Naked mesoporous rhodium nanospheres with glutathione depletion and photothermal capabilities for tumor therapy.

Pancreatic and colon cancer are malignant tumors of the digestive system that currently lack effective treatments. In cancer cells, a high level of glutathione (GSH) is indispensable to scavenge excessive reactive oxygen species (ROS) and detoxify xenobiotics, which make it a potential target for cancer therapy. GSH depletion has been proved to improve the therapeutic efficacy of photodynamic therapy. Here, we reported that naked mesoporous rhodium nanospheres (Rh MNs), prepared by soft template redox method, can act as GSH depletion agent and photothermal conversion agent to achieve synergistic therapy respectively. Different from conventional nanoagents, Rh MNs with the characteristics of easy synthesis, simple structure and multiple functions can decrease the GSH level in tumor and depict excellent photothermal ability with a high photothermal conversion efficiency (PTCE) up to 39%. Notably, multiple anti-tumor mechanisms in CT26 and BxPC-3 tumor models, include inhibited anti-apoptosis, DNA replication repair, and GSH synthesis are revealed, and the pancreatic tumor cure rate of the cooperative treatment group is 80%. Collectively, we developed Rh MNs to combine GSH depletion with photothermal therapy for cancer treatment.

Tumor-targeted delivery of hyaluronic acid/polydopamine-coated Fe2+-doped nano-scaled metal-organic frameworks with doxorubicin payload for glutathione depletion-amplified chemodynamic-chemo cancer therapy.

Chemodynamic therapy (CDT), an emerging cancer treatment modality, uses multivalent metal elements to convert endogenous hydrogen peroxide (H2O2) to toxic hydroxyl radicals (•OH) via a Fenton or Fenton-like reaction, thus eliciting oxidative damage of cancer cells. However, the antitumor potency of CDT is largely limited by the high glutathione (GSH) concentration and low catalytic efficiency in the tumor sites. The combination of CDT with chemotherapy provides a promising strategy to overcome these limitations. In this work, to enhance antitumor potency by tumor-targeted and GSH depletion-amplified chemodynamic-chemo therapy, the hyaluronic acid (HA)/polydopamine (PDA)-decorated Fe2+-doped ZIF-8 nano-scaled metal-organic frameworks (FZ NMs) were fabricated and utilized to load doxorubicin (DOX), a chemotherapy drug, via hydrophobic, π-π stacking and charge interactions. The attained HA/PDA-covered DOX-carrying FZ NMs (HPDFZ NMs) promoted DOX and Fe2+ release in weakly acidic and GSH-rich milieu and exhibited acidity-activated •OH generation. Through efficient CD44-mediated endocytosis, the HPDFZ NMs internalized by CT26 cells not only prominently enhanced •OH accumulation by consuming GSH via PDA-mediated Michael addition combined with Fe2+/Fe3+ redox couple to cause mitochondria damage and lipid peroxidation, but also achieved intracellular DOX release, thus eliciting apoptosis and ferroptosis. Importantly, the HPDFZ NMs potently inhibited CT26 tumor growth in vivo at a low DOX dose and had good biosafety, thereby showing promising potential in tumor-specific treatment.

An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: potential impact of radiolytic oxygen depletion on tumor growth curves and tumor control probability.

Objective: This work aims to investigate the iso-effectiveness of conventional and FLASH radiotherapy on tumors through in-silico mathematical models. We focused on the role of radiolytic oxygen depletion (ROD), which has been argued as a possible factor to explain the FLASH effect. Approach: We used a spatiotemporal reaction-diffusion model, including ROD, to simulate tumor oxygenation and response. From those oxygen distributions we obtained surviving fractions (SFs) using the linear-quadratic (LQ) model with the oxygen enhancement ratios (OER). We then employed the calculated SFs to describe the evolution of preclinical tumor volumes through a mathematical model of tumor response, and we also extrapolated those results to calculate tumor control probabilities (TCPs) using the Poisson-LQ approach. Main results: Our study suggests that the ROD effect may cause differences in SF between FLASH and conventional radiotherapy, especially in low α/ß and poorly oxygenated cells. However, a statistical analysis showed that these changes in SF generally do not result in significant differences in the evolution of preclinical tumor growth curves when the sample size is small, because such differences in SF may not be noticeable in the heterogeneity of the population of animals}. Nonetheless, when extrapolating this effect to TCP curves, we observed important differences between both techniques (TCP is lower in FLASH radiotherapy). When analyzing the response of tumors with heterogeneous oxygenations, differences in TCP are more important for well oxygenated tumors. This apparent contradiction with the results obtained for homogeneously oxygenated cells is explained by the complex interplay between the heterogeneity of tumor oxygenation, the OER effect, and the ROD effect. Significance: This study supports the experimentally observed iso-effectiveness of FLASH and conventional radiotherapy when analyzing the volume evolution of preclinical tumors (that are far from control). However, this study also hints that tumor growth curves may be less sensitive to small variations in SF than tumor control probability: ROD may lead to increased SF in FLASH radiotherapy, which while not large enough to cause significant differences in tumor growth curves, could lead to important differences in clinical TCPs. Nonetheless, it cannot be discarded that other effects not modeled in this work, like radiation-induced immune effects, can contribute to tumor control and maintain the iso-effectiveness of FLASH radiotherapy. The study of tumor growth curves may not be the ideal experiment to test the iso-effectiveness of FLASH, and experiments reporting TCP or D50 may be preferred.

Reprogramming the Tumor Immune Microenvironment Through Activatable Photothermal Therapy and GSH depletion Using Liposomal Gold Nanocages to Potentiate Anti-Metastatic Immunotherapy.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.

Prospective study of risk factors for community-acquired acute kidney injury.

BACKGROUND AND HYPOTHESIS: Causes and risk factors for community-acquired acute kidney injury (CA-AKI) have not been thoroughly studied. The aim of this study was to examine the risk factors for CA-AKI. METHODS: In this prospective study, we examined serum creatinine from all individuals visiting a university hospital's emergency department (ED) over an 11-month period for the presence of AKI defined according to the KDIGO criteria. Patients with AKI were invited to participate. Randomly selected controls (1:2) were paired according to age, sex, and date of admission. Participants answered questions about their medical history and medication use, including over-the-counter (OTC) drugs. Conditional logistic regression was used to identify factors associated with AKI. RESULTS: Of 602 AKI cases identified, 512 participated in the study. AKI cases were significantly more likely than controls to have used nonsteroidal anti-inflammatory drugs (NSAIDs) (26.0 % vs 18.0 %, p = 0,001) in the week preceding the ED visit, particularly OTC NSAIDs (23.3 % vs 15.9 %, p < 0.001). AKI was associated with a recent history of vomiting (OR 2.52 [95 %CI 1.87-3.39]), diarrhea (1.30 [1.00-1.70]) and urinary retention (1.92 [1.36-2.72]), use of non-selective NSAIDs (1.84, [1.37-2.48]), RAAS blockers (1.63 [1.21-2.19]), and diuretics (1.53 [1.13-2.08]), and a history of diabetes (1.42 [1.04-1.94]), CKD (1.36 [1.01-1.83]) and smoking (1.72 [1.24-2.37]). CONCLUSIONS: Events in the setting of acute illness and medication use, including OTC NSAIDs, may play a greater role in the development of CA-AKI than comorbid conditions. Frequent use of OTC NSAIDs is a concern and should be addressed in view of serious adverse effects.

Biomimetic Single-Atom Nanozyme for Dual Starvation-Enhanced Breast Cancer Immunotherapy.

Cold exposure (CE) therapy is an innovative and cost-efficient cancer treatment that activates brown adipose tissue to compete for glucose uptake, leading to metabolic starvation in tumors. Exploring the combined antitumor mechanisms of CE and traditional therapies (such as nanocatalysis) is exciting and promising. In this study, a platelet membrane biomimetic single-atom nanozyme (SAEs) nanodrug (PFB) carrying bis-2-(5-phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide (BPTES) is developed for use in cancer CE therapy. Owing to the platelet membrane modification, PFB can effectively target tumors. Upon entering cancer cells, the dual starvation effect induced by CE treatment and BPTES can significantly diminish intracellular glucose and ATP levels, resulting in a substantial reduction in cellular (glutathione) GSH, which can enhance the cytotoxic efficacy of reactive oxygen species generated by SAEs. This strategy not only boosts ROS production in tumors, but also strengthens immune responses, particularly by increasing memory T-cell abundance and suppressing distant tumor growth and tumor metastasis. Compared with SAEs therapy alone, this combined approach offers superior benefits for tumor immunotherapy. This study achieves a combination of CE and nanomedicines for the first time, providing new ideas for future nanomedicine combination therapy modalities.

Residue Depletion of Nitrofurazone Metabolites, Semicarbazide and 5-Nitro-2-Furaldehyde, in Broiler Chickens After Oral Administration.

Nitrofurazone (NFZ) antibiotic is banned in food-producing animals, and its metabolite, semicarbazide (SEM), is used as a marker residue for nitrofurazone abuse. However, SEM can also be generated during food processing without veterinary treatment. Therefore, SEM cannot be considered an unequivocal marker of NFZ. This study investigates the use of 5-nitro-2-furaldehyde (5-NF) as an additional marker for nitrofurazone in broiler chickens. After oral administration of NFZ and 5-NF at 25 mg·kg-1 BW for 10 days, tissues (muscle and liver) and plasma samples were analyzed by liquid chromatography-tandem mass spectrometry. In NFZ-treated chickens, 5-NF was detected within 1 h in plasma at a peak concentration of 1.4 ± 0.25 µg·kg-1, while in 5-NF-treated ones, the maximum concentration was 0.85 ± 0.06 µg·kg-1 after 2 h. 5-NF was not detected in muscle and liver for both treated groups from 0 to 21 days. However, SEM persisted for up to 3 weeks in muscle (0.3 ± 0.018 µg·kg-1), 2 weeks in liver (0.16 ± 0.008 µg·kg-1), and 1 week in plasma (0.4 ± 0.05 µg·kg-1) with a faster elimination rate in liver tissues (half-life of 4.6 days) compared to muscle tissues (half-life of 6.5 days). These findings suggest that SEM remains a better marker for detecting nitrofurazone abuse in chickens compared to 5-NF.

Relevance of charged and polar amino acids for functionality of membrane toxin TisB.

Bacterial dormancy is marked by reduced cellular activity and the suspension of growth. It represents a valuable strategy to survive stressful conditions, as exemplified by the long-term tolerance towards antibiotics that is attributable to a fraction of dormant cells, so-called persisters. Here, we investigate the membrane toxin TisB (29 amino acids) from the chromosomal toxin-antitoxin system tisB/istR-1 in Escherichia coli. TisB depolarizes the inner membrane in response to DNA damage, which eventually promotes a stress-tolerant state of dormancy within a small fraction of the population. Using a plasmid-based system for moderate tisB expression and single amino acid substitutions, we dissect the importance of charged and polar amino acids. We observe that the central amino acids lysine 12 and glutamine 19 are of major importance for TisB functionality, which is further validated for lysine 12 in the native context upon treatment with the DNA-damaging antibiotic ciprofloxacin. Finally, we apply a library-based approach to test additional TisB variants in higher throughput, revealing that at least one positive charge at the C-terminus (either lysine 26 or 29) is mandatory for TisB-mediated dormancy. Our study provides insights into the molecular basis for TisB functionality and extends our understanding of bacterial membrane toxins.

Polypeptide-Based Copper Ionophore for In Situ Glutathione-Triggered Chemodynamic and Chemotherapy.

Intracellular copper ion homeostasis has become an attractive target for cancer therapy. Herein, we report a 2,2'-dipicolylamine (DPA) functionalized polyglutamate derivative (PDHB) which is capable of rapidly forming PDHB-copper complex (PDHB@Cu) due to the strong coordination ability of pendant DPA with Cu2+. High drug loading content of doxorubicin (DOX) (>30 wt %) is realized due to the strong affinity of Cu2+ to DOX, while that is about 10 wt % for PDHB without Cu2+. The obtained PDHB@Cu-DOX can respond to specific endogenous stimuli (pH and glutathione (GSH)), releasing Cu2+ and DOX. The released DOX directly damages the DNA of tumor cells to cause apoptosis, while Cu2+ depletes intracellular GSH and is reduced to Cu+ simultaneously, which reacts with local H2O2 to produce highly toxic ·OH via a Fenton-like reaction, thus realizing synergistic chemodynamics and chemotherapy. This report provides an interesting polymeric ionophore strategy to deliver enough copper ions into cancer cells, which can also easily extend to other metal ions by replacing the ionophore components, thus having a wide application in nanomedicine.

Simple ROS-responsive micelles loaded Shikonin for efficient ovarian cancer targeting therapy by disrupting intracellular redox homeostasis.

Ovarian cancer is the most common malignant tumor in women. Shikonin (SHK), an herbal extract from Chinese medicine, shows promise in treating ovarian cancer by inducing reactive oxygen species (ROS). However, its clinical use is limited by poor tumor targeting and low bioavailability, and its therapeutic potential is further compromised by the elevated levels of antioxidants such as glutathione (GSH) within tumor cells. In this study, a novel formulation of ROS-responsive micelles loaded with SHK was developed using hyaluronic acid-phenylboronic acid pinacol ester conjugation (HA-PBAP) for targeted therapy of ovarian cancer through disruption of intracellular redox homeostasis. The SHK@HA-PBAP exhibits targeted delivery to ovarian cancer cells through the interaction between HA and CD44 receptors. Upon internalization by cancer cells, the high levels of intracellular ROS triggered the degradation of SHK@HA-PBAP and simultaneously released SHK and generated GSH scavenger quinone methide (QM). The SHK and QM released from the SHK@HA-PBAP effectively induce the production of ROS and deplete intracellular GSH, leading to the disruption of intracellular redox homeostasis and subsequent induction of cell death. These characteristics collectively inhibit the growth of ovarian cancer. In vitro and in vivo studies have demonstrated that SHK@HA-PBAP micelles exhibit superior antitumor efficacy compared to free SHK in both A2780 cells and A2780 tumor-bearing mice. The ROS-responsive SHK@HA-PBA presents a promising therapeutic approach for the treatment of ovarian cancer.

The combined effects of polystyrene nanoplastics and dissolved organic matter on the environmental bioavailability of carbamazepine.

The bioavailability of active pharmaceutical ingredients (APIs) plays a crucial role in determining the toxicity and risk of contaminants in the environment. However, the bioavailability of APIs in complex environmental matrices is still unclear. In this study, the combined effects of polystyrene nanoplastics (PS NPs) with various particle sizes (50, 100, and 1000 nm) and fulvic acid (FA) on the bioavailability of carbamazepine (CBZ) were investigated via negligible depletion solid-phase microextraction (nd-SPME) and Daphnia magna (D. magna) accumulation. The uptake kinetic study revealed that both PS NPs and FA reduced the elimination rate (k2) in most cases. The availability of CBZ to nd-SPME was determined by the hydrodynamic particle size of PS NPs, whereas the bioavailability to D. magna depended on the intrinsic particle size. The CBZ bioavailability was greater in co-exposed matrices due to the attenuated sorption of PS NPs to CBZ by FA modification. Notably, co-exposure of PS NPs and FA resulted in a higher bioaccumulation factor (BAF) of CBZ, probably due to the desorption and reabsorption of particle-associated CBZ. This study demonstrated that both PS NP particle size and FA binding affect the bioavailability of CBZ, and nd-SPME can mimic only the bioaccumulation of CBZ via diffusion.

Assessment of skeletal muscle dynamics and milk production across a 300-day lactation in multiparous dairy cattle.

The objective of this study was to evaluate changes in longissimus dorsi muscle depth (LDD) across lactation (0 to 300 DIM) and identify the impact of low versus high muscle reserves immediately after parturition on body weight and body reserve changes as well as production variables across a 300-d lactation. Forty multiparous cows were classified as high muscle (HM; LDD > 5.0 cm; n = 18) or low muscle (LM; LDD ≤ 5.0 cm; n = 22) based on LDD measurements collected within 24 h of parturition. Body weights (BW) and ultrasound scans to assess LDD and back fat depth (BFD) were collected monthly from parturition until 300 DIM. Ultrasound scans captured and measured using available software. Blood samples were taken at 7, 150 and 300 DIM, and plasma was analyzed for markers of metabolic status by measuring insulin, nonesterified fatty acids (NEFA), creatinine, and 3-methylhistidine (3-MH). Milk yield was recorded daily and milk components were analyzed monthly. Data analysis was performed and the statistical models included the fixed effect of muscle group, time, their interaction, and the random effect of cow nested within muscle group with repeated measures using a first-order autoregressive covariance structure. Muscle group was not related with BW or BFD for any of the time points measured. Cows lost BW from 0 to 60 DIM and gained weight from 60 to 300 DIM. Similarly, BFD decreased between 0 to 90 DIM and increased BFD after 90 DIM until 300 DIM. A muscle group by time interaction was observed for LDD. The HM cows had more muscle at 0 DIM, indicative of treatment assignment (1.34 cm more), and 300 DIM (0.78 cm more) and tended to have more muscle at 60 DIM (0.66 cm more) compared with LM. After 240 DIM, both muscle groups began net accretion of muscle reserves until 300 DIM. No differences were observed for blood metabolites measured based on muscle group. However, there were significant time effects for creatinine, 3-MH, and NEFA concentrations, which reflected the observed changes in BFD and LDD measured in ultrasound scans. For statistical analysis of daily milk production, observations were grouped into 3 stages of lactation, early (0-60 DIM), mid (60-240 DIM), and late lactation (240-300 DIM). There was a muscle group by stage of lactation interaction, where in early and mid-lactation, HM cows produced, on average, 1.9 kg more milk/d; however, in late lactation, LM cows produced 1.8 kg more milk/d. Our results indicate that muscle reserves are depleted in early lactation, and accreted in late lactation, whereas BW and BFD started to increase by 90 DIM. Data also supports that cows with more extensive muscle depletion in early lactation had greater milk production, however, substantial muscle accretion in late lactation may result in reduced milk production.

Assessing the persistence of a contaminant plume generated by linear aquifer source depletion and back diffusion from an aquitard.

This study presents analytical solutions for describing contaminant storage and release from an aquitard with linear source depletion (LSD) boundary conditions. We investigated three scenarios for trichloroethylene (TCE) mass exchange before and after the LSD period in an aquifer bounded by an adjacent aquitard based on the LSD dynamics, a resistance coefficient, and the aquitard thickness. The developed analytical solutions showed good agreement with measured profiles and breakthrough curves from a previous study. In three scenarios, the factors delaying the onset of TCE release into the aquifer were a decrease in the resistance coefficient, an increase in LSD period and aquitard thickness. The changes in the duration, mass, and rate of TCE storage in the aquitard during LSD loading process affected the equilibrium of the aquifer-aquitard concentration gradient. After TCE loading, the period maintained above the maximum contaminant level was directly related to the three variables; the longest plume persistence occurred when TCE penetration distance at transition point from storage to release coincided with the aquitard thickness. Overall, the developed analytical solution aids in evaluating the risk of plume persistence, enhancing site management efficiency, and reducing remediation costs.

Too much information! When job resources become job demands, producing a curvilinear relationship between informational social support and creativity.

OBJECTIVE: Informational social support can have both positive and negative effects on employees. This research aims to examine the curvilinear relationship between informational social support and employees' cognitive processes, specifically cognitive depletion and creativity. Additionally, we investigate the moderating role of emotional stability on this curvilinear relationship, particularly regarding cognitive depletion. METHODS: A total of 108 male employees in South Korea participated in the study, completing 864 two-wave, time-lagged daily diary questionnaires. The surveys measured informational social support, cognitive depletion, creativity, and emotional stability. RESULTS: The findings reveal that informational social support enhances employees' cognitive processes up to a certain threshold, after which its effects become detrimental, demonstrating a curvilinear pattern. Furthermore, emotional stability moderates this relationship: emotionally stable employees show a linear relationship between informational social support and cognitive depletion, while emotionally unstable employees exhibit a curvilinear relationship. CONCLUSION: Our results suggest that excessive informational social support may harm employees' cognitive processes, indicating that there is an optimal level of support, beyond which the effects become counterproductive.

A Loss Cycle of Burnout Symptoms and Reduced Coping Self-Efficacy: A Latent Change Score Modelling Approach.

Police officers are frequently faced with chronic and acute stressors, such as excessive workload, organizational stressors and emotionally charged reports. This study aims to examine the relationship between a form of chronic strain (ie, burnout symptoms) and a resource (ie, coping self-efficacy) in a sample of Dutch police officers. Specifically, we aim to investigate the existence of a loss cycle of resources. We use Latent Change Score modeling to investigate the potential depletion or loss cycle of coping self-efficacy as a result of burnout symptoms in a sample of 95 police officers who completed a survey on three consecutive timepoints. The lag between the measurements was approximately one year. We found that, during both one-year intervals, within-person increases in burnout symptoms were related to within-person decreases in coping self-efficacy. Also, the results emphasize the buffering role of coping self-efficacy for burnout symptoms, as within-person decreases in coping self-efficacy during the first year were associated with within-person increases in burnout symptoms during the following year. Together, the results imply that a loss cycle of coping self-efficacy and burnout symptoms may occur. For this we used Latent Change Score modeling, which is a relatively new approach which provides researchers with the opportunity to analyse multi-wave longitudinal data while focusing on within-person changes over time. Practically, police organizations are advised to monitor personnel wellbeing and resources, to maintain and promote sustainable employability of police officers and to be able to timely provide individuals with interventions. Limitations discussed are the use of self-report measures and large intervals between the measurements. Finally, future directions of research are discussed that would circumvent the reported limitations, such as multiple wave with shorter lags and incorporating confounding factors that could affect coping self-efficacy.

Macrophage-derived amphiregulin promoted the osteogenic differentiation of chondrocytes through EGFR/Yap axis and TGF-ehß activation.

Endochondral ossification represents a crucial biological process in skeletal development and bone defect repair. Macrophages, recognized as key players in the immune system, are now acknowledged for their substantial role in promoting endochondral ossification within cartilage. Concurrently, the epidermal growth factor receptor (EGFR) ligand amphiregulin (Areg) has been documented for its contributory role in restoring bone tissue homeostasis post-injury. However, the mechanism by which macrophage-secreted Areg facilitates bone repair remains elusive. In this study, the induction of macrophage depletion through in vivo administration of clodronate liposomes was employed in a standard open tibial fracture mouse model to assess bone healing using micro-computed tomography (micro-CT) analysis, histomorphology, and ELISA serum evaluations. The investigation revealed sustained expression of Areg during the fracture healing period in wild-type mice. Macrophage depletion significantly reduced the number of macrophages on the local bone surface and vital organs. This reduction led to diminished Areg secretion, decreased collagen production, and delayed fracture healing. However, histological and micro-CT assessments at 7 and 21 days post-local Areg treatment exhibited a marked improvement of bone healing compared to the vehicle control. In vitro studies demonstrated an increase of Areg secretion by the Raw264.7 cells upon ATP stimulation. Indirect co-culture of Raw264.7 and ATDC5 cells indicated that Areg overexpression enhanced the osteogenic potential of chondrocytes, and vice versa. This osteogenic promotion was attributed to Areg's activation of the membrane receptor EGFR in the ATDC5 cell line, the enhanced phosphorylation of transcription factor Yap, and the facilitation of the expression of bioactive TGF-ß by chondrocytes. Collectively, this research elucidates the direct mechanistic effects of macrophage-secreted Areg in promoting bone homeostasis following bone injury.

L-Cysteine mitigates ROS-induced apoptosis and neurocognitive deficits by protecting against endoplasmic reticulum stress and mitochondrial dysfunction in mouse neuronal cells.

Oxidative stress and mitochondrial dysfunction play critical roles in neurodegenerative diseases. Glutathione (GSH), a key brain antioxidant, helps to neutralize reactive oxygen species (ROS) and maintain redox balance. We investigated the effectiveness of L-cysteine (L-Cys) in preventing apoptosis induced by the ROS generator 2,3-dimethoxy-1,4-naphthoquinone (DMNQ) in mouse hippocampal neuronal HT22 cells, as well as alleviating memory and cognitive impairments caused by the GSH synthesis inhibitor L-buthionine sulfoximine (BSO) in mice. DMNQ-induced apoptotic events in HT22 cells, including elevated cytosolic and mitochondrial ROS levels, DNA fragmentation, endoplasmic reticulum stress, and mitochondrial damage-mediated apoptotic pathways were dose-dependently abrogated by L-Cys (0.5-2 mM). The reduced intracellular GSH level, caused by DMNQ treatment, was restored by L-Cys cotreatment. Although L-Cys did not significantly restore GSH in the presence of BSO, it prevented DMNQ-induced ROS elevation, mitochondrial damage, and apoptosis. Furthermore, compared to N-acetylcysteine and GSH, L-Cys had higher 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzothiazoline-6-sulphonic acid radical-scavenging activity. L-Cys also restored mitochondrial respiration capacity in DMNQ-treated HT22 cells by reversing mitochondrial fission-fusion dynamic balance. BSO administration (500 mg/kg/day) in mice led to neuronal deficits, including memory and cognitive impairments, which were effectively mitigated by oral L-Cys (15 or 30 mg/kg/day). L-Cys also reduced BSO-induced ROS levels in the mice hippocampus and cortex. These findings suggest that even though it does not contribute to intracellular GSH synthesis, exogenous L-Cys protects neuronal cells against oxidative stress-induced mitochondrial damage and apoptosis, by acting as a ROS scavenger, which is beneficial in ameliorating neurocognitive deficits caused by oxidative stress.

A Metal Chelation Therapy to Effectively Eliminate Breast Cancer and Intratumor Bacteria While Suppressing Tumor Metastasis by Copper Depletion and Zinc Ions Surge.

The intratumor microbiota results in the immunosuppressive microenvironment and facilitates tumor growth and metastasis. However, developing a synergistic therapy with antitumor, antibacterial, and antimetastatic effects faces enormous challenges. Here, we propose an metal chelation therapy to effectively eliminate tumor and intratumor bacteria and suppress tumor metastasis. Different from traditional chelation therapy that only consumes metal elements, this therapy not only eliminates the crucial metal elements for tumor metabolism but also releases new metal ions with antitumor and antibacterial properties. Based on the high demand for copper in breast cancer, we prepare a fibrous therapeutic nanoagent (Zn-PEN) by chelating D-Penicillamine (D-PEN) with Zn2+. Firstly, Zn-PEN achieves dual inhibition of oxidative phosphorylation and glycolysis metabolism  through copper depletion and Zn2+ activated cGAS-STING pathway, thus inducing tumor cell death. Secondly, Zn-PEN has the capability to eradicate Fusobacterium nucleatum in breast cancer, thereby mitigating its immunosuppressive impact on the tumor microenvironment. Finally, Zn-PEN effectively inhibits tumor metastasis through multiple routes, including the inhibition of epithelial-mesenchymal transition process, activation of cGAS-STING pathway, and elimination with F. nucleatum. Therefore, we verify the feasibility of Zn-PEN mediated metal chelation therapy in a 4T1 model infected with F. nucleatum, providing a new therapeutic strategy for inhibiting tumor metastasis.

[Research Progress of Ferroptosis in Ulcerative Colitis].

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by continuous inflammation and ulcer formation in the intestinal mucosa.Its pathogenesis involves immune dysfunction,dysbiosis of gut microbiota,and mucosal damage caused by inflammation.Ferroptosis is an iron-dependent form of cell death regulated by disturbances in iron metabolism,lipid peroxidation,and depletion of glutathione (GSH).Studies have indicated that ferroptosis plays a crucial role in the pathogenesis of UC,particularly in regulating inflammatory responses and damaging intestinal epithelial cells.This article reviews the regulatory mechanisms and roles of ferroptosis in UC and discusses the potential therapeutic strategies to alleviate UC symptoms by modulating iron metabolism,reducing lipid peroxidation,and maintaining GSH levels,providing new targets and directions for the diagnosis and treatment of UC.

FLIM nanoscopy resolves the structure and preferential adsorption in the co-nonsolvency of PNIPAM microgels in methanol-water.

Polymer microgels are swollen macromolecular networks with a typical size of hundred of nanometers to several microns that show an extraordinary open and responsive architecture to different external stimuli, being therefore important candidates for nanobiotechnology and nanomedical applications such as biocatalysis, sensing and drug delivery. It is therefore crucial to understand the delicate balance of physical-chemical interactions between the polymer backbone and solvent molecules that to a high extent determine their responsivity. In particular, the co-nonsolvency effect of poly(N-isopropylacrylamide) in aqueous alcohols is highly discussed, and there is a disagreement between molecular dynamics (MD) simulations (from literature) of the preferential adsorption of alcohol on the polymer chains and the values obtained by several empirical methods that mostly probe the bulk solvent properties. It is our contention that the most efficacious method for addressing this problem requires a nanoscopic method that can be combined with spectroscopy and record fluorescence spectra and super-resolved fluorescence lifetime images of microgels labeled covalently with the solvatochromic dye Nile Red. By employing this approach, we could simultaneously resolve the structure of sub-micron size objects in the swollen and in the collapsed state and estimate the solvent composition inside of them in - mixtures for two very different polymer architectures. We found an outstanding agreement between the MD simulations and our results that estimate a co-solvent molar fraction excess of approximately 3 with a very flat profile in the lateral direction of the microgel.