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Human serum albumin (HSA) is the frontline antioxidant protein in blood with established anti-inflammatory and anticoagulation functions. Here, we report that COVID-19-induced oxidative stress inflicts structural damages to HSA and is linked with mortality outcome in critically ill patients. We recruited 39 patients who were followed up for a median of 12.5 days (1–35 days), among them 23 had died. Analyzing blood samples from patients and healthy individuals (n=11), we provide evidence that neutrophils are major sources of oxidative stress in blood and that hydrogen peroxide is highly accumulated in plasmas of non-survivors. We then analyzed electron paramagnetic resonance spectra of spin-labeled fatty acids (SLFAs) bound with HSA in whole blood of control, survivor, and non-survivor subjects (n=10–11). Non-survivors’ HSA showed dramatically reduced protein packing order parameter, faster SLFA correlational rotational time, and smaller S/W ratio (strong-binding/weak-binding sites within HSA), all reflecting remarkably fluid protein microenvironments. Following loading/unloading of 16-DSA, we show that the transport function of HSA may be impaired in severe patients. Stratified at the means, Kaplan–Meier survival analysis indicated that lower values of S/W ratio and accumulated H 2 O 2 in plasma significantly predicted in-hospital mortality (S/W≤0.15, 81.8% (18/22) vs. S/W>0.15, 18.2% (4/22), p=0.023; plasma [H 2 O 2 ]>8.6 μM, 65.2% (15/23) vs. 34.8% (8/23), p=0.043). When we combined these two parameters as the ratio ((S/W)/[H 2 O 2 ]) to derive a risk score, the resultant risk score lower than the mean (<0.019) predicted mortality with high fidelity (95.5% (21/22) vs. 4.5% (1/22), log-rank χ 2 =12.1, p=4.9×10 −4 ). The derived parameters may provide a surrogate marker to assess new candidates for COVID-19 treatments targeting HSA replacements and/or oxidative stress.

Both copper (Cu 2+/+ ) and iodine (I − ) are essential elements in all living organisms. Increasing the intracellular concentrations of Cu or I ions may efficiently inhibit tumor growth. However, efficient delivery of Cu and I ions into tumor cells is still a challenge, as Cu chelation and iodide salts are highly water-soluble and can release in untargeted tissue. Here we report mitochondria-targeted Cu-I cluster nanoparticles using the reaction of Cu + and I − to form stable bovine serum albumin (BSA) radiation-induced phosphors (Cu-I@BSA). These solve the stability issues of Cu + and I − ions. Cu-I@BSA exhibit bright radioluminescence, and easily conjugate with the emission-matched photosensitizer and targeting molecule using functional groups on the surface of BSA. Investigations in vitro and in vivo demonstrate that radioluminescence under low-dose X-ray irradiation excites the conjugated photosensitizer to generate singlet oxygen, and combines with the radiosensitization mechanism of the heavy atom of iodine, resulting in efficient tumor inhibition in female mice. Furthermore, our study reveals that BSA protection causes the biodegradable Cu-I clusters to release free Cu and I ions and induce cell death by modulating mitochondrial function, damaging DNA, disrupting the tricarboxylic acid cycle, decreasing ATP generation, amplifying oxidative stress, and boosting the Bcl-2 pathway. Efficient delivery of copper and iodine ions into tumor cells is promising for boosting the antitumor effect but elusive. Here the authors report a mitochondrial-targeted copper-iodide nanoparticles for the cancer treatment in which copper and iodide ions induce cell death by modulating mitochondrial functions under low-dose Xray irradiation.

Thiosemicarbazones (TSCs) constitute a pharmacologically versatile class of compounds with documented antimicrobial, antiviral, and anticancer properties. Despite their therapeutic potential, their biological mechanisms and pharmacokinetic behaviour remain insufficiently characterized. In this study, we investigated the biological activity of the library consisting of 28 aromatic and heteroaromatic compounds against twelve cancer cell and two normal cell lines, and four parasites. Six N -heteroaromatic thiosemicarbazones based on pyridine ( 13 , 14 , and 18 ), quinoline ( 24 and 26 ), and indole ( 27 ) moieties show promising anticancer and/or antiparasitic activity. Density functional theory (DFT) calculations indicated that the biological activity of 13 , 14 , 18 , 24 , and 26 arises from their ability to chelate d -metals, whereas 27 operates via a distinct mechanism. The passive gastrointestinal absorption and Human serum albumin (HSA) binding ability of these six compounds were evaluated by the Parallel artificial membrane permeability (PAMPA) technique and high-performance affinity chromatography, respectively. Compound 26 emerged as the most potent and selective anticancer agent and was further examined through cell cycle profiling, caspase-3/7 activation, DNA double-strand break quantification, 3D spheroid assays, and an in ovo chorioallantoic membrane (CAM) model, supported by HSA docking and molecular dynamics simulations. Collectively, our results indicate that 26 is a selective anticancer agent that exerts cytotoxic effects preferentially in cancer cells, by inducing apoptosis and DNA double-strand breaks.

Gyrophoric acid (GA), a lichen secondary metabolite, has attracted more attention during the last years because of its potential biological effects. Until now, its effect in vivo has not yet been demonstrated. The aim of our study was to evaluate the basic physicochemical and pharmacokinetic properties of GA, which are directly associated with its biological activities. The stability of the GA in various pH was assessed by conducting repeated UV-VIS spectral measurements. Microsomal stability in rat liver microsomes was performed using Ultra-Performance LC/MS. Binding to human serum albumin (HSA) was assessed using synchronous fluorescence spectra, and molecular docking analysis was used to reveal the binding site of GA to HSA. In the in vivo experiment, 24 Sprague-Dawley rats (Velaz, Únetice, Czech Republic) were used. The animals were divided as follows. The first group (n = 6) included healthy males as control intact rats (♂INT), and the second group (n = 6) included healthy females as controls (♀INT). Groups three and four (♂GA/n = 6 and ♀GA/n = 6) consisted of animals with daily administered GA (10 mg/kg body weight) in an ethanol-water solution per os for a one-month period. We found that GA remained stable under various pH and temperature conditions. It bonded to human serum albumin with the binding constant 1.788 × 106 dm3mol−1 to reach the target tissue via this mechanism. In vivo, GA did not influence body mass gain, food, or fluid intake during the experiment. No liver toxicity was observed. However, GA increased the rearing frequency in behavioral tests (p < 0.01) and center crossings in the elevated plus-maze (p < 0.01 and p < 0.001, respectively). In addition, the time spent in the open arm was prolonged (p < 0.01 and p < 0.001, respectively). Notably, GA was able to pass through the blood–brain barrier, indicating its ability to permeate into the brain and to stimulate neurogenesis in the hilus and subgranular zone of the hippocampus. These observations highlight the potential role of GA in influencing brain function and neurogenesis.

Exercise‐induced muscle damage (EIMD) can affect athlete performance and is a risk factor for major muscle injury. The temporal profile of thiol‐oxidized albumin, a marker of oxidative stress, has shown potential in assessing recovery from EIMD in non‐athletically trained participants but not yet in trained participants. Our primary aim was to assess whether there are changes in the level of thiol‐oxidized albumin after a marathon in athletically trained participants. Twenty participants completed a marathon and collected daily dried blood spots from 3 days prior to and 7 days after the marathon to measure thiol‐oxidized albumin using a novel methodology (OxiDx). Participants were also assessed for indirect markers of EIMD prior to and on days 2 and 5 post‐marathon. The level of thiol‐oxidized albumin peaked at 2 days and remained elevated until 5 days after the marathon and correlated with indirect measures of EIMD. Furthermore, time of recovery for thiol‐oxidized albumin varied between participants, some recovered at 3 days post‐marathon whereas others extended beyond 7 days post marathon. Tracking temporal changes in the level of thiol‐oxidized albumin has potential to be useful in managing recovery from EIMD in athletes, particularly considering the ease of the OxiDx methodology.

PurposeCerebral ischemia–reperfusion (I/R) injury remains a leading cause of mobility and mortality among patients with ischemic stroke. This study aims to develop a human serum albumin (HSA)-enriched nanoparticle platform for solubilizing clopidogrel bisulfate (CLP) for intravenous administration, and to explore the protective effect of HSA-enriched nanoparticles loaded with CLP (CLP-ANPs) against cerebral I/R injury in transient middle cerebral artery occlusion (MCAO) rat model.MethodsCLP-ANPs were synthesized via a modified nanoparticle albumin-bound technology, lyophilized, and then characterized by morphology, particle size, zeta potential, drug loading capacity, encapsulation efficiency, stability and in vitro release kinetics. In vivo pharmacokinetic studies were conducted using Sprague–Dawley (SD) rats. Also, an MCAO rat model was established to explore the therapeutic effect of CLP-ANPs on cerebral I/R injury.ResultsCLP-ANPs remained spherical particles with a layer of proteins forming protein corona. Lyophilized CLP-ANPs after dispersion displayed an average size of about 235.6 ± 6.6 nm (PDI = 0.16 ± 0.08) with a zeta potential of about − 13.5 ± 1.8 mV. CLP-ANPs achieved sustained release for up to 168 h in vitro. Next, a single injection of CLP-ANPs dose-dependently reversed the histopathological changes induced by cerebral I/R injury possibly via attenuating apoptosis and reducing oxidative damages in the brain tissues.ConclusionsCLP-ANPs represent a promising and translatable platform system for the management of cerebral I/R injury during ischemic stroke.

Bovine serum albumin (BSA) is commonly incorporated in vaccines to improve stability. However, owing to potential allergic reactions in humans, the World Health Organization (WHO) mandates strict adherence to a BSA limit (≤50 ng/vaccine). BSA detection with conventional techniques is time-consuming and requires specialized equipment. Efficient alternatives such as the ion-sensitive field-effect transistor (ISFET), despite rapid detection, affordability, and portability, do not detect BSA at low concentrations because of inherent sensitivity limitations. This study proposes a silicon-on-insulator (SOI) substrate-based dual-gate (DG) ISFET platform to overcome these limitations. The capacitive coupling DG structure significantly enhances sensitivity without requiring external circuits, owing to its inherent amplification effect. The extended-gate (EG) structure separates the transducer unit for electrical signal processing from the sensing unit for biological detection, preventing chemical damage to the transducer, accommodating a variety of biological analytes, and affording easy replaceability. Vapor-phase surface treatment with (3-Aminopropyl) triethoxysilane (APTES) and the incorporation of a SnO2 sensing membrane ensure high BSA detection efficiency and sensitivity (144.19 mV/log [BSA]). This DG-FET-based biosensor possesses a simple structure and detects BSA at low concentrations rapidly. Envisioned as an effective on-site diagnostic tool for various analytes including BSA, this platform addresses prior limitations in biosensing and shows promise for practical applications.

Limited therapeutic options are available for patients with platinum-resistant ovarian cancer (OC). Herein, we developed gallium sulfide-embedded bovine serum albumin nanoformulations (Ga 2 S 3 -BSA NMs) with a size of ~ 11 nm via a self-assembly approach. As the nanoformulations degraded in an acidic cancer microenvironment, Ga 3+ and H 2 S gas were simultaneously released to exert their combined anticancer effects. In A2780-CIS and SKOV3-CIS platinum-resistant OC cells, Ga 3+ and H 2 S released from Ga 2 S 3 -BSA NMs synergistically enhanced DNA damage, which arrested the cell cycle at S and G2/M phases and suppressed cell proliferation. Meanwhile, Ga 2 S 3 -BSA NMs significantly inhibited NF-κB signaling and Bcl2 protein expression, leading to cell apoptosis. Furthermore, Ga 2 S 3 -BSA NMs increased cellular lipid peroxidation and triggered ferroptosis. RNA-seq analysis further clarified the comprehensive antitumor mechanisms of Ga 2 S 3 -BSA NMs. More importantly, the therapeutic efficacy of Ga 2 S 3 -BSA NMs and their ability to enhance the sensitivity to carboplatin and fluzoparib with negligible toxicity were further confirmed in a platinum-resistant OC animal model. Altogether, our results demonstrated a potentially safe and practical strategy by using Ga 2 S 3 -BSA NMs to combat drug resistance in platinum-resistant OC. Graphical Abstract

PurposeExercise-induced muscle damage (EIMD) results in the generation of reactive oxygen species (ROS), but little is known about the temporal profile of change in ROS post-EIMD and how ROS levels relate to the onset of and recovery from EIMD. Our primary aim was to examine the effect of EIMD on the pattern of change in the blood level of thiol-oxidised albumin, a marker of oxidative stress.MethodsSeven male participants were subjected on separate days to eccentric muscle contraction to cause EIMD or a no-exercise condition. After each session, the participants collected daily dried blood spots to measure thiol-oxidised albumin and returned to the laboratory every 2 days for the assessment of indirect markers of EIMD, namely maximal voluntary contraction (MVC), delayed onset muscle soreness (DOMS), creatine kinase (CK), and myoglobin.ResultsEccentric exercise resulted in a significant decrease in MVC and increase in DOMS, CK, myoglobin, and thiol-oxidised albumin with the latter reaching above baseline level within 24–48 h post-exercise. All the markers of EIMD returned to baseline level within 6 days post-exercise, but not the level of thiol-oxidised albumin which remained elevated for 10 days after exercise. There was a moderate correlation between changes in thiol-oxidised albumin and DOMS, but no significant relationship between any other markers of muscle damage.ConclusionThe levels of thiol-oxidised albumin increase in response to EIMD and remain elevated for several days post-exercise. The temporal pattern of change in the level of thiol-oxidised albumin suggests that this may be a useful biomarker of muscle repair post-EIMD.

A novel ruthenium(II) complex, [RuCl2(η6-p-cymene)(bph-κN)] (1), was synthesized and structurally characterized using FTIR and NMR spectroscopy. Density functional theory (DFT) calculations supported the proposed geometry and allowed for comparative analysis of experimental and theoretical spectroscopic data. The interaction of complex 1 with human serum albumin (HSA) and calf thymus DNA was investigated through fluorescence quenching experiments, revealing spontaneous binding driven primarily by hydrophobic interactions. The thermodynamic parameters indicated mixed quenching mechanisms in both protein and DNA systems. Ethidium bromide displacement assays and molecular docking simulations confirmed DNA intercalation as the dominant binding mode, with a Gibbs free binding energy of −34.1 kJ mol−1. Antioxidant activity, assessed by EPR spectroscopy, demonstrated effective scavenging of hydroxyl and ascorbyl radicals. In vitro cytotoxicity assays against A375, MDA-MB-231, MIA PaCa-2, and SW480 cancer cell lines revealed selective activity, with pancreatic and colorectal cells showing the highest sensitivity. QTAIM analysis provided insight into metal–ligand bonding characteristics and intramolecular stabilization. These findings highlight the potential of 1 as a promising candidate for further development as an anticancer agent, particularly against multidrug-resistant tumors.