Woolcock Institute of Medical Research

Reactive oxygen species play an integral role in physiological signaling but contribute to pathology when dysregulated. Elevated ROS levels in diseased tissues such as tumors, inflamed sites, and ischemic regions present unique biochemical triggers for targeted drug delivery. Furthermore, strategies utilizing exogenously generated ROS (e.g., via photodynamic action) provide an alternative route for spatiotemporal control. This review summarizes recent advances in ROS-responsive systems, beginning with the chemistry of ROS-cleavable linkers and the design of nanocarrier platforms capable of spatiotemporally controlled release. The integration of these carriers with theranostic functions is highlighted as a strategy to enhance selectivity and reduce systemic toxicity. Applications across oncology, inflammatory disorders, ischemia-reperfusion injury, and regenerative medicine illustrate the breadth of therapeutic potential. Key design considerations including sensitivity thresholds, payload compatibility, and surface functionalization are discussed alongside translational challenges such as stability, reproducibility, and scalability. Emerging opportunities, notably patient-specific redox profiling and biosensor-guided adaptive delivery are identified as promising routes to clinical translation. By bridging redox biology with materials science and nanomedicine, ROS-triggered drug delivery platforms demonstrate the capacity to exploit endogenous oxidative cues for improved therapeutic precision and safety, positioning them as a transformative approach in the development of next-generation controlled release systems.

Abstract Objectives Chronic insomnia (INS) is particularly prevalent in older adults and females. Sex-and age-related differences in neurophysiological markers of sleep quality (sleep spindles and slow-wave activity [SWA]) may underlie differential vulnerability to INS. This study investigated the effects of sex and insomnia on spindle and SWA beyond aging, to better understand the mechanistic differences contributing to the higher prevalence of INS in females. Methods After a habituation night, one night of sleep assessed with polysomnography was analyzed in 222 adults (aged 18-82) including 119 INS (71% female) and 103 healthy sleepers (HS; 61% female). Spindle density, slow oscillation (SO) density, relative sigma power and SWA were derived during NREM sleep. Age, group, sex, and group-by-sex interactions were examined, with age as a covariate. Results Age, insomnia, and sex each contributed uniquely to NREM oscillatory activity. INS primarily reduced spindle and SO density, while sex accounted for differences in SWA. While SWA was higher in females overall, sex differences were not significant within the INS or HS groups. Female INS reported highest rates of insomnia severity as well as lower sigma power than males in the INS group. Spindle and SO density deficits were also present in female INS relative to female HS, as well as male INS relative to male HS. Conclusions The combination of reduced sigma power in females with insomnia relative to their male counterparts, as well as less spindle and SO density compared to female healthy sleepers may contribute to greater insomnia severity in females. Statement of Significance Insomnia is a growing public health concern that is more commonly reported in females, yet the neural mechanisms underlying this sex difference remain poorly understood. Our findings suggest that specific markers of sleep quality are disproportionately disrupted in females with insomnia, potentially contributing to greater vulnerability and symptom severity. These results provide new insight into how sex influences the neurophysiology of insomnia disorder and identify oscillatory markers that could serve as targets for personalized interventions. Future research should investigate whether these alterations represent persistent dysfunction or reversible changes, which could advance understanding of the biological basis of insomnia and inform strategies to improve sleep health in at-risk populations.

The objective of this review is to evaluate how formulation-dependent PK characteristics of oral, transdermal, intramuscular (IM), and subcutaneous testosterone therapies translate to metabolic effects in hypogonadal men with T2D. A narrative review of clinical trials, PK studies, and endocrinology guidelines indexed in PubMed and Scopus up to October 2025. Evidence was synthesized comparing absorption pathways, kinetic variability, androgen receptor (AR) engagement patterns, and downstream metabolic endpoints including insulin sensitivity and glycemic control. Transdermal formulations provide relatively stable, circadian-like testosterone concentrations supporting gradual anabolic effects, whereas oral TU produces short-lived peaks with larger fluctuations that limit sustained anabolic and metabolic signaling. Oral TU utilizes lymphatic transport to reduce first-pass hepatic metabolism, increases free testosterone via hepatic SHBG suppression, yet yields lower total serum testosterone concentrations relative to injectables. Transdermal absorption is highly anatomical site-dependent, with scrotal application significantly enhancing systemic levels and DHT conversion. Short-acting IM esters generate supraphysiological peaks and deep troughs, destabilizing glucose regulation and enhancing aromatase/5α-reductase activity. In contrast, long-acting esters demonstrate flip-flop kinetics with prolonged, stable serum testosterone exposure, enabling continuous AR activation and sustained improvements in insulin sensitivity and glycemic control. Formulation-specific PK dictate hormonal stability and metabolic benefit in hypogonadal men with T2D. Long-acting injectable therapies provide the most favorable and durable endocrine-metabolic profile by maintaining continuous physiologic AR stimulation. In comparison, the more oscillatory exposure produced by transdermal gels, oral TU, and short-acting esters may deliver anabolic benefits yet insufficient hormonal stability for consistent improvements in glycaemic control. These findings reinforce the need to prioritise sustained-release formulations when targeting metabolic endpoints in men with T2D receiving TRT.

Freezing of gait (FOG) is a debilitating motor symptom observed in the advanced stages of Parkinson's disease (PD), characterized by an abrupt inability to initiate or continue forward walking. Whole-brain functional connectivity analysis has shown promise in elucidating the underlying pathophysiology and identifying potential biomarkers in PD. However, the specific changes in local brain networks during the transition from normal gait to freezing remain unclear. This study aimed to investigate changes in brain network organization during the transition to FOG compared with the transition to voluntary stopping. Eighteen PD patients with FOG performed walking tasks designed to trigger either freezing or voluntary stop events, while undergoing simultaneous ambulatory electroencephalography (aEEG) recording. Functional connectivity was estimated using phase-locking value (PLV) across multiple frequency bands, measuring the consistency of phase synchrony between brain regions, and examined network organization using graph modularity, an index of how strongly the brain segregates into functionally specialized subnetworks, focusing on the 2-second time windows preceding each event. Transitions to freezing were characterized by increased local beta-band connectivity within right frontoparietal, middle-frontal, parietal-occipital, visual, and bilateral insula regions, alongside reduced connectivity between frontal and posterior areas in lower-frequency bands. Increased local beta segregation and reduced fronto-posterior connectivity may reflect network alterations that precedes freezing episodes. Such patterns could help identify neurophysiological markers for predicting and potentially preventing FOG in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Excessive oxidative stress can cause irreversible cytotoxic damage to both healthy and cancer cells through the induction of reactive oxygen species (ROS) mediated lipid peroxidation. Ferroptosis has recently been shown to promote lipid peroxidation due to the over-accumulation of iron. Although cancer cells possess elevated antioxidant capacity to neutralize chemotherapy-induced oxidative stress, the co-delivery of polyphenol compounds such as curcumin (CUR) can overwhelm these defenses by elevating intracellular ROS levels to a toxic threshold, thereby increasing anticancer efficacy. In this study, we evaluated the potential of CUR to chemosensitize doxorubicin (DOX) towards the DOX-resistant lung cell line (H69AR). Our results demonstrated that the combination of DOX and CUR resulted in a concentration-dependent behavior, where low-dose concentrations exhibited antagonistic effects, while high-dose IC50-equivalent concentrations shifted towards synergism. The combination induced significantly greater mitochondrial dysfunction, ATP depletion, cytochrome C release, and caspase-3 activation. This also resulted in excessive ROS generation, intracellular iron overload, and lipid peroxidation, accompanied by a reduction in antioxidant enzymatic activities. Pretreatment with N-acetyl-L-cysteine (ROS inhibitor) and ferrostatin-1 (ferroptosis inhibitor) further supported the involvement of oxidative stress and ferroptosis in modulating apoptosis and DNA fragmentation. Molecular docking analyses supported the binding of CUR and DOX to key ferroptosis regulators. This study shows the potential of CUR to sensitize DOX-resistant cancer cells through ferroptosis-linked-oxidative stress targeting.

In asthma, augmented airway wall smooth muscle (ASM) bulk is a major remodeling feature, promoted by increased transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF). Runt-related transcription factor-2 (RUNX2) represses TGF-β1-induced CTGF through interactions with SMAD3. This study aimed to investigate the expression and role of RUNX2 in asthmatic and nonasthmatic ASM cells. mRNA and protein were detected by microarray, PCR, and western blot in nonasthmatic and asthmatic ASM cells. Immunohistochemistry identified RUNX2 in lung tissues from asthmatic patients and nonasthmatic subjects. Different RUNX2 isoforms were transfected into immortalized-asthmatic ASM cells, and markers of inflammation and airway remodeling were measured. RUNX2 alternatively spliced forms were examined in bronchial biopsies from asthmatic and healthy subjects. The abundance of RUNX2 was decreased in isolated ASM cells from asthmatic compared with nonasthmatic subjects. The ASM layer around airways in lung tissue sections from asthmatic and nonasthmatic patients had a heterogeneous pattern of RUNX2 protein detection. TGF-β1 stimulation increased RUNX2/RUNX2 variant 1 mRNA in nonasthmatic but not asthmatic ASM cells, facilitating SMAD3 activation and nuclear translocation in asthmatic ASM cells. RUNX2 isoform overexpression in immortalized asthmatic ASM cells failed to alter markers of inflammation (IL-6) but significantly reduced markers of remodeling (CTGF), ASM cell hypertrophy (GSK-3β and desmin), and proliferation (pSer795 Rb and α-tubulin). In bronchial biopsies, RUNX2 mRNA splicing was higher in asthmatic patients compared with healthy subjects. These data suggest RUNX2 plays a role in the homeostasis of healthy airways. Restoring RUNX2 may provide a new therapeutic approach for asthma.

Obstructive sleep apnea (OSA) is prevalent in memory clinic patients and is associated with learning and memory deficits. In a memory clinic sample, we investigated the relationship between memory-related white matter pathways and OSA. Eighty-two participants (mean age 67.0) underwent neuropsychological testing and neuroimaging. Fixel-based white matter analyses were conducted in the anterior thalamic radiation (ATR), cingulum, uncinate fasciculus (UF), and fornix. Oxygen desaturation index (ODI) from overnight polysomnography classified participants as controls (ODI<5, n=26), mild OSA (ODI 5-14, n=32), or moderate and severe OSA (ODI ≥ 15, n=24). In mild OSA, white matter changes were seen in the ATR, UF, and fornix. In moderate and severe OSA, alterations were observed in the cingulum and fornix. Cingulum changes were linked to poorer verbal learning and memory. OSA is associated with disrupted memory-related pathways. Cingulum changes are associated with memory performance in moderate and severe cases.

Precise targeting of the tumor micro-environment (TME) through nanotherapeutic innovations offers a transformative approach to cancer treatment. In order to increase the treatment efficacy, this review delves into the complex tactics for targeting different parts of the TME. Targeting the extracellular matrix, controlling acidosis and hypoxia, and preventing neovascularization by concentrating on pericytes and endothelial cells are important areas covered in this article. Strategies to stimulate anti-tumor immunity, regulate chronic inflammation, and restrict macrophage recruitment emphasize the immune system's participation. We have also highlighted the role of fibroblasts and exosomes linked to the cancer progression. The EPR effect, which is vital for cancer nanotherapeutics to work, and vascular pathophysiology are also included in the review. We examine how changes to the dynamics of pH inside the TME affect by nano-therapeutics. Additionally, the possibility of prodrug therapy within the TME, the use of controlled release mechanisms in nanocarriers to imitate metronomic therapy has been discussed. Lastly, the paper examines nanoparticle preference targeting as a potential strategy to improve treatment specificity and therapeutic efficacy in cancer management.

BackgroundThe Global Initiative for Asthma recommends as-needed combination inhaled corticosteroid-formoterol reliever for mild asthma. Its cost-effectiveness is uncertain outside double-blind regulatory trials. The study objectives were to assess the cost-effectiveness of as-needed budesonide-formoterol versus maintenance budesonide plus as-needed salbutamol, and versus as-needed salbutamol, in averting exacerbations in adults with mild asthma during 12-month follow-up of the New Zealand participants (n=551) of the open-label Novel START multicountry clinical trial.MethodsNew Zealand health-system and societal perspectives were adopted using 2025 resource costs. Healthcare utilisation comprised electronically monitored inhaler use (with multiple imputation for missing data), asthma-related pharmaceuticals, primary-care visits, emergency-department visits and hospitalisations. Regression methods were used for cost-effectiveness analysis. Scenarios included generic substitution and prescription-charge exemption.ResultsAs-needed budesonide-formoterol, compared with maintenance budesonide plus as-needed salbutamol, is more effective at reducing severe exacerbations and provides an annual health-system cost saving of NZD 12 (95% CI 0–28) per patient, increasing to NZD 22 (95% CI −15–58) if a societal perspective is adopted. Compared with as-needed salbutamol alone, as-needed budesonide-formoterol costs the health system NZD 38 and NZD 111, respectively, to prevent an exacerbation and a severe exacerbation. From a societal perspective it is cost-saving NZD 70 (95% CI 2–134). Findings were robust to scenario analyses.ConclusionFor patients with mild asthma, as-needed budesonide-formoterol 200/6 μg is cost-saving from health-system, patient and societal perspectives, while improving outcomes, dominating maintenance budesonide plus as-needed salbutamol. Compared with as-needed salbutamol, as-needed budesonide-formoterol is cost-effective from a health-system perspective and dominates from a societal perspective.