Activation of <i>PPARγ2</i> by PPARγ1 through a functional PPRE in transdifferentiation of myoblasts to adipocytes induced by EPA

<p>PPARγ and Wnt signaling are central positive and negative regulators of adipogenesis, respectively. Here we identified that, eicosapentaenoic acid (EPA) could effectively induce the transdifferentiation of myoblasts into adipocytes through modulation of both <i>PPAR</i>γ expression and Wnt signaling. During the early stage of transdifferentiation, EPA activates PPARδ and PPARγ1, which in turn targets β-catenin to degradation and down-regulates Wnt/β-catenin signaling, such that the myogenic fate of myoblasts could be switched to adipogenesis. In addition, EPA up-regulates the expression of <i>PPAR</i>γ<i>1</i> by activating RXRα, then PPARγ1 binds to the functional peroxisome proliferator responsive element (PPRE) in the promoter of adipocyte-specific <i>PPAR</i>γ<i>2</i> to continuously activate the expression of <i>PPAR</i>γ<i>2</i> throughout the transdifferentiation process. Our data indicated that EPA acts as a dual-function stimulator of adipogenesis that both inhibits Wnt signaling and induces <i>PPAR</i>γ<i>2</i> expression to facilitate the transdifferentiation program, and the transcriptional activation of <i>PPAR</i>γ<i>2</i> by PPARγ1 is not only the key factor for the transdifferentiation of myoblasts to adipocytes, but also the crucial evidence for successful transdifferentiation. The present findings provided insight for the first time as to how EPA induces the transdifferentiation of myoblasts to adipocytes, but also provide new clues for strategies to prevent and treat some metabolic diseases.</p

Perylene Diimide-Grafted Polymeric Nanoparticles Chelated with Gd³⁺ for Photoacoustic/<i>T</i>₁‑Weighted Magnetic Resonance Imaging-Guided Photothermal Therapy

Developing versatile and easily prepared nanomaterials with both imaging and therapeutic properties have received significant attention in cancer diagnostics and therapeutics. Here, we facilely fabricated Gd³⁺-chelated poly­(isobutylene-<i>alt</i>-maleic anhydride) (PMA) framework pendent with perylene-3,4,9,10-tetracarboxylic diimide (PDI) derivatives and poly­(ethylene glycol) (PEG) as an efficient theranostic platform for dual-modal photoacoustic imaging (PAI) and magnetic resonance imaging (MRI)-guided photothermal therapy. The obtained polymeric nanoparticles (NPs) chelated with Gd³⁺ (PMA–PDI–PEG–Gd NPs) exhibited a high <i>T</i>₁ relaxivity coefficient (13.95 mM^–1 s^–1) even at the higher magnetic fields. After 3.5 h of tail vein injection of PMA–PDI–PEG–Gd NPs, the tumor areas showed conspicuous enhancement in both photoacoustic signal and <i>T</i>₁-weighted MRI intensity, indicating the efficient accumulation of PMA–PDI–PEG–Gd NPs owing to the enhanced permeation and retention effect. In addition, the excellent tumor ablation therapeutic effect in vivo was demonstrated with living mice. Overall, our work illustrated a straightforward synthetic strategy for engineering multifunctional polymeric nanoparticles for dual-modal imaging to obtain more accurate information for efficient diagnosis and therapy

Engineering Lysosome-Targeting BODIPY Nanoparticles for Photoacoustic Imaging and Photodynamic Therapy under Near-Infrared Light

Developing lysosome-targeting organic nanoparticles combined with photoacoustic imaging (PAI) and photodynamic therapy (PDT) functions toward personalized medicine are highly desired yet challenging. Here, for the first time, lysosome-targeting BODIPY nanoparticles were engineered by encapsulating near-infrared (NIR) absorbed BODIPY dye within amphiphilic DSPE-mPEG5000 for high-performing lysosomal PAI and acid-activatable PDT against cancer cells under NIR light

Additional file 1: of Splenic responses play an important role in remote ischemic preconditioning-mediated neuroprotection against stroke

The flow cytometry scatter plots for isotype controls that were used as negative control. (PDF 120 kb

Multifunctional Copper-Containing Carboxymethyl Chitosan/Alginate Scaffolds for Eradicating Clinical Bacterial Infection and Promoting Bone Formation

Repairing infected bone defects relies on a scaffold that can not only fill the defects to promote bone formation but also kill clinically present bacterial pathogens such as <i>Staphylococcus aureus</i> (<i>S. aureus</i>). To meet this demand, here, we develop a new copper (Cu) containing natural polymeric scaffold with a full potential for repairing infected bone defects. Instead of directly adding antibacterial Cu²⁺ ions to the polymer mixtures, which caused uncontrolled polymer cross-linking, we added Cu nanoparticles to the mixture of anionic carboxymethyl chitosan (CMC) and alginate (Alg). Then, the Cu²⁺ ions released from the Cu nanoparticles gradually cross-linked the polymer mixtures, which was further turned into a scaffold (CMC/Alg/Cu) with an interconnected porous structure by freeze-drying. We found that the CMC/Alg/Cu scaffolds showed significantly improved capabilities of osteogenesis and killing clinical bacteria compared to CMC/Alg scaffolds fabricated by the same procedure but without adding Cu nanoparticles. Specifically, <i>in vitro</i> studies showed that the CMC/Alg/Cu scaffolds with excellent biocompatibility could enhance preosteoblastic cell adhesion by upregulating the expression level of adhesion-related genes (focal adhesion kinase (FAK), paxillin (PXN), and vinculin (VCL)), promoting osteogenic differentiation and mineralization by upregulating the osteogenesis-related gene expression and extracellular calcium deposition. <i>In vivo</i> studies further demonstrated that CMC/Alg/Cu scaffolds could induce the formation of vascularized new bone tissue in 4 weeks while avoiding clinical bacterial infection even when the implantation sites were challenged with the clinically collected <i>S. aureus</i> bacteria. This work represents a facile and innovative approach to the fabrication of Cu containing polymer scaffolds that can potentially be used to repair infected bone defects

Circulating HFMD-Associated Coxsackievirus A16 Is Genetically and Phenotypically Distinct from the Prototype CV-A16

<div><p>Human enteroviruses (HEV) have been linked to hand, foot, and mouth disease (HFMD) in the Pacific and Southeast Asia for decades. Many cases of HFMD have been attributed to coxsackievirus A16 (CV-A16, CA16), based on only partial viral genome determination. Viral phenotypes are also poorly defined. Herein, we have genetically and phenotypically characterized multiple circulating CV-A16 viruses from HFMD patients and determined multiple full-length sequences of these circulating viruses. We discovered that the circulating CV-A16 viruses from HFMD patients are genetically distinct from the proto-type CV-A16 G10. We have also isolated circulating CV-A16 viruses from hospitalized HFMD patients and compared their virological differences. Interestingly, circulating CV-A16 viruses are more pathogenic in a neonatal mouse model than is CV-A16 G10. Thus, we have found circulating recombinant forms of CV-A16 (CRF CV-A16) that are related to, but different from, the prototype CV-A16 G10 that have distinct biological phenotypes.</p></div

Phylogenetic analysis of eight CV-A16 full-length genomic sequences isolated from HFMD patients in Changchun, China.

<p>(A)The complete genomic sequences of 3 other CV-A16 strains from China and all of the 21 HEV reference sequences were retrieved from Genbank. Phylogenetic analysis was conducted using MEGA4 software employing the neighbor-joining method with 1,000 replications and the Kimura 2-parameter model. Bootstrap values greater than 70% are shown. The ▪icon indicates CV-A16 strains isolated from Changchun; the ♦icon indicates the prototype CV-A16-G10. (B) and (C) Identification of recombinant circulating CV-A16 strains of Changchun024 and Changchun029 by bootscanning. (B) Bootscanning analysis of Changchun024 as the query sequence. (C) Bootscanning analysis of Changchun029 as the query sequence. For all HEV-A sequences together with other two outgroups EV68 and poliovirus 1, Changchun024 and Changchun029 showed possible recombination with CA4, CV-A16-G10, and EV71A. Bootscanning was generated with Simplot 3.5.1 software using a sliding window size of 500 bases and step size of 20 bases at a time. The <i>y</i> axis shows the percentage of the permuted tree in which the selected HEV virus sequences cluster with the query sequence.</p

Summary of Changchun024 recombination events detected by RDP4.

<p>Summary of Changchun024 recombination events detected by RDP4.</p

Clinical features of eight HFMD patients infected with CV-A16 viruses from Changchun.

<p>Clinical features of eight HFMD patients infected with CV-A16 viruses from Changchun.</p

Phylogenetic analysis of the 5′UTR and P1 regions of eight circulating Changchun CV-A16 strains.

<p>(A) The neighbor-joining tree was generated based on the 5′UTR sequences (nucleotide 24–718 using CV-A16-G10 sequence as reference) of eight circulating CV-A16 viruses and the HEV reference sequences. (B) The neighbor-joining tree was generated based on the P1 sequences (nucleotides 751–3327 using the CV-A16-G10 sequence as the reference) of eight circulating CV-A16 viruses and reference sequences. The ▪icon indicates CV-A16 strains isolated from Changchun; ♦icon indicates the prototype CV-A16-G10.(C) Detailed bootscanning analysis of the 5′UTR region from CV-A16 strains circulating in Changchun. Bootscanning analysis was performed based on the 5′UTR region sequences (nucleotides 2–718 using the CV-A16-G10 sequence as reference) of Changchun024 and Changchun029, using HEV type A sequences and poliovirus 1 and EV68 as outgroups. A sliding window size of 200 bases and step size of 20 bases was used.</p