Age-related impaired wounds represent a major health burden resulting in considerable morbidity and mortality in the elderly. When injury occurs, monocytes migrate to the damaged site and undergo differentiation into tissue-resident macrophages, which are crucial for wound repair. For proper resolution of the inflammatory response, macrophages differentiate into two distinct phenotypes classified as classically-activatedpro-inflammatory and alternatively-activatedanti-inflammatory macrophages. Pro-inflammatory macrophages are commonly linked with pro-inflammatory events, while anti-inflammatory macrophages are known to be pro-regenerative. The age-related delay in wound repair is often attributed to the age-related decrease in local and systemic estrogen levels in both genders. However, despite its well-documented anti-inflammatory effect in wound healing, the role of estrogen and involvement of Estrogen Receptors (ERs) in macrophage polarization has gained little attention to date. To investigate the impact of estrogen and ERs on the polarization of macrophages, monocyte-derived macrophages were pre-treated with estrogen, ER-alpha agonist/antagonist or ER-beta agonist/antagonist prior to stimulation with LPS/IFN-γ or IL-4/IL-13 to produce pro-inflammatory or anti-inflammatory macrophages. Our findings confirm that estrogen promotes the alternative activation of macrophages via possible ER-α signalling. Selective targeting of ER-α with agents like PPT could potentially lead to the development of novel therapies to treat excessive inflammation in impaired wounds.

A retrospective descriptive study included patients admitted with severe burns over the course of 10 years (2008–2018). Across all patients, there were 39 different species of bacteria, with 23 species being Gram-negative and 16 being Gram-positive bacteria, with also five different species of fungi cultured. Pseudomonas aeruginosa was the most commonly isolated organism, with 57.45% of patients having a positive culture. There was a significant difference in the number of P. aeruginosa isolated from patients that acquired their burns at work, in a garden, inside a vehicle, in a garage or in a public place. In patients that were positive for P. aeruginosa, the number of operations was higher (2.4) and the length of stay was significantly increased (80.1 days). Patients that suffered from substance abuse demonstrated significantly higher numbers of isolated P. aeruginosa (14.8%). Patients that suffered from both mental health illness and substance abuse demonstrated significantly higher numbers of P. aeruginosa isolated (18.5%). In the P. aeruginosa-negative group, there were significantly fewer patients that had been involved in a clothing fire. Furthermore, in the P. aeruginosa-negative patient cohort, the mortality rate was significantly higher (p = 0.002). Since the incidence of P. aeruginosa was also associated with a decreased mortality rate, it may be that patients admitted to hospital for shorter periods of time were less likely to be colonised with P. aeruginosa. This study demonstrates novel factors that may increase the incidence of P. aeruginosa isolated from burn patients.

Background/Objectives: Dyslipidemia is frequently linked to various disorders, and its clinical relevance is now recognized. The role of inflammation and oxidative stress (OS) in dyslipidemia has been acknowledged. This study assessed the potential of arbutin (ARB) to prevent dyslipidemia and its associated OS and inflammation in rats with acute hyperlipidemia. Methods: Rats received ARB orally for 14 days and a single intraperitoneal injection of poloxamer-407 on day 15. Results: Poloxamer-407 elevated circulating cholesterol (CHOL), triglycerides (TG), very low-density lipoprotein (vLDL), and LDL, and reduced high-density lipoprotein (HDL)-C and lipoprotein lipase (LPL). ARB ameliorated the circulating lipids and LPL, and suppressed 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR) in rat liver and in vitro. Fatty acid synthase (FAS) in rat liver and its in vitro activity were suppressed by ARB, which also upregulated the LDL receptor (LDL-R) and ABCA1, and had no effect on ABCG5 and ABCG8 mRNA. ARB ameliorated liver malondialdehyde and nitric oxide and enhanced antioxidants in rats with dyslipidemia. Liver NF-κB p65 and blood inflammatory cytokines were increased in dyslipidemic rats, effects that were reversed by ARB. Moreover, ARB effectively suppressed lymphocyte E-NTPDase and E-ADA activities in dyslipidemic rats. The biochemical findings were supported by in silico data showing the affinity of ARB to bind LDL-R PCSK9 binding domain, HMGCR, FAS, and E-NTPDase. Conclusions: ARB possessed anti-dyslipidemia, anti-inflammatory, and antioxidant effects mediated via the modulation of CHOL and TG synthesis, LPL, lymphocyte E-NTPDase and E-ADA, and cytokine release in rats. Thus, ARB could be an effective agent to attenuate dyslipidemia and its associated OS and inflammation, pending further studies as well as clinical trials.

Age-related impaired wounds often become infected with bacteria, leading to substantial mortality and morbidity in the elderly. The decline in androgen levels with increasing age is believed to exacerbate inflammation during wound infections. Despite its well-documented anti-inflammatory activities in wound repair, little is known about the effect of age-related androgen deprivation on bacterial phagocytosis in impaired chronic wounds. The aim of this study was to investigate the effect of age-related testosterone deprivation on the phagocytic functions of THP-1 monocyte-derived macrophages to eliminate Gram-positive and Gram-negative bacteria in vitro. Host–pathogen interaction experiments were conducted to quantify the macrophage-mediated clearance of two common wound-associated bacteria, methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, under in vitro environments that model testosterone levels representative of those found in elderly males, healthy young adults and testosterone replacement therapy (TRT). Testosterone and its metabolite 5α-dihydrotestosterone (DHT) significantly dampened the macrophage-mediated phagocytosis of both MRSA and P. aeruginosa in a dose-dependent manner (p < 0.05). Blockade of the androgen receptor (AR) using enzalutamide confirmed that testosterone mediates bacterial clearance through binding to the AR. Blocking the conversion of testosterone to DHT through stimulation of macrophages with the 5-α-reductase inhibitor finasteride reversed the testosterone-mediated effects on bacterial clearance, which confirmed that testosterone could potentially dampen the innate phagocytic responses in macrophages through conversion to DHT. Novel findings in this study suggest that the selective manipulation of the AR and/or blockade of testosterone–DHT conversion may provide effective therapeutic treatments to combat wound infections in the elderly.