Carbapenem-resistant Acinetobacter baumannii (CRAB) which is noted as a major pathogen associated with healthcare-associated infections has steadily developed beyond antibiotic control. Lytic bacteriophages with the characteristics of infecting and lysing specific bacteria have been used as a potential alternative to traditional antibiotics to solve multidrug-resistant bacterial infections. Here, we isolated A. baumannii-specific lytic phages and evaluated their potential therapeutic effect against lung infection caused by CRAB clinical strains. The combined lysis spectrum of four lytic phages’ ranges was 87.5% (42 of 48) against CRAB clinical isolates. Genome sequence and analysis indicated that phage SH-Ab15519 is a novel phage which does not contain the virulence or antibiotic resistance genes. In vivo study indicated that phage SH-Ab15519 administered intranasally can effectively rescue mice from lethal A. baumannii lung infection without deleterious side effects. Our work explores the potential use of phages as an alternative therapeutic agent against the lung infection caused by CRAB strains.

Current treatments for diabetic ulcers (DUs) remain unsatisfactory due to the risk of bacterial infection and impaired angiogenesis during the healing process. The increased degradation of polyubiquitinated hypoxia‐inducible factor‐1α (HIF‐1α) compromises wound healing efficacy. Therefore, the maintenance of HIF‐1α protein stability might help treat DU. Nitric oxide (NO) is an intrinsic biological messenger that functions as a ubiquitination flow repressor and antibacterial agent; however, its clinical application in DU treatment is hindered by the difficulty in controlling NO release. Here, an intelligent near‐infrared (NIR)‐triggered NO nanogenerator (SNP@MOF‐UCNP@ssPDA‐Cy7/IR786s, abbreviated as SNP@UCM) is presented. SNP@UCM represses ubiquitination‐mediated proteasomal degradation of HIF‐1α by inhibiting its interaction with E3 ubiquitin ligases under NIR irradiation. Increased HIF‐1α expression in endothelial cells by SNP@UCM enhances angiogenesis in wound sites, promoting vascular endothelial growth factor (VEGF) secretion and cell proliferation and migration. SNP@UCM also enables early detection of wound infections and ROS‐mediated killing of bacteria. The potential clinical utility of SNP@UCM is further demonstrated in infected full‐thickness DU model under NIR irradiation. SNP@UCM is the first reported HIF‐1α‐stabilizing advanced nanomaterial, and further materials engineering might offer a facile, mechanism‐based method for clinical DU management.

Diabetic osteoporosis (DOP) is the leading complication continuously threatening the bone health of patients with diabetes. A key pathogenic factor in DOP is loss of osteocyte viability. However, the mechanism of osteocyte death remains unclear. Here, we identified ferroptosis, which is iron-dependent programmed cell death, as a critical mechanism of osteocyte death in murine models of DOP. The diabetic microenvironment significantly enhanced osteocyte ferroptosis in vitro, as shown by the substantial lipid peroxidation, iron overload, and aberrant activation of the ferroptosis pathway. RNA sequencing showed that heme oxygenase-1 (HO-1) expression was notably upregulated in ferroptotic osteocytes. Further findings revealed that HO-1 was essential for osteocyte ferroptosis in DOP and that its promoter activity was controlled by the interaction between the upstream NRF2 and c-JUN transcription factors. Targeting ferroptosis or HO-1 efficiently rescued osteocyte death in DOP by disrupting the vicious cycle between lipid peroxidation and HO-1 activation, eventually ameliorating trabecular deterioration. Our study provides insight into DOP pathogenesis, and our results provide a mechanism-based strategy for clinical DOP treatment.

Osteocytes, essential regulators of bone homeostasis, are embedded in the mineralized bone matrix. Given the spatial arrangement of osteocytes, bioprinting represents an ideal method to biofabricate a 3D osteocyte network with a suitable surrounding matrix similar to native bone tissue. Here, we reported a 3D bioprinted osteocyte-laden hydrogel for biomimetic mineralization in vitro with exceptional shape fidelity, a high cell density (107 cells per ml) and high cell viability (85%–90%). The bioinks were composed of biomimetic modified biopolymers, namely, gelatine methacrylamide (GelMA) and hyaluronic acid methacrylate (HAMA), with or without type I collagen. The osteocyte-laden constructs were printed and cultured in mineralization induction media. After 28 d, increased dendritic cell connections and enhanced mineralized matrix production were observed after the addition of type I collagen. These results were further confirmed by the expression of osteocyte-related genes, markers of osteocyte morphology (Connexin43 and E11/Podoplanin), markers of mineralization (dentin matrix acidic phosphoprotein 1 (Dmp1)) and the cellular response to parathyroid hormone (PTH). Moreover, the 3D bioprinting constructs outperformed the 2D monolayer culture and they were at least comparable to 3D casted hydrogels in mimicking the natural osteocyte phenotype. All results indicated that the 3D bioprinting osteocyte network shows promise for mechanistic studies and pharmaceutical screening in vitro.

No abstract

tRNA-derived fragments, a class of small noncoding RNAs (sncRNAs), have been identified in numerous studies in recent years. tRNA-derived fragments are classified into two main groups, including tRNA halves (tiRNAs) and tRNA-derived small RNA fragments (tRFs), according to different cleavage positions of the precursor or mature tRNAs. Instead of random tRNA degradation debris, a growing body of evidence has shown that tRNA-derived fragments are precise products of specific tRNA modifications and play important roles in biological activities, such as regulating protein translation, affecting gene expression, and altering immune signaling. Recently, the relations between tRNA-derived fragments and the occurrence of human diseases, especially cancers, have generated wide interest. It has been demonstrated that tRNA-derived fragments are involved in cancer cell proliferation, metastasis, progression and survival. In this review, we will describe the biogenesis of tRNA-derived fragments, the distinct expression and function of tRNA-derived fragments in the development of cancers, and their emerging roles as diagnostic and prognostic biomarkers and precise targets of future treatments.

Large bone defects face a high risk of pathogen exposure due to open wounds, which leads to high infection rates and delayed bone union. To promote successful repair of infectious bone defects, fabrication of a scaffold with dual functions of osteo-induction and bacterial inhibition is required. This study describes creation of an engineered progenitor cell line (C3H10T1/2) capable of doxycycline (DOX)-mediated release of bone morphogenetic protein-2 (BMP2). Three-dimensional bioprinting technology enabled creation of scaffolds, comprising polycaprolactone/mesoporous bioactive glass/DOX and bioink, containing these engineered cells. In vivo and in vitro experiments confirmed that the scaffold could actively secrete BMP2 to significantly promote osteoblast differentiation and induce ectopic bone formation. Additionally, the scaffold exhibited broad-spectrum antibacterial capacity, thereby ensuring the survival of embedded engineered cells when facing high risk of infection. These findings demonstrated the efficacy of this bioprinted scaffold to release BMP2 in a controlled manner and prevent the occurrence of infection; thus, showing its potential for repairing infectious bone defects.

Summary Pyruvate is a key metabolite in glycolysis and the tricarboxylic acid (TCA) cycle. Exogenous pyruvate modulates metabolism, provides cellular protection, and is essential for the maintenance of human preimplantation embryos and human embryonic stem cells (hESCs). However, little is known about how pyruvate contributes to cell-fate determination during epiblast stage. In this study, we used hESCs as a model to demonstrate that elevated exogenous pyruvate shifts metabolic balance toward oxidative phosphorylation in both maintenance and differentiation conditions. During differentiation, pyruvate potentiates mesoderm and endoderm lineage specification. Pyruvate production and its mitochondrial metabolism are required in BMP4-induced mesoderm differentiation. However, the TCA-cycle metabolites do not have the same effect as pyruvate on differentiation. Further study shows that pyruvate increases AMP/ATP ratio, activates AMPK, and modulates the mTOR pathway to enhance mesoderm differentiation. This study reveals that exogenous pyruvate not only controls metabolism but also modulates signaling pathways in hESC differentiation.