Apoptotic Vesicles Modulate Endothelial Metabolism and Ameliorate Ischemic Retinopathy via PD1/PDL1 Axis.

Pathological angiogenesis with subsequent disturbed microvascular remodeling is a major cause of irreversible blindness in a number of ischemic retinal diseases. The current anti-vascular endothelial growth factor therapy can effectively inhibit angiogenesis, but it also brings significant side effects. The emergence of stem cell derived extracellular vesicles provides a new underlining strategy for ischemic retinopathy. Apoptotic vesicles (apoVs) are extracted from stem cells from human exfoliated deciduous teeth (SHED). SHED-apoVs are delivered into the eyeballs of oxygen-induced retinopathy (a most common model of angiogenic retinal dieseases) mice through intravitreal injection. The retinal neovascularization and nonperfusion area, vascular structure, and density changes are observed during the neovascularization phase (P17) and vascular remodeling phase (P21), and visual function is measured. The expression of extracellular acidification rate and lactic acid testing are used to detect endothelial cells (ECs) glycolytic activity. Furthermore, lentivirus and neutralizing antibody are used to block PD1-PDL1 axis, investigating the effects of SHED-apoVs on glycolysis and angiogenic activities. This work shows that SHED-apoVs are taken up by ECs and modulate the ECs glycolysis, leading to the decrease of abnormal neovessels and vascular remodeling. Furthermore, it is found that, at the molecular level, apoVs-carried PD1 interacts with PDL1 on hypoxic ECs to regulate the angiogenic activation. SHED-apoVs inhibit pathological angiogenesis and promote vascular remodeling in ischemic retinopathy partially by modulating ECs glycolysis through PD1/PDL1 axis. This study provides a new potential strategy for the clinical treatment of pathological retinal neovascularization.

Identification of Putative Bacterial Pathogens for Orofacial Granulomatosis Based on 16S rRNA Metagenomic Analysis.

Orofacial granulomatosis (OFG) is a chronic inflammatory disease characterized by nontender swelling of the orofacial tissues, the underlying cause of which remains unknown. Our previous study demonstrated that tooth apical periodontitis (AP) is involved in the development of OFG. To characterize the AP bacterial signatures of OFG patients and identify possible pathogenic bacteria that cause OFG, the compositions of the AP microbiotas in OFG patients and controls were compared using 16S rRNA gene sequencing. Pure cultures of putative bacterial pathogens were established by growing bacteria as colonies followed by purification, identification, and enrichment and then were injected into animal models to determine the causative bacteria contributing to OFG. A specific AP microbiota signature in the OFG patients was shown, characterized by the predominance of phyla Firmicutes and Proteobacteria, notably members of the genera Streptococcus, Lactobacillus, and Neisseria, were found. Streptococcus spp., Lactobacillus casei, Neisseria subflava, Veillonella parvula, and Actinomyces spp. from OFG patients were isolated and successfully cultured in vitro and then injected into mice. Ultimately, footpad injection with N. subflava elicited granulomatous inflammation. IMPORTANCE Infectious agents have long been considered to play a role in the initiation of OFG; however, a direct causal relationship between microbes and OFG has not yet been established. In this study, a unique AP microbiota signature was identified in OFG patients. Moreover, we successfully isolated candidate bacteria from AP lesions of OFG patients and assessed their pathogenicity in laboratory mice. Findings from this study may help provide in-depth insights into the role of microbes in OFG development, providing the basis for targeted therapeutic approaches for OFG.

Natural Small Molecules Enabled Efficient Immunotherapy through Supramolecular Self-Assembly in P53-Mutated Colorectal Cancer.

Nanomedicine, constructed from therapeutics, presents an advantage in drug delivery for cancer therapies. However, nanocarrier-based treatment systems have problems such as interbatch variability, multicomponent complexity, poor drug delivery, and carrier-related toxicity. To solve these issues, the natural molecule honokiol (HK), an anticancer agent in a phase I clinical trial (CTR20170822), was used to form a self-assembly nanoparticle (SA) through hydrogen bonding and hydrophobicity. The preparation of SA needs no molecular precursors or excipients in aqueous solution, and 100% drug-loaded SA exhibited superior tumor-targeting ability due to the enhanced permeability and retention (EPR) effect. Moreover, SA significantly enhanced the antitumor immunity relative to free HK, and the mechanism has notable selectivity to the p53 pathway. Furthermore, SA exhibited excellent physiological stability and inappreciable toxicity. Taken together, this supramolecular self-assembly strategy provides a safe and "molecular economy" model for rational design of clinical therapies and is expected to promote targeted therapy of HK, especially in colorectal cancer patients with obvious p53 status.

Intersection between macrophages and periodontal pathogens in periodontitis.

Periodontitis is a chronic infectious disease characterized by loss of periodontal attachment and resorption of alveolar bone. Dysregulated oral microbial community is the initial factor of periodontitis and causes excessive infiltration of immune cells in periodontal tissues. Macrophage, as an important part of the innate immune system, interacts continually with oral pathogens. Macrophages can recognize and phagocytize pathogens and apoptotic neutrophils and produce the specialized pro-resolving mediators (SPMs) playing an important role in maintaining the homeostasis of tissue microenvironment. However, macrophages may also induce abnormal immune responses with the overstimulation from pathogens, leading to the destruction of periodontal tissues and alveolar bone. Looking for targeted drugs that can regulate the activities of oral pathogens and the functions of macrophages provides a new idea for periodontitis treatment. This review summarizes the interaction between macrophages and periodontal pathogens in periodontitis, focusing on the pro-inflammation and anti-inflammation phenotypes of macrophages, and briefly concludes potential new methods of periodontitis therapy targeted at oral pathogens and macrophages.