Background: There are still no detailed data about the burden of bacterial antimicrobial resistance (AMR) in urinary tract infections (UTI). Concrete knowledge of global and regional bacterial AMR data is crucial for developing informed programs and policies to control bacterial AMR and for prudent use of antibiotics to optimize antibiotic therapy in patients with UTI. This study aimed to provide comprehensive global and regional estimates for the AMR burden of UTI in 2019. Methods: Data were obtained from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), including death, disability-adjusted life-years (DALYs), year lived with disability (YLD), and years of life lost (YLL) for bacterial AMR in UTI for 7 GBD super-regions, 21 regions, 14 pathogens, 13 antibiotic classes, and 66 pathogen-antibiotic combinations in 2019. The estimates were based on two counterfactual scenarios: drug-susceptible infection and no infection. Results: Globally, there were 64.89 thousand deaths (95% uncertainty interval [UI]: 45.86–93.35) attributed to and 0.26 million deaths (95% UI: 0.18–0.36) associated with bacterial AMR in UTI in 2019. Among regions, the all-age death rates were higher in southern Latin America, tropical Latin America, and Europe and lower in sub-Saharan Africa. Escherichia coli and Klebsiella pneumoniae accounted for more than 50% of deaths attributable to and associated with AMR, and resistance was high among multiple types of antibiotic class, including fluoroquinolones, carbapenems, and third-generation cephalosporins. There were 2 pathogen-drug combinations that caused more than 6000 resistance-attributable deaths: third-generation cephalosporin-resistant Escherichia coli and fluoroquinolone-resistant Escherichia coli. Conclusions: AMR in UTI is an unignorable health problem, both for the management of urology disease and for global antibiotic resistance. Special tailored strategies, including enhanced surveillance and rational use of antibiotics, should be developed for different regions according to the region-specific pathogen-antibiotic situations and resources.

Ferroptosis plays a crucial role in the progression of diabetic wounds, suggesting potential therapeutic strategies to target ferroptosis. Transient receptor potential ankyrin 1 (TRPA1) is a non-selective calcium channel that acts as a receptor for a variety of physical or chemical stimuli. Cinnamaldehyde (CA) is a specific TRPA1 agonist. In in vitro experiments, we observed that high glucose (HG) treatment induced endothelial cell ferroptosis, impairing cell function. CA successfully inhibited endothelial cell ferroptosis, improving migration, proliferation, and tube formation. Further mechanistic studies showed that CA-activated TRPA1-induced Ca²⁺ influx promoted the phosphorylation of calmodulin-dependent protein kinase II (CaMKII) and nuclear factor-E 2-related factor 2 (Nrf2) translocation, which contributed to the elevation of glutathione peroxidase 4 (GPX4), leading to the inhibition of endothelial cell ferroptosis. In addition, CA was incorporated into an MMP-9-responsive injectable duplex hybrid hydrogel (CA@HA-Gel), allowing its efficient sustained release into diabetic wounds in an inflammation-responsive manner. The results showed that CA@HA-Gel inhibited wound endothelial cell ferroptosis and significantly promoted diabetic wound healing. In summary, the results presented in this study emphasize the potential therapeutic application of CA@HA-Gel in the treatment of diseases associated with ferroptosis.

It is imperative to develop and implement newer, more effective strategies to address refractory diabetic wounds. As of now, there is currently no optimal solution for these wounds. Hypoxic human umbilical vein endothelial cells (HUVECs)-derived exosomes have been postulated to promote diabetic wound healing, however, its effect and molecular mechanism need further study. In this study, we aimed to investigate whether hypoxic exosomes enhance wound healing in diabetics. Based on our high-throughput sequencing, differentially expressed lncRNAs (including 64 upregulated lncRNAs and 94 downregulated lncRNAs) were found in hypoxic exosomes compared to normoxic exosomes. Interestingly, lncHAR1B was one of the prominently upregulated lncRNAs in hypoxic exosomes, showing a notable correlation with diabetic wound healing. More specifically, hypoxic exosomes were transmitted to surrounding cells, which resulted in a significant increase in lncHAR1B level, thereby relieving the dysfunction of endothelial cells and promoting the switch from M1 to M2 macrophages under high glucose conditions. Mechanistically, lncHAR1B directly interacted with the transcription factor basic helix-loop-helix family member e23 (BHLHE23), which subsequently led to its binding to the KLF transcription factor 4 (KLF4) and promoted KLF4 expression. In our in vivo experiments, the use of hypoxic exosomes-loaded HGM-QCS hydrogels (Gel-H-Exos) resulted in rapid wound healing compared to that of normoxic exosomes-loaded HGM-QCS hydrogels (Gel-N-Exos) and diabetic groups. Consequently, our study provides potentially novel therapeutic approaches aimed at accelerating wound healing and developing a practical exosomes delivery platform.

The diabetic wounds remain to be unsettled clinically, with chronic wounds characterized by drug-resistant bacterial infections, compromised angiogenesis and oxidative damage to the microenvironment. To ameliorate oxidative stress and applying antioxidant treatment in the wound site, we explore the function of folliculin-interacting protein 1 (FNIP1), a mitochondrial gatekeeper protein works to alter mitochondrial morphology, reduce oxidative phosphorylation and protect cells from unwarranted ROS accumulation. And our in vitro experiments showed the effects of FNIP1 in ameliorating oxidative stress and rescued impaired angiogenesis of HUVECs in high glucose environment. To realize the drug delivery and local regulation of FNIP1 in diabetic wound sites, a novel designed glucose-responsive HA-PBA-FA/EN106 hydrogel is introduced for improving diabetic wound healing. Due to the dynamic phenylboronate ester structure with a phenylboronic acid group between hyaluronic acid (HA) and phenylboronic acid (PBA), the hydrogel is able to realize a glucose-responsive release of drugs. Fulvic acid (FA) is added in the hydrogel, which not only severs as crosslinking agent but also provides antibacterial and anti-inflammatory abilities. Moreover, the release of FEM1b-FNIP1 axis inhibitor EN106 ameliorated oxidative stress and stimulated angiogenesis through FEM1b-FNIP1 axis regulation. These in vivo and in vitro results demonstrated that accelerated diabetic wounds repair with the use of the HA-PBA-FA/EN106 hydrogel, which may provide a promising strategy for chronic diabetic wound repair.