Promising applications of D-amino acids in periprosthetic joint infection

Due to the rise in our aging population,a disproportionate demand for total joint arthroplasty(TJA)in the elderly is forecast.Periprosthetic joint infection(PJI)represents one of the most challenging complications that can occur following TJA,and as the number of primary and revision TJAs continues to rise,an increasing PJI burden is projected.Despite advances in operating room sterility,antiseptic protocols,and surgical techniques,approaches to prevent and treat PJI remain difficult,primarily due to the formation of microbial biofilms.This difficulty motivates researchers to continue searching for an effective antimicrobial strategy.The dextrorotatory-isoforms of amino acids(D-AAs)are essential components of peptidoglycan within the bacterial cell wall,providing strength and structural integrity in a diverse range of species.Among many tasks,D-AAs regulate cell morphology,spore germination,and bacterial survival,evasion,subversion,and adhesion in the host immune system.When administered exogenously,accumulating data have demonstrated that D-AAs play a pivotal role against bacterial adhesion to abiotic surfaces and subsequent biofilm formation;furthermore,D-AAs have substantial efficacy in promoting biofilm disassembly.This presents D-AAs as promising and novel targets for future therapeutic approaches.Despite their emerging antibacterial efficacy,their role in disrupting PJI biofilm formation,the disassembly of established TJA biofilm,and the host bone tissue response remains largely unexplored.This review aims to examine the role of D-AAs in the context of TJAs.Data to date suggest that D-AA bioengineering may serve as a promising future strategy in the prevention and treatment of PJI.

A novel multifunctional radioprotective strategy using P7C3 as a countermeasure against ionizing radiation-induced bone loss

Radiotherapy is a critical component of cancer care but can cause osteoporosis and pathological insufficiency fractures in surrounding and otherwise healthy bone.Presently,no effective countermeasure exists,and ionizing radiation-induced bone damage continues to be a substantial source of pain and morbidity.The purpose of this study was to investigate a small molecule aminopropyl carbazole named P7C3 as a novel radioprotective strategy.Our studies revealed that P7C3 repressed ionizing radiation(IR)-induced osteoclastic activity,inhibited adipogenesis,and promoted osteoblastogenesis and mineral deposition in vitro.We also demonstrated that rodents exposed to clinically equivalent hypofractionated levels of IR in vivo develop weakened,osteoporotic bone.However,the administration of P7C3 significantly inhibited osteoclastic activity,lipid formation and bone marrow adiposity and mitigated tissue loss such that bone maintained its area,architecture,and mechanical strength.Our findings revealed significant enhancement of cellular macromolecule metabolic processes,myeloid cell differentiation,and the proteins LRP-4,TAGLN,ILK,and Tollip,with downregulation of GDF-3,SH2B1,and CD200.These proteins are key in favoring osteoblast over adipogenic progenitor differentiation,cell matrix interactions,and shape and motility,facilitating inflammatory resolution,and suppressing osteoclastogenesis,potentially via Wnt/β-catenin signaling.A concern was whether P7C3 afforded similar protection to cancer cells.Preliminarily,and remarkably,at the same protective P7C3 dose,a significant reduction in triple-negative breast cancer and osteosarcoma cell metabolic activity was found in vitro.Together,these results indicate that P7C3 is a previously undiscovered key regulator of adipo-osteogenic progenitor lineage commitment and may serve as a novel multifunctional therapeutic strategy,leaving IR an effective clinical tool while diminishing the risk of adverse post-IR complications.Our data uncover a new approach for the prevention of radiation-induced bone damage,and further work is needed to investigate its ability to selectively drive cancer cell death.