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The efficacy of conventional antimicrobials is falling to critical levels and raising alarming concerns around the globe. In this scenery, engineered nanoparticles emerged as a solid strategy to fight growing deadly infections. Here, we show the in vitroand in vivoperformance of pharmadendrimers, a novel class of engineered polyurea dendrimers that are synthetic mimics of antibacterial peptides, against a collection of both Gram-positive and Gram-negative bacteria and fungi. These nanobiomaterials are stable solids prepared by low-cost and green processes, display a dense positively charged core–shell, and are biocompatible and hemocompatible drugs. Mechanistic data, corroborated by coarse-grained molecular dynamics simulations, points towards a fast-killing mechanism viamembrane disruption, triggered by electrostatic interactions. Altogether this study provides strong evidence and support for the future use of polyurea pharmadendrimers in antibacterial and antifungal nanotherapeutics.

Chronic kidney disease (CKD), a pressing global health issue, affects millions and leads to end-stage renal disease (ESRD). Hemodialysis (HD) is a crucial treatment for ESRD, yet its limited efficiency in removing protein-bound uremic toxins (PBUTs) results in high morbidity and mortality rates. A high affinity of pharmaceutical drugs for human serum albumin (HSA) can be leveraged to compete effectively with PBUTs for the same HSA binding sites, thereby enabling them to be capable of displacing these toxins. One such drug is ibuprofen (IBF), known for its very high affinity for HSA and sharing the same binding site as indoxyl sulfate (IS). This study explores the development of IBF-immobilized cellulose acetate-based (CA-based) thin films. The films were created by reacting CA with IBF-modified silica precursors at varying concentrations. The presence of IBF in CA/TEOS/APTES-IBF-3 and CA/TEOS-IBF-25 films, containing 3 and 25 wt % IBF, respectively, was confirmed through 1H NMR spectra. Competitive displacement binding assays indicated that while the incorporation of 3 wt % IBF showed no significant enhancement in IS displacement, the 25 wt % IBF film increased the dialyzed IS by 1.3 when normalized to non-IBF films. Furthermore, there was a 1.2-fold decrease in the total percentage of IS, and the free percentage of IS increased 1.3 to 3.0 times. Although direct systemic infusion of IBF in HD patients achieves a 2.4 times higher removal of IS, it is impractical due to the risks it poses to ESRD patients. The IBF-immobilized films offer the advantage of localized binding, thus eliminating the need for systemic exposure. This innovative approach lays a foundation for developing more efficient HD membranes, aiming to address the challenging issue of PBUT elimination and potentially enhance the quality of life and treatment outcomes for ESRD patients.

IntroductionTraumatic brain injury (TBI) affects both young and elderly populations and results in a significant global healthcare burden. TBI patients often suffer from costly long-term neurological and cognitive problems that reduce quality of life and ability to work, including motor deficits, gait abnormalities, memory impairments and anxiety. Current clinical practice for TBI is largely supportive, centred on non-specific endpoints such as management of tissue oxygenation, cerebral perfusion pressure and intracranial pressure. At present there are no clinically validated drug treatments aimed specifically at preventing neuronal loss following TBI. Xenon is a noble gas used medically as a general anaesthetic and in MRI imaging. We previously showed xenon-treatment improves short and long-term outcomes, prevents late-onset cognitive impairments and improves survival after moderate TBI in mice. The aim of this study is to evaluate the efficacy of xenon in a second species, rats, and in a severe injury model.MethodAdult male Sprague Dawley rats (N=22) underwent controlled cortical impact (CCI) brain trauma or sham surgery. Animals were randomised to receive either 50%Xe:25%O2:25%N2 or 75%N2:25%O2. Locomotor function (CatwalkXT) and histological outcomes [lesion volume, neuronal cell count (NeuN), microglia (Iba1) and astrocytes (GFAP)] were assessed by blinded observers.ResultsThe xenon-treated group exhibited a reduction in locomotor deficits. Lesion volume was reduced in the xenon-treated group. Xenon-treatment resulted in preservation of neurons in cortical and subcortical regions that was associated with increases in numbers of resting microglia and reactive astrocytes.ConclusionWe show xenon is neuroprotective after severe TBI in rats. Functional improvement and neuronal preservation was associated with a xenon-induced enhancement of resting microglial cell numbers and astrocyte activation. These findings are consistent with a role for early beneficial neuroinflammation in xenon’s neuroprotective effect. Xenon may be of benefit in the treatment of clinical brain trauma.

Tributyltin chloride (TBT) is an environmental contaminant that is used as a biocide in antifouling paints. TBT has been shown to induce endocrine-disrupting effects. However, studies evaluating the effects of TBT on the hypothalamus-pituitary-adrenal (HPA) axis are especially rare. The current study demonstrates that exposure to TBT is critically responsible for the improper function of the mammalian HPA axis as well as the development of abnormal morphophysiology in the pituitary and adrenal glands. Female rats were treated with TBT, and their HPA axis morphophysiology was assessed. High CRH and low ACTH expression and high plasma corticosterone levels were detected in TBT rats. In addition, TBT leads to an increased in the inducible nitric oxide synthase protein expression in the hypothalamus of TBT rats. Morphophysiological abnormalities, including increases in inflammation, a disrupted cellular redox balance, apoptosis, and collagen deposition in the pituitary and adrenal glands, were observed in TBT rats. Increases in adiposity and peroxisome proliferator-activated receptor-γ protein expression in the adrenal gland were observed in TBT rats. Together, these data provide in vivo evidence that TBT leads to functional dissociation between CRH, ACTH, and costicosterone, which could be associated an inflammation and increased of inducible nitric oxide synthase expression in hypothalamus. Thus, TBT exerts toxic effects at different levels on the HPA axis function.