand (COD), chroma, pH, suspended solids, and the organic compound changes in wastewater were analyzed by fourier transform infrared spectroscopy (FT-IR). Under the optimal conditions of pH 7, carrier filling rate of 5%, aeration rate of 2 L/min, and reaction time of 7 h, the degradation efficiencies of AOX, COD, and DOC were 95%, 91%, and 82%, respectively. The X-ray photoelectron spectroscopy (XPS) results of the ICPB carrier after the reaction were almost identical to those before the reaction. The biomass and its activity on the ICPB system were analyzed by the dominant bacteria during degradation (Curaneotrichosporon, Paenibacillus, Cellulonas, Phanerochaete, Dechlorobacter, Rhodotorula, Sphingobacterium, and Ruminiclostridium), which had a good degradation effect on wastewater. This study affords a novel method for the degradation of ECF bleaching wastewater and a new idea for ICPB technology optimization.

Biofilm response and removal via the coupling of visible-light-driven photocatalysis and biodegradation in an environment of sulfamethoxazole and Cr(VI).

The widespread contamination of water systems with antibiotics and heavy metals has gained much attention. Intimately coupled visible -light-responsive photocatalysis and biodegradation (ICPB) provides a novel approach for removing such mixed pollutants. In ICPB, the photocatalysis products are biodegraded by a protected biofilm, leading to the mineralization of refractory organics. In the present study, the ICPB approach exhibited excellent photocatalytic activity and biodegradation, providing up to ∼1.27 times the degradation rate of sulfamethoxazole (SMX) and 1.16 times the Cr(VI) reduction rate of visible-light-induced photocatalysis . Three-dimensional fluorescence analysis demonstrated the synergistic ICPB effects of photocatalysis and biodegradation for removing SMX and reducing Cr(VI). In addition, the toxicity of the SMX intermediates and Cr(VI) in the ICPB process significantly decreased. The use of MoS2/CoS2 photocatalyst accelerated the separation of electrons and holes, with•O2- and h+ attacking SMX and e- reducing Cr(VI), providing an effective means for enhancing the removal and mineralization of these mixed pollutants via the ICPB technique. The microbial community results demonstrate that bacteria that are conducive to pollutant removal are were enriched by the acclimation and ICPB operation processes, thus significantly improving the performance of the ICPB system.

An Activity-Based Fluorescent Probe for Imaging Fluctuations of Peroxynitrite (ONOO- ) in the Alzheimer's Disease Brain.

Peroxynitrite (ONOO- ) plays a critical role in Alzheimer's disease (AD). To reveal the ONOO- influx in AD brains, an activatable activity-based fluorescence probe Rd-DPA3 was designed by a structure-modulated strategy. Taking advantage of ONOO- -initiated two-step cascade reactions of a novel chemical trigger, Rd-DPA3 specifically responds to ONOO- in 0.3 mM of other reactive oxygen species (ROS) and varied proteins, and gives an intensive fluorescence enhancement (F/F0 =50). Moreover, with its mitochondria-targeting ability, Rd-DPA3 can be used to efficiently monitor the alternations of intracellular ONOO- levels in cerebral cells during oxidative stress. Significantly, due to NIR emission and good blood-brain barrier (BBB) crossing ability, Rd-DPA3 is suitable for in vivo imaging of cerebral ONOO- influx and illustrating an age-dependent accumulation of ONOO- in AD mice brains.

Degradation of chlorine dioxide bleaching wastewater and response of bacterial community in the intimately coupled system of visible-light photocatalysis and biodegradation.

Intimate coupling of visible-light photocatalysis and biodegradation (ICPB) offers potential for degrading chlorine dioxide bleaching wastewater. In this study, we reported a TiO2-coated sponge biofilm carrier with significant adhesion of TiO2 and the ability to accumulate biomass in its interior. Four mechanisms possibly acting in ICPB were tested separately: adsorption of chlorine dioxide bleaching wastewater to the carrier, photolysis, photocatalysis, and biodegradation by the biofilm inside the carrier. The carrier had an adsorption capacity of 17% and 16% for CODcr and AOX, respectively, in the wastewater. The photodegradation rate of wastewater was very low and could be ignored. Both biodegradation (AOX 30.1%, CODcr 33.8%, DOC 26.2%) and photocatalysis (AOX 65.1%, CODcr 71.2%, DOC 62.3%) possessed a certain degradation efficiency of wastewater. However, the removal rate of AOX, CODcr, and DOC in wastewater treatment by protocol ICPB reached 80.3%, 90.5%, and 86.7%. FT-IR and GC-MS analysis showed that the ICPB system had photocatalytic activity on the surface of the porous carrier in vitro, which could transform organic into small molecules for microbial utilization or complete mineralization. Moreover, the biofilm in the interior of the TiO2-coated sponge carrier could mineralize the photocatalytic products, which enhanced the removal of AOX, CODcr, and DOC by more than 15.2%, 20.0%, and 24.0%, respectively. The biofilm in the carrier of the ICPB system evolved, enriched in Proteobacteria, Chloroflexi, Bacteroidetes, and Actinobacteria, microorganisms known to play active roles in the biodegradation of papermaking wastewater.

MoS2 quantum dots and titanium carbide co-modified carbon nanotube heterostructure as electrode for highly sensitive detection of zearalenone.

A novel electrochemical sensor has been fabricated for sensitive determination of zearalenone (ZEA) in food samples based on molybdenum disulfide quantum dots (MoS2 QDs) and two-dimensional titanium carbide (2D-Ti3C2Tx MXene) co-modified multi-walled carbon nanotube (MWCNT) heterostructure. Physical and electrochemical characterizations reveal that 2D-Ti3C2Tx and MoS2 QDs co-modified MWCNTs yields synergistic signal amplification effect, together with large specific surface area and excellent conductivity for the heterostructure, endowing the developed sensor with high detection performance to ZEA. Under optimized conditions, the sensor shows a wide linear range from 3.00 to 300 ng mL-1 and a low limit of detection (LOD) of 0.32 ng mL-1, which is far lower than the maximum residue limits (MRLs) settled by the European Commission. In addition, it exhibits excellent selectivity, high reproducibility with a relative standard deviation (RSD) of 1.1%, and good repeatability (RSD 1.1%). In real sample analysis recoveries ranged from 94.8 to 105% showing the proposed electrochemical sensor has high potential in practical applications. This work presents an effective and valuable pathway for the use of novel heterostructure in the biosensing field.

Activatable Two-Photon Near-Infrared Fluorescent Probe Tailored toward Peroxynitrite In Vivo Imaging in Tumors.

A malignant tumor remains one of the leading causes of deaths across the world. Thus, diagnosis of tumor development with noninvasive visualizing methods is significant for tumor therapy. Herein, an activatable two-photon NIR fluorescent probe DHQ-Rd-PN for in vivo imaging of peroxynitrite in a tumor was elaborately designed. The probe demonstrated an increased NIR emission in response to peroxynitrite in vitro, which ensured that the probe detects ONOO- in cell and in vivo. Cellular imaging results disclosed that the probe was competent to detect adscititious ONOO- level change in HeLa cells, as well as endogenous ONOO- concentration in lipopolysaccharides (LPS) and IFN-γ-stimulated RAW 264.7 cells. Additionally, zebrafish in vivo imaging revealed that the probe accumulated in the pancreas and was lightened up by the addition of ONOO-. Remarkably, the probe can be harnessed to image an ONOO- production profile in xenograft 4T1 tumor mice by both one-photon and two-photon in vivo fluorescence imaging. Benefiting with the two-photon excitable properties and NIR emissive properties, the probe can be used for noninvasive in vivo imaging of ONOO- in the onset and development of tumors for the first time. This work provided a noninvasive and efficient detection method for ONOO- in a tumor, which would find more applications in tumor diagnosis and therapies.

Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Hemangioblastoma (HB) is an abnormal intracranial buildup of blood vessels that exhibit a great potential for hemorrhage. Surgical options are limited, and few medications are available for treatment. We show here by immunohistochemical analysis that HB lesions display highly increased levels of VEGF expression and macrophage/microglia infiltration compared with those in normal brain tissues. In the meantime, TNF superfamily 15 (TNFSF15) (also known as vascular endothelial growth inhibitor), an antiangiogenic cytokine, is highly expressed in normal brain blood vessels but diminished in HB lesions. We set up a brain hemangioma model by using mouse bEnd.3 cells of a T antigen-transformed endothelial cell line that produce a large amount of VEGF. When implanted in mouse brains, these cells form lesions that closely resemble the pathologic characteristics of HB. Retroviral infection of bEnd.3 cells with TNFSF15 leads to inhibition of VEGF production and retardation of hemangioma formation. Similar results are obtained when wild-type bEnd.3 cells are implanted in the brains of transgenic mice overexpressing TNFSF15. Additionally, TNFSF15 treatment results in enhanced pericyte coverage of the blood vessels in the lesions together with reduced inflammatory cell infiltration and decreased hemorrhage. These findings indicate that the ability of TNFSF15 to counterbalance the abnormally highly angiogenic and inflammatory potential of the microenvironment of HB is of therapeutic value for the treatment of this disease.-Yang, G.-L., Han, Z., Xiong, J., Wang, S., Wei, H., Qin, T.-T., Xiao, H., Liu, Y., Xu, L.-X., Qi, J.-W., Zhang, Z.-S., Jiang, R., Zhang, J., Li, L.-Y. Inhibition of intracranial hemangioma growth and hemorrhage by TNFSF15.

Sonic hedgehog signaling regulates the mammalian cardiac regenerative response.

Certain organisms, including zebrafish, are capable of complete cardiac regeneration in response to injury. This response has also been observed in newborn mice, although in this case, the regenerative capacity is lost at approximately one week of age. The mechanisms regulating this short temporal window of cardiac regeneration in mice are not well understood. Here, we show that sonic hedgehog (Shh) signaling modulates the neonatal mouse regenerative response. In particular, we demonstrate that following apical resection of the heart on postnatal day 1, mice activate Shh ligand expression and downstream signaling. This response is largely absent when surgery is performed on non-regenerative, postnatal day 7 pups. Furthermore, an enhanced cardiac regeneration response was detected in ptch heterozygous mice which have a genetically-based constitutive increase in Shh signaling. We further show that Shh ligand is produced in the myocardium by non-myocytes and appears to regulate cardiomyocyte proliferation, as well as the recruitment of monocytes/macrophages to the regenerating area. Finally, we demonstrate that a small molecule activator of Shh signaling promotes heart regeneration, whereas an inhibitor of Shh signaling impairs the regenerative response. Together, these results implicate Shh signaling as a regulator of mammalian heart regeneration and suggest that modulating this pathway may lead to new potential therapies for cardiovascular diseases.