Fiber scaffolds augment aged bone regeneration by modulating energy metabolism, immunity and angiogenesis.

Abstract Most clinically used chemotherapeutic agents act by inducing apoptosis. However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti‐tumor immune responses. Herein, we present the first iridium(III)‐based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS–STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)‐based oncosis‐inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug‐resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt‐DNA damage, leading to robust activation of the cGAS–STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)‐based immunogenic oncosis inducers were able to effectively kill drug‐resistant cancer cells and enhance the anticancer immune response in tumor mouse models.

Most clinically used chemotherapeutic agents act by inducing apoptosis. However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti-tumor immune responses. Herein, we present the first iridium(III)-based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS-STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)-based oncosis-inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug-resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt-DNA damage, leading to robust activation of the cGAS-STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)-based immunogenic oncosis inducers were able to effectively kill drug-resistant cancer cells and enhance the anticancer immune response in tumor mouse models.

Adenosine triphosphate (ATP) and glucose serve as coupled molecular hubs in energy transductions, functioning as the primary energy currency and fundamental carbon substrate, respectively. However, distinguishing and quantifying ATP and glucose in sweat presents significant challenges for current analytical techniques. Herein, we report an efficient method for visualizing and quantifying ATP and glucose content at various concentration levels using fluorescent detection. This method utilizes a customized ZIF-90 (SRB&GOx@ZIF-90) that reacts with ATP and glucose to produce fluorescence at distinct emission wavelengths. The peaks of these waves exhibit a linear dependence on the concentrations of ATP and glucose, respectively. The MOFs react rapidly and quantitatively with ATP and glucose to exhibit good stability, maintaining a stable fluorescence response across the sweat pH range. Moreover, incorporating photonic crystals (PCs) significantly amplifies the fluorescent intensity of the reaction, enabling ultrasensitive detection. The high performance of this method offers a novel approach for identifying abnormally elevated ATP and glucose levels in metabolism-related diseases. By combining band gap-matched photonic crystals with reactive SRB&GOx@ZIF-90, this approach achieves simultaneous, accurate, and precise detection of ATP and glucose levels without interference from similar substances or background signals.

The blood-brain barrier (BBB) is commonly known to be distributed evenly within the central nervous system. This study elucidates previously unexplored physiological phenomena associated with the spatial heterogeneity of the BBB. We found that isoflurane facilitates hemispheric lateralization in BBB permeability, leading to different responses between the left and right hemispheres. To substantiate this finding, we used neural optical imaging to comprehensively map the spatial homeostasis of BBB. Image segmentation and feature extraction exhibited hemispheric lateralization in vascular microstructure and function. Gait analysis confirmed that the lateralization of BBB homeostasis influences behavioral functions. Our results indicate that the left hemisphere enhances its self-protective mechanisms by disrupting the balance of mitochondrial fission and fusion, resulting in structural changes in mitochondria and reduced ATP (adenosine 5′-triphosphate) production, which are crucial for maintaining BBB homeostasis. This study offers insights into the molecular pathways that regulate BBB integrity and their potential implications for drug delivery.

Copper (Cu) is an essential trace element for cellular metabolism, while excessive Cu accumulation leads to neurotoxicity. Current therapeutic strategies for Cu overload remain inadequate in mitigating neurological symptoms. The recently discovered Cu-dependent mitochondrial cell death pathway, cuproptosis, offers novel insights into Cu-mediated neurotoxicity. In this study, the mechanistic link between mitochondrial respiration and cuproptosis is elucidated. The current study demonstrates that activated dihydrolipoamide dehydrogenase (DLD), induced by excess Cu under alkaline mitochondrial pH conditions, drives nicotinamide adenine dinucleotide (NADH) accumulation. Cu mediated mitochondrial permeability transition pore (mPTP) opening that facilitates NADH translocation to the cytosol, triggering NADH-reductive stress. This promotes aberrant purine biosynthesis, leading to severe adenosine triphosphate depletion and energy stress. Pharmacological interventions targeting DLD activity, cytosolic NADH, mPTP opening, purine biosynthesis, or energy stress effectively rescued Cu-induced cell death in SH-SY5Y neuroblastoma cells. Collectively, these findings reveal characteristics of NADH-reductive stress under excessive Cu exposure, establishing cuproptosis as a novel NADH-reductive stress-dependent cell death pathway. This mechanistic insight provides new therapeutic avenues for Cu-associated neurological pathologies and new aspects to explore Cu cellular physiology.

Reversing adenosine-mediated immunosuppression in triple-negative breast cancer by synergistic chemo-immunotherapy via stimuli-responsive nanomedicines.

BackgroundHealthcare-associated infections (HAIs) are a significant public health issue. HAIs cause extended hospital stays, increased mortality, reduced quality of life and cost the NHS an estimated £2.7 Billion annually. In 2023, the most reported HAI bacterial pathogens in England were Escherichia coli (16.5%) and Staphylococcus aureus (10.6%). In healthcare, infection prevention and control (IPC) teams use evidence-based interventions to control the spread of infectious agents. The built environment is a potential reservoir for pathogens, and surfaces frequently touched by healthcare workers, patients and/or visitors are known to play a role in HAI transmission. To minimize infection spread, IPC cleaning protocols routinely include hydrogen peroxide fumigation (known as Deprox) to decontaminate a room following discharge of a patient with an infection. Commercial adenosine triphosphate (ATP) luminometers are widely used to monitor cleaning protocols in clinical settings. However, ATP detection methods have limitations including no clear industry standards and the ability to detect a variety of biological contaminants (e.g. non-pathogenic microorganisms and organic soil).Objectives and methodsTo explore the hospital environmental microbiome, we performed ATP detection, 16S rRNA sequencing and quantitative PCR on various sampling sites (door, floor, sink, bed tray and wall) in side-rooms shortly after patient stays. In addition, for a subset of rooms we analysed two sample areas before and after Deprox, to assess the impact of decontamination on the environmental microbiome.ResultsBacterial burden data was used to inform quality control for the microbiome analyses, and 64% of samples were defined as having a significant microbiome. A few taxa were found consistently in all areas sampled: Escherichia-Shigella, Staphylococcus, Corynebacterium and Streptococcus. Acinetobacter was identified in all sample areas, excluding wall samples. Some taxa appeared to be more predominant in one sampling site, including Bacteroides in floor samples, and Methylobacterium in sink samples. ATP levels and microbiome diversity varied significantly between the areas sampled, with the highest levels found in floor then bed-tray samples. Bacterial burden was also highest in floor samples. ATP levels dropped significantly following the decontamination procedure and 70% of samples were below a ‘strict’ RLU cutoff of 250 (all were below a commonly used RLU cutoff of 500). Although not significant, there were reductions in bacterial burden and microbiome diversity following Deprox. However, 37% of samples had a significant microbiome remaining after Deprox. Overall, ATP levels did not significantly correlate with bacterial burden or microbiome diversity.ConclusionsAlthough it gives a useful indication of surface cleanliness, ATP monitoring does not give a clear picture of the bacteria present in the environment. Molecular analyses provided a detailed insight into the bacterial burden and specific Genera present in the environment and identified pathogen-containing Genera in all sample sites tested. As ATP levels did not correlate with bacterial burden or diversity, the viability of the potential pathogenic bacteria in the environment is unclear. Future studies are needed to investigate the viability of common pathogens in the hospital environment and further our understanding of the potential environmental reservoir for HAIs.

Background: Amiodarone is a widely used class III antiarrhythmic agent, but its use can lead to peripheral neuropathy mediated by mitochondrial dysfunction, oxidative stress, and neuroinflammatory injury, while effective preventive options remain limited. Agents that support mitochondrial energy metabolism, sustain redox balance, and modulate inflammation, including adenosine triphosphate (ATP), melatonin, and thiamine pyrophosphate (TPP), may counteract these mechanisms; however, their relative neuroprotective potential in amiodarone-induced neuropathy remains unclear. This study aimed to comparatively evaluate the effects of ATP, melatonin, and TPP on amiodarone-induced peripheral neuropathy and neuropathic pain in rats. Methods: Thirty male albino Wistar rats were assigned to five groups: healthy; amiodarone (50 mg/kg/orally); amiodarone + ATP (5 mg/kg/intraperitoneally); amiodarone + melatonin (10 mg/kg/orally); or amiodarone + TPP (20 mg/kg/intraperitoneally). Treatments were given once daily for 14 days. Oxidative stress indices (malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), catalase (CAT)) and proinflammatory cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1 Beta (IL-1β), interleukin-6 (IL-6)) were quantified in sciatic nerve by Enzyme-Linked Immunosorbent Assay (ELISA). Paw withdrawal thresholds were measured with the Randall-Selitto test before and after treatment. Histopathology was performed using Hematoxylin-eosin staining. Results: Amiodarone exposure resulted in pronounced elevations in MDA and proinflammatory cytokine levels, accompanied by significant reductions in tGSH, SOD, CAT activities, and paw withdrawal thresholds. ATP, melatonin and TPP ameliorated these alterations to varying degrees. Among them, TPP provided the most robust antioxidant and anti-inflammatory effects, followed by ATP and melatonin. Histopathological examination confirmed most severe axonal degeneration, interstitial edema and Schwann cell proliferation in the amiodarone group, with substantial amelioration in the TPP-treated rats. Conclusions: Amiodarone induces neuropathic pain through oxidative and inflammatory injury to peripheral nerves. TPP exhibited superior neuroprotective efficacy compared with ATP and melatonin, highlighting its potential as a candidate therapeutic agent for amiodarone-related neuropathy. Further clinical research is warranted to support translational application of these findings.

Aim: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) persist in effectively treated HIV-infected individuals, in part due to HIV reservoirs in brain microglia, which express low levels of viral proteins such as Nef. This study aimed to elucidate how microglia release Nef into the extracellular space, where it exerts its biological functions. Methods: Here, we systematically characterized extracellular particles released from immortalized human microglia (h-microglia) expressing Nef alone or after HIV infection. Importantly, we established a novel h-microglia model harboring a stably integrated Nef tagged with green fluorescent protein (Nef.GFP) transgene under an inducible promoter. Extracellular vesicles (EVs) were enriched from culture media and analyzed for morphology, size, concentration and molecular composition, including Nef content, by (super-resolution) fluorescence microscopy, (immunogold) transmission electron microscopy, asymmetric flow field-flow fractionation coupled to a multi-angle light-scattering detector, nanoparticle tracking analysis, and nano-flow cytometry and immunoblotting. Results: Nef.GFP expression increased particle release up to 11.7-fold compared with controls or known stimulants adenosine triphosphate (ATP) and ionomycin. Compared to the latter, the particles were also significantly smaller (root mean square radius, Rrms = 172 nm) and displayed unique protein and density profiles. All data support the EV nature of the released particles. Approximately half of the Nef.GFP-induced EVs contained Nef (45.5% ± 15.8%), with immunogold labeling confirming its intraluminal localization. Notably, infection with HIV isolates NL4-3 and YU-2 likewise produced Nef-positive EVs distinct from virions. Conclusion: Our findings importantly contribute to understanding the source and characteristics of extracellular Nef in the central nervous system of HIV infected individuals and offer new tools to study HIV Nef biology. Nef-laden EVs should be further investigated as potential therapeutic targets in HAND.

Effects of vascular disease risk factors on brain metabolism in multiple sclerosis.

Brown adipocytes facilitate non-shivering thermogenesis, which is critical for maintaining energy balance and heat production in response to environmental stimuli. Here, we delineate the physiological and biochemical role of etoposide-induced 2.4 (Ei24) in adenosine triphosphate (ATP) production and thermogenesis in brown adipocytes. We generated Ei24 adipocyte-specific knockout (EiaKO) mice that exhibited brown adipose tissue hypertrophy, lipid accumulation, and various mitochondrial abnormalities. Despite mitochondrial defects, uncoupling protein 1 (UCP1) expression and activity remained unchanged. However, those impairments caused lethal hypothermia in mice subjected to cold challenge, underscoring the key role of Ei24 in mitochondrial functions. Mechanistically, Ei24 deficiency disrupted cristae structure, dissipated mitochondrial membrane potential, and reduced matrix pH, leading to severe ATP depletion. We further identify the C-terminal region of Ei24 as essential for supporting ATP synthase function. Those bioenergetic defects not only destabilized the mitochondrial environment necessary for efficient UCP1-mediated thermogenesis, but also impaired ATP-dependent futile cycles such as SERCA-mediated calcium cycling and creatine substrate cycling. Together, our findings indicate that Ei24 functions as a thermogenic regulator that ensures mitochondrial ATP synthesis and structural integrity, enabling both coupled and uncoupled respiration in brown adipose tissue.

Assessing the effectiveness of hospital cleaning using fluorescence: a proof-of-concept study and comparison with ATP testing.

Mitochondria-targeted zeolitic imidazole framework-90: Toward sequential detection and bioimaging of ATP and GSH.

Intranasal LAG3 antibody infusion induces microglia-dependent antidepressant effect by mobilizing astrocytic P2Y1R-mediated BDNF synthesis in the hippocampus.

Triple-helix molecular switch-based aptasensor integrating exonuclease I-assisted target recycling and CRISPR-Cas13a-mediated signal amplification for fluorescence detection of adenosine triphosphate.

Metabolomic profiling identifies the mitochondria as a target of pentachlorophenol toxicity in the blood clam (Tegillarca granosa).

A Before-and-After Study on Hand Hygiene Knowledge, Practices, and Environmental Cleanliness in an Anaesthesia Department Following Educational and Protocol Interventions.

Cavitation bubble-assisted high-intensity focused ultrasound induces abscopal immune responses.

The mitochondrial nexus: Dysfunction, inhibition, and therapeutic frontiers in lung disease.