Gut microbiota affects obesity susceptibility in mice through gut metabolites.

Introduction: It is well-known that different populations and animals, even experimental animals with the same rearing conditions, differ in their susceptibility to obesity. The disparity in gut microbiota could potentially account for the variation in susceptibility to obesity. However, the precise impact of gut microbiota on gut metabolites and its subsequent influence on susceptibility to obesity remains uncertain. Methods: In this study, we established obesity-prone (OP) and obesity-resistant (OR) mouse models by High Fat Diet (HFD). Fecal contents of cecum were examined using 16S rDNA sequencing and untargeted metabolomics. Correlation analysis and MIMOSA2 analysis were used to explore the association between gut microbiota and intestinal metabolites. Results: After a HFD, gut microbiota and gut metabolic profiles were significantly different between OP and OR mice. Gut microbiota after a HFD may lead to changes in eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), a variety of branched fatty acid esters of hydroxy fatty acids (FAHFAs) and a variety of phospholipids to promote obesity. The bacteria g_Akkermansia (Greengene ID: 175696) may contribute to the difference in obesity susceptibility through the synthesis of glycerophosphoryl diester phosphodiesterase (glpQ) to promote choline production and the synthesis of valyl-tRNA synthetase (VARS) which promotes L-Valine degradation. In addition, gut microbiota may affect obesity and obesity susceptibility through histidine metabolism, linoleic acid metabolism and protein digestion and absorption pathways.

High-Density Dynamic Bonds Cross-Linked Hydrogel with Tissue Adhesion, Highly Efficient Self-Healing Behavior, and NIR Photothermal Antibacterial Ability as Dressing for Wound Repair.

Multifunctional hydrogels with tissue adhesion, self-healing behavior, and antibacterial properties have potential in wound healing applications. However, their inefficient self-healing behavior and antibacterial agents can cause long-term cytotoxicity and drug resistance, considerably limiting their clinical use. Herein, we reported a PDA@LA hydrogel constructed by introducing polydopamine nanoparticles (PDA-NPs) into a high-density dynamic bonds cross-linked lipoic acid (LA) hydrogel that was formed by the polymerization of LA. Because of its rich carboxyl groups, the LA hydrogel could adhere firmly to various tissues. Owing to the high-density dynamic bonds, the cut LA hydrogel exhibited highly inefficient self-healing behavior and recovered to its uncut state after self-healing for 10 min. After the introduction of the PDA-NPs, the hydrogel was able to heat up to more than 40 °C to kill approximately 100% of the Escherichia coli and Staphylococcus aureus under near-infrared (NIR) laser, thus resisting wound infections. Because no toxic antibacterial agent was used, the PDA@LA hydrogel caused mild long-term cytotoxicity or drug resistance. Consequently, the adhesive, highly efficient self-healing, and NIR photothermal antibacterial PDA@LA hydrogel exhibits considerable potential for clinical use.

In Situ Implantation of Chitosan Oligosaccharide-Doped Lipoic Acid Hydrogel Breaks the "Vicious Cycle" of Inflammation and Residual Tumor Cell for Postoperative Skin Cancer Therapy.

Surgical excision is the main treatment for skin cancer, but the tumor recurrence caused by the "vicious cycle" between residual tumor cells and postoperative inflammation remains a challenge. Herein, a new material, which can break the "vicious cycle", was developed by incorporating chitosan oligosaccharides into lipoic acid hydrogel (COS@LA-hydrogel). When implanted at the resection site, the COS@LA-hydrogel would have a sustained release of LA and COS, which could not only kill residual tumor cells by synergistically reducing AKT phosphorylation but also decrease inflammation by inhibiting the expression of tumor necrosis factor-α (TNF-α) and inhibiting bacterial infection, respectively. As a proof of concept, in the postoperative melanoma resection model, the COS@LA-hydrogel reduced the expression of pro-inflammatory factors TNF-α and interleukin-6 (IL-6) by up to 78 and 80%, respectively, and they showed almost no tumors and the median survival of the mice was 2.5 times longer than that of the control group. The hydrogel with the function of "vicious cycle" breaking holds clinical potential.

Emodin alleviates lung ischemia-reperfusion injury by suppressing gasdermin D-mediated pyroptosis in rats.

BACKGROUND: Pyroptosis refers to programmed cell death associated with inflammation. Emodin has been reported to alleviate lung injuries caused by various pathological processes and attenuate ischemia-reperfusion (I/R) injuries in diverse tissues. METHODS: Lewis rats were assigned into the sham, the I/R, and the I/R + emodin groups. Emodin and phosphate-buffered saline were intraperitoneally injected into rats of the emodin group and I/R group for 30 min, respectively. These rats were then subjected to left thoracotomy followed by 90-min clamping of the left hilum and 120-min reperfusion. Sham-operated rats underwent 210-min ventilation. Lung functions, histological changes, lung edema, and cytokine levels were assessed. Protein levels were measured by western blotting. Immunofluorescence staining was conducted to evaluate pyroptosis. RESULTS: Emodin alleviated the I/R-induced lung dysfunction, lung damages, and inflammation. Protective effects of emodin against I/R-mediated endothelial pyroptosis was observed in vivo and in vitro. Mechanistically, emodin inactivated the TLR4/MyD88/NF-κB/NLRP3 pathway. CONCLUSION: Emodin attenuates lung ischemia-reperfusion injury by inhibiting GSDMD-mediated pyroptosis in rats.

Scavenging ROS and inflammation produced during treatment to enhance the wound repair efficacy of photothermal injectable hydrogel.

Injectable hydrogels with near infrared (NIR) photothermal ability show attractive application prospects in the treatment of wound infection and promoting skin defect repair. Nevertheless, excess reactive oxygen species (ROS) and inflammatory responses caused by bacterial infection and photothermal therapy (PTT) would delay tissue regeneration and wound healing. In this study, a novel NIR photothermal injectable hydrogel with anti-oxidation and anti-inflammation by incorporating α-lipoic acid modified palladium nanoparticles into calcium ions crosslinked sodium alginate hydrogel was developed. The resulting hydrogel facilitated to fill perfectly various irregular wounds, and could convert NIR light into local high-heat to kill >80 % of Escherichia coli and Staphylococcus aureus. Remarkably, the hydrogel exhibited excellent anti-oxidant and anti-inflammatory activity, which could scavenge >60 % of ROS in cells and decrease the relative expression level of tumor necrosis factor-alpha and interleukin-1ß genes by 52.9 % and 53.3 % respectively. It was found that the NIR photothermal injectable hydrogel with anti-oxidation and anti-inflammation could effectively reduce ROS and inflammation caused by bacterial infection and PPT. Additionally, it could also enhance wound repair efficiency. The hydrogel is expected to be a potential wound dressing for the treatment of clinical skin defects.

Hydrogen-bond super-amphiphile based drug delivery system: design, synthesis, and biological evaluation.

Drug delivery systems (DDSs) show great application prospects in tumor therapy. So far, physical encapsulation and covalent grafting were the two most common strategies for the construction of DDSs. However, physical encapsulation-based DDSs usually suffered from low drug loading capacity and poor stability, and covalent grafting-based DDSs might reduce the activity of original drug, which greatly limited their clinical application. Therefore, it is of great research value to design a new DDS with high drug loading capacity, robust stability, and original drug activity. Herein, we report a super-amphiphile based drug delivery system (HBS-DDS) through self-assembly induced by hydrogen bonds between amino-substituted N-heterocycles of the 1,3,5-triazines and hydrophilic carmofur (HCFU). The resulting HBS-DDS had a high drug loading capacity (38.1%) and robust stability. In addition, the drug delivery system exhibited pH-triggered size change and release of drugs because of the pH responsiveness of hydrogen bonds. In particular, the anticancer ability test showed that the HBS-DDS could be efficiently ingested by tumor cells, and its half-maximal inhibitory concentration (IC50 = 3.53 µg mL-1) for HeLa cells was close to that of free HCFU (IC50 = 5.54 µg mL-1). The hydrogen bond-based DDS represents a potential drug delivery system in tumor therapy.

Cross-linked small-molecule capsules with excitation wavelength-dependent photoluminescence and high loading capacity: design, synthesis and application in imaging-guided drug delivery.

The cross-linked small-molecule micelles (cSMs) have found applications in many fields but their low loading capacity and non-fluorescence property hindered their further development. Herein, water-soluble organic nanoparticles were applied as templates to "stretch" the hydrophobic core of cSMs and photo-cross-linking was employed to supply photoluminescence. The resulting cross-linked small-molecule capsules (cSCs) not only reserve the superior properties of cSMs of accurate monomer, easy functionalization and robust stability, but also achieve high drug loading capacity and excitation wavelength-dependent fluorescence, where the drug loading contents (DLCs) for various hydrophobic drugs were more than 30-fold higher than that of cSMs, and the maximum quantum yield could be as high as 12.0%. Featuring these superiorities, the cSCs hold promising potential in many fields and an example of doxorubicin-loaded cSCs (DOX@cSCs) for multichannel imaging-guided drug delivery is shown in this work.

Cytotoxic T lymphocyte antigen-2 alpha induces apoptosis of murine T-lymphoma cells and cardiac fibroblasts and is regulated by cAMP/PKA.

The mechanism of cAMP-promoted apoptosis is not well defined. In wild-type (WT) murine S49 lymphoma cells, cAMP promotes apoptosis in a protein kinase A (PKA)-dependent manner. We find that treatment of WT S49 cells with 8-CPT-cAMP prominently increases the expression (as determined by DNA microarray analysis, real-time PCR and immunblotting) of cytotoxic T lymphocyte antigen-2α (CTLA-2α), a cathepsin L-like cysteine protease inhibitor. By contrast, CTLA-2α expression is only slightly increased by 8-CPT-cAMP treatment of D-S49 cells, which lack cAMP/PKA-promoted apoptosis. Raising endogenous cAMP (by use of forskolin or inhibition of phosphodiesterase [PDE] 4) or a PKA-selective, but not an Epac-selective, cAMP analogue, increases CTLA-2α mRNA expression; PKA, and not Epac, thus mediates the increase in CTLA-2α expression. An adenoviral CLTA-2α (Ad-CTLA-2α) construct induces apoptosis and enhances cAMP-promoted apoptosis in WT S49 cells but such cells do not have an increase in cathepsin L activity nor does a cathepsin L inhibitor alter cAMP-promoted apoptosis. 8-CPT-cAMP also increases CTLA-2α expression and induces apoptosis in murine cardiac fibroblasts; knockdown of CTLA-2α expression by siRNA blocks 8-CPT-cAMP-promoted apoptosis. Thus, cAMP increases CTLA-2α expression in murine lymphoma and cardiac fibroblasts and this increase in CTLA-2α contributes to cAMP/PKA-promoted apoptosis by mechanisms that are independent of the ability of CTLA-2α to inhibit cathepsin L.