Zn2+ offers significant advantages for cancer therapy via mitochondrial disruption, immune activation, and metal homeostasis perturbation, but faces challenges of rapid clearance and systemic toxicity. Existing zinc‑based (e.g., zinc oxide (ZnO), and zinc peroxide) nanoparticles often lack internal voids and sufficient surface area, restricting drug loading and functionalization. In this study, we developed a crystallinity‑gradient selective etching method to tailor biodegradable hollow mesoporous zinc nanoparticle (HMZN). Typically, zinc peroxide nanoparticles with low‑crystallinity core and high‑crystallinity shell were synthesized, and ammonia water was used to selectively etch the inner low‑crystallinity core, producing HMZN. Hemin (HEM) and Gd‑poly(acrylic acid) macrochelates (GP) were then loaded to construct HEM@HMZN@GP for dual-source H2O2 surge-driven tumor ferroptosis therapy. In acidic tumor microenvironment, Zn2+, H2O2, HEM, and GP can be released from HEM@HMZN@GP. The released Zn2+ damages mitochondrial electron transport chain (ETC) and generates superoxide anions (•O2 -), which can be rapidly catalyzed by superoxide dismutase into H2O2. The dual-source of H2O2 markedly elevates local oxidative stress. HEM can be enzymatically converted by heme oxygenase‑1 to Fe2+, which reacts with the abundant H2O2 via Fenton reaction to produce hydroxyl radicals, initiating lipid peroxidation and ferroptosis. GP enhances T1‑weighted magnetic resonance imaging signals, facilitating drug delivery visualization in tumors.

BACKGROUNDS:The study was designed to analyze early pregnancy loss rates in first-time fresh embryo transfer cycles in low prognosis patients according to the POSEIDON criteria. METHODS:This was a retrospective cohort study, including patients with positive human chorionic gonadotropin after first fresh cycles in the Reproductive Center of Henan Province People's Hospital from June 2018 to February 2023. A total of 2392 cycles were included in this study, which were divided into 4 groups according to the POSEIDON criteria. The general condition, laboratory indexes, and early pregnancy loss rates of patients were compared in each group and the prediction model was constructed in POSEIDON group 4. RESULTS:The early pregnancy loss rate ranked from high to low in order of Group D (32.82%), Group B (23.31%), Group C (15.34%), and Group A (13.68%). After adjusting confounding factors, multivariate logistic regression analysis revealed that the early pregnancy loss rate was significantly higher in groups B and D than in groups A and C (all P < 0.05). The comparison between Group A and Group C, as well as between Group B and Group D, showed no statistical differences (both P > 0.05). Group D was randomly divided into training and validation cohorts according to 7:3. The prediction model was constructed based on risk factors. The AUC of the training cohort was 0.761(95% CI: 0.680-0.841), and the AUC of the validation cohort was 0.604(95% CI: 0.440-0.767). CONCLUSIONS:Patients in POSEIDON group 4 have the highest early pregnancy loss rate, followed by group 2, while patients in groups 3 and 1 have the lowest rate in first-time fresh cycles. The prediction model was successfully established which can predict the occurrence of early pregnancy loss in first-time fresh cycles in POSEIDON group 4.

To investigate associations between fecal microbiota, short-chain fatty acids (SCFAs), and the efficacy of recombinant human growth hormone (rhGH) treatment in children with growth hormone deficiency (GHD) or idiopathic short stature (ISS). A 2-phase cohort study was conducted. Phase I included 102 participants (GHD: n = 33, ISS: n = 28, controls: n = 41) for cross-sectional analysis using 16S rRNA sequencing and targeted metabolomics to compare microbial diversity, predicted metabolic pathways, and SCFA levels. Phase II longitudinally monitored 61 rhGH-treated children (GHD = 33, ISS = 28) over 2 years, assessing growth velocity, IGF-1 levels, and fecal microbiota/SCFA dynamics. Statistical analyses included alpha/beta diversity metrics, LEfSe, PERMANOVA, and redundancy analysis (RDA) to link microbial/SCFA profiles with clinical outcomes. (1). Microbiota Dysbiosis: Untreated GHD/ISS children exhibited reduced beneficial taxa (e.g., Faecalibacterium, Akkermansia) and increased pathobionts (e.g., Streptococcus, Collinsella) compared to controls (PERMANOVA: R 2 = 0.114, P = 0.001). (2). Metabolic Pathways: GHD/ISS groups showed enrichment in xenobiotic degradation (e.g., atrazine) and deficits in nutrient-associated pathways (e.g., carotenoid biosynthesis). (3). rhGH Effects: Treatment increased beneficial taxa (e.g., Bifidobacterium, Faecalibacterium) and modulated amino acid/lipid metabolism pathways (e.g., glycine-serine-threonine metabolism, P = 0.035). (4). SCFAs and Growth Velocity: Higher growth velocity percentiles correlated with elevated acetic acid (GHD-treated: 1952 ± 962.4 vs. untreated: 1290 ± 886.0 μg/g, P = 0.037) and butyric acid levels. GHD, ISS, and healthy children have different fecal microbiota compositions and SCFA metabolisms. rhGH therapy partially restores microbial balance and alters metabolic pathways, with SCFA levels associated with treatment efficacy. These findings highlight the gut microbiome as a potential modulator of rhGH response and provide insight into microbiota-targeted therapies to improve growth outcomes (e.g., "probiotic interventions").

Traditional drug delivery system (DDS) such as hollow mesoporous organosilica nanoparticle (HMON) can achieve efficient delivery of ferroptosis-inducing agents for tumor therapy due to its high drug loading content (DLC), but is limited by their slow degradation and the uselessness of their silicon-based compounds. In this study, a novel hollow mesoporous superparamagnetic iron oxide nanoparticle (HMSPION) was developed with 100 nm of hollow core and 40 nm of mesoporous shell with a high DLC (up to 22.9 %) of beta-Lapachone (LAP), doxorubicin (DOX), sorafenib (SFN) and/or Zn2+. Furthermore, we propose a new strategy to strengthen Fenton reaction and weaken antioxidant defense systems in tumors by co-loading Zn2+ and LAP into HMSPION to generate LAP@HMSPION@Zn. Specifically, i) LAP@HMSPION@Zn is degraded into Fe2+/3(+), Zn2+, and LAP in acidic tumor microenvironment. ii) LAP catalyzes O-2 to be superoxide anion radical (O2(-center dot)) and Zn2+ raises the O2(-center dot) production in mitochondria. iii) The O2(-center dot) can be catalyzed into hydrogen peroxide (H2O2) via superoxide dismutase. iv) H2O2 and the released Fe2+ accelerate the Fenton reaction, generating highly toxic hydroxyl radical (center dot OH). v) The Fe3+ consumes GSH and LAP downregulates GSH level by NADPH consumption, thereby relieving the antioxidant defense systems in tumor cells.

Polo-like kinase 1 (PLK1), a key regulator of the G2/M phase in mitosis, is frequently overexpressed in numerous tumors. Although PLK1 inhibitors have emerged as promising therapeutic agents for cancer, their use has been linked to significant anemia in a subset of patients, yet the underlying mechanisms remain poorly understood. In this study, we utilized an in vitro human umbilical cord blood-derived CD34+ cell-based erythroid differentiation system, alongside a murine model, to investigate the impact of PLK1 inhibitors on erythropoiesis. Our results indicate that PLK1 inhibitors, specifically GSK461364 and BI6727, significantly suppress the proliferation of erythroid cells, resulting in G2/M phase cell cycle arrest, increased apoptosis in erythroid cells, and the formation of abnormally nucleated late-stage erythroblasts. In vivo, administration of PLK1 inhibitors in mice induced severe anemia, as evidenced by a marked reduction in red blood cells and hemoglobin levels. More specifically, PLK1 inhibition impaired the differentiation and erythroid commitment of hematopoietic stem cells in the bone marrow, resulting in abnormal accumulation of BFU-E cells and reduced proliferation and differentiation of CFU-E, and a decrease in the number of terminal erythrocytes. Mechanistically, PLK1 inhibitors primarily induce apoptosis in erythroid cells by reducing Mitochondrial membrane potential and arresting the cell cycle at the G2/M phase. Overall, our findings underscore the critical role of PLK1 in erythropoiesis and shed light on the mechanisms underlying PLK1 inhibitor-induced anemia, providing essential guidance for developing strategies to prevent and manage anemia in clinical applications of PLK1-targeted therapies.

Cuproptosis in antitumor therapy faces challenges from copper homeostasis efflux mechanisms and high glutathione (GSH) levels in tumor cells, hindering copper accumulation and treatment efficacy. Herein, we propose a strategy of "adding fuel to the flames" for potent antitumor therapy through a self-accelerating cycle of ferroptosis-cuproptosis. Disulfiram (DSF) loaded hollow mesoporous copper-iron sulfide (HMCIS) nanoparticle with conjugation of polyethylene glycol (PEG) and folic acid (FA) ( i.e. , DSF@HMCIS-PEG-FA) was developed to swiftly release DSF, H 2 S, Cu 2 + , and Fe 2 + in the acidic tumor microenvironment (TME). The hydrogen peroxide (H 2 O 2 ) levels and acidity within tumor cells enhanced by the released H 2 S induce acceleration of Fenton (Fe 2 + ) and Fenton-like (Cu 2 + ) reactions, enabling the powerful tumor ferroptosis efficacy. The released DSF acts as a role of "fuel", intensifying catalytic effect ("flame") in tumor cells through the sustainable Fenton chemistry ( i.e. , "add fuel to the flames"). Robust ferroptosis in tumor cells is characterized by serious mitochondrial damage and GSH depletion, leading to excess intracellular copper that triggers cuproptosis. Cuproptosis disrupts mitochondria, compromises iron-sulfur (Fe-S) proteins, and elevates intracellular oxidative stress by releasing free Fe 3 + . These interconnected processes form a self-accelerating cycle of ferroptosis-cuproptosis with potent antitumor capabilities, as validated in both cancer cells and tumor-bearing mice.

Rationale: A common challenge of drug loading and delivery using magnetic resonance imaging (MRI) contrast agents (CAs) is the tendency of aggregation and precipitation at high drug loading conditions. Herein, we propose a generic strategy of controlled ideal aggregation (CIA) to restrict the tendency. Methods: Fe2+, β-Lapachone (LAP), brequinar (BQR), or Sorafenib (SOR) was respectively loaded onto Gd poly (acrylic acid) macrochelate (GP), an MRI CA, in the hollow core of nitrite-modified hollow mesoporous organosilica nanoparticles (HMON-SNO). The aggregation of FeGP, LAPGP, BQRGP, and SORGP was controlled to be ideal without precipitation by the fixed space of the HMON-SNO hollow core. The sizes of the ideal aggregates are larger than the mesopore size of HMON-SNO, which prevents premature drug leakage and release. Results: After the accumulation of FeGP@HMON-SNO in tumors, the presence of glutathione (GSH) in the tumor microenvironment (TME) triggers the HMON-SNO degradation to release NO, Fe2+, and GP. The released Fe2+ reacts with endogenous hydrogen peroxide (H2O2) to generate Fe3+ and hydroxyl radical (•OH). The -SNO groups on the surface of HMON-SNO react with GSH, enabling sustained NO generation. The elevated NO level induces mitochondrial dysfunction, down-regulates lipid droplets through the alleviation of hypoxia and consequently promotes the accumulation of lipid peroxidation (LPO) under excess •OH to induce tumor cell ferroptosis. Moreover, the released GP facilitates high contrast T 1-weighted MRI of tumors due to its high r 1 value, enabling real-time monitoring for the in vivo delivery of FeGP@HMON-SNO. Conclusions: The proposed strategy of CIA with universality was successfully utilized to restrict the aggregation of MRI CAs at high drug loading conditions. The developed FeGP@HMON-SNO with eminent drug loading content were used for tumor ferroptosis-gas synergistic therapy with high efficacy.

Objectives Assisted reproductive technology (ART) is an important part of reproductive medicine, whose possible effects on offspring’s health have drawn widespread attention in recent years. However, relevant studies are limited to postnatal short-term follow-up and lack of diverse sample sources analysis other than blood. Methods In this study, a mouse model was used to explore the effects of ART on fetal development and gene expression in the organs of offspring in the adulthood using next-generation sequencing. The sequencing results were then analyzed. Results The results showed that it caused abnormal expression in 1060 genes and 179 genes in the heart and spleen, respectively. Differentially expressed genes (DEGs) in the heart are mainly enriched in RNA synthesis and processing, and the cardiovascular system development also shows enrichment. STRING analysis identified Ccl2, Ptgs2, Rock1, Mapk14, Agt, and Wnt5a as the core interacting factors. DEGs in the spleen are significantly enriched in anti-infection and immune responses, which include the core factors Fos, Jun and Il1r2. Further exploration revealed the abnormal expression of 42 and 5 epigenetic modifiers in the heart and spleen, respectively. The expression of the imprinted genes Dhcr7, Igf2, Mest and Smoc1 decreased in the hearts of ART offspring, and the DNA methylation levels of Igf2- and Mest-imprinting control regions (ICRs) increased abnormally. Conclusion In the mouse model, ART can interfere with the gene expression pattern in the heart and spleen of the adult offspring and that these changes are related to the aberrant expression of epigenetic regulators.

Se-biofortified agricultural products receive considerable interest due to the worldwide severity of selenium (Se) deficiency. Alfalfa (Medicago sativa L.), the king of forage, has a large biomass, a high protein content, and a high level of adaptability, making it a good resource for Se biofortification. Analyses of agronomic, quality, physiological, and microstructure results indicated the mechanism of biomass increase and quality development in alfalfa during Se treatment. Se treatment effectively increased Se content, biomass accumulation, and protein levels in alfalfa. The enhancement of antioxidant capacity contributes to the maintenance of low levels of reactive oxygen species (ROS), which, in turn, serves to increase alfalfa's stress resistance and the stability of its intracellular environment. An increase in the rate of photosynthesis contributes to the accumulation of biomass in alfalfa. To conduct a more comprehensive investigation of the regulatory networks induced by Se treatment, the transcriptome sequencing of non-coding RNA (ncRNA) was employed to compare 100 mg/kg Se treatment and control groups. The analysis identified 1,414, 62, and 5 genes as DE-long non-coding RNAs (DE-lncRNA), DE-microRNAs (DE-miRNA), and DE-circular RNA (DE-circRNA), respectively. The function of miRNA-related regulatory networks during Se biofortification in alfalfa was investigated. Subsequent enrichment analysis revealed significant involvement of transcription factors, DNA replication and repair mechanisms, photosynthesis, carbohydrate metabolism, and protein processing. The antioxidant capacity and protein accumulation of alfalfa were regulated by the modulation of signal transduction, the glyoxalase pathway, proteostasis, and circRNA/lncRNA-related regulatory networks. The findings offer new perspectives on the regulatory mechanisms of Se in plant growth, biomass accumulation, and stress responses, and propose potential strategies for enhancing its utilization in the agricultural sector.

Introduction:Insulin resistance (IR) may play a central role in the pathophysiology of polycystic ovary syndrome (PCOS). Controlled ovarian stimulation (COS) in PCOS women in the setting of assisted reproductive technology (ART) is always a challenge for clinicians. However, it remains unclear whether IR in women with PCOS correlates with reduced ovarian sensitivity to exogenous gonadotropin (Gn). This study aimed to explore the association between homeostasis model assessment of insulin resistance (HOMA-IR) and ovarian sensitivity index (OSI).Methods:In this retrospective cohort study, we explored the association between Ln HOMA-IR and Ln OSI based on smoothing splines generated by generalized additive model (GAM). Then the correlation between HOMA-IR and OSI was further tested with a multivariable linear regression model and subgroup analysis.Results:1508 women with PCOS aged 20-39 years undergoing their first oocyte retrieval cycle were included consecutively between 2018 until 2022. We observed a negative association between Ln HOMA-IR and Ln OSI by using smoothing splines. In multivariable linear regression analysis, the inverse association between Ln HOMA-IR and Ln OSI was still found in PCOS women after adjustment for potential confounders (β = -0.18, 95% CI -0.25, -0.11). Compared with patients with the lowest tertile of HOMA-IR, those who had the highest tertile of HOMA-IR had lower OSI values (β = -0.25, 95% CI -0.36, -0.15).Discussion:Our study provided evidence for the inverse correlation between IR and the ovarian sensitivity during COS in PCOS women. Herein, we proposed new insights for individualized manipulation in PCOS patients with IR undergoing ART.

Voltage-dependent anion-selective channel protein 1 (VDAC1) is the most abundant protein in the mitochondrial outer membrane and plays a crucial role in the control of hepatocellular carcinoma (HCC) progress. Our previous research found that cytosolic molecular chaperone heat shock protein 90 (Hsp90) interacted with VDAC1, but the effect of the C-terminal and N-terminal domains of Hsp90 on the formation of VDAC1 oligomers is unclear. In this study, we focused on the effect of the C-terminal domain of Hsp90 on VDAC1 oligomerization, ubiquitination, and VDAC1 channel activity. We found that Hsp90 C-terminal domain inhibitor Novobiocin promoted VDAC1 oligomerization, release of cytochrome c, and activated mitochondrial apoptosis pathway. Atomic coarse particle modeling simulation revealed C-terminal domain of Hsp90α stabilized VDAC1 monomers. The purified VDAC1 was reconstituted into a planar lipid bilayer, and electrophysiology experiments of patch clamp showed that the Hsp90 C-terminal inhibitor Novobiocin increased VDAC1 channel conductance via promoting VDAC1 oligomerization. The mitochondrial ubiquitination proteomics results showed that VDAC1 K274 mono-ubiquitination was significantly decreased upon Novobiocin treatment. Site-directed mutation of VDAC1 (K274R) weakened Hsp90α-VDAC1 interaction and increased VDAC1 oligomerization. Taken together, our results reveal that Hsp90 C-terminal domain inhibition promotes VDAC1 oligomerization and VDAC1 channel conductance by decreasing VDAC1 K274 mono- ubiquitination, which provides a new perspective for mitochondria-targeted therapy of HCC.

Background Insulin resistance (IR) may adversely impact the in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) outcomes. However, the association of IR with ovarian sensitivity during controlled ovarian hyperstimulation (COH) remains controversial. Purpose We aimed to explore the association between homeostasis model assessment of insulin resistance (HOMA-IR) and ovarian sensitivity index (OSI). Patients and Methods In this retrospective cohort study, 7836 patients aged between 20 and 39 years with good ovarian reserve were included consecutively between June 2018 and May 2022. HOMA-IR was calculated to evaluate the degree of IR and OSI was used to measure ovarian sensitivity. Owing to skewed distribution, HOMA-IR and OSI were log e transformed to Ln HOMA-IR and Ln OSI. Smoothing splines were generated by generalized additive models to explore the correlation between Ln HOMA-IR and Ln OSI. Then, the relationship between Ln HOMA-IR and Ln OSI was tested with multivariable linear regression model after adjustments for the potential confounders. Results We observed negative association between Ln HOMA-IR and Ln OSI after adjustment for potential confounders by using smoothing spline fitting curves in generalized additive model. In the multivariable linear regression model, after full adjustments, each one unit increase in Ln HOMA-IR was related to reduced Ln OSI values (β = −0.12, 95% CI, −0.15, −0.09). As sensitivity analysis, those who had HOMA-IR of quartile 3 (HOMA-IR 2.33–3.43) and quartile 4 (HOMA-IR ≥3.43) had decreases in Ln OSI values (β = −0.07, 95% CI −0.11, −0.03 and β = −0.18, 95% CI −0.22, −0.13, respectively) when compared with patients in the quartile 1 (HOMA-IR <1.63). Furthermore, stratified and interaction analysis showed a strong inverse association of Ln HOMA-IR with Ln OSI in subgroups of PCOS patients and overweight/obese populations (P-value for interaction <0.0001). Conclusion HOMA-IR value was negatively associated with the ovarian sensitivity assessed by OSI. Among the PCOS and overweight/obese populations, this inverse relationship may be strong. These findings will increase the understanding of the contribution of IR to the development of decreased ovarian sensitivity within the assisted reproductive technology (ART) setting. It may have implications for optimizing gonadotropin dose manipulation in patients with IR undergoing IVF/ICSI.

Anemia affects 1.8 billion people worldwide, and diet is one of the key modifiable factors for treating anemia in children. The dietary pattern has changed rapidly in recent decades, but its effect on childhood anemia has not been reported. This study aimed to identify dietary patterns among children in rural areas of Guangzhou, China, and explore their association with anemia. A total of 1476 children aged 9–16 years old were included in this study. Demographics, lifestyle, and anthropometric and dietary information were collected. Factor analysis was used to identify dietary patterns, and anemia was diagnosed based on hemoglobin levels. Robust Poisson regression and subgroup analysis were used to analyze the association between dietary patterns and anemia. The prevalence of anemia in children was 10.4%, with 6.1% in boys and 15.4% in girls. Four dietary patterns were identified, including a fast food pattern, a vegetarian pattern, a meat and egg pattern, and a rice and wheat pattern. A high score in the fast food pattern was positively associated with risk of anemia in children entering puberty (PR = 1.767, 95% CI: 1.026~3.043, p = 0.039), especially in girls after menarche, with marginal significance (PR = 1.740, 95% CI: 0.977~3.097, p = 0.059). A high score in the meat and egg pattern was negatively associated with risk of anemia in children entering puberty (PR = 0.498, 95% CI: 0.286~0.866, p = 0.013), especially in boys after spermatorrhea (PR = 0.237, 95% CI: 0.031~0.590, p = 0.007). The fast food pattern was a risk factor for anemia in children, and the meat and egg pattern was a protective factor for anemia in children entering puberty. The findings of this study could be used to guide the strategies of evidence-based preventive nutrition interventions to curb anemia in children.

Backgroud Hypoadiponectinemia is the important cause of insulin resistance. Recent studies have shown that periodontitis is associated with hypoadiponectinemia. The purpose of this study was to investigate the effect of periodontitis-induced endoplasmic reticulum stress (ERS) in visceral adipocytes on hypoadiponectinemia. Methods Rat periodontitis models were established by local ligation with silk around the bilateral maxillary second molars. Porphyromonas gingivalis- lipopolysaccharid ( P.g -LPS) was also used to stimulate the visceral adipocytes in vitro. The protein expression levels of glucose regulated protein 78 (GRP78), inositol-requiring protein 1α (IRE1α), protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6) and adiponectin were detected. IRE1α lentiviruses were transfected into visceral adipocytes in vitro, and an IRE1α inhibitor (KIRA6) was injected in epididymal adipose tissue of rats to detect and verify the effect of ERS on adiponectin expression in visceral adipocytes in vivo. Results Hypoadiponectinemia was observed in periodontitis rat, and the expression levels of ERS key proteins GRP78 and the phosphorylation levels of IRE1α (p-IRE1α)/IRE1α in visceral adipocytes were increased, while the expression levels of adiponectin protein were decreased. After KIRA6 injection into epididymal adipose tissue of rats with periodontitis, adiponectin levels in visceral adipocytes increased, and serum adiponectin levels recovered to a certain extent. The protein expression levels of GRP78 and p-IRE1α/IRE1α were increased and adiponectin protein expression was decreased in P.g -LPS-induced visceral adipocytes. Overexpression of IRE1α further inhibited adiponectin expression in P.g -LPS-stimulated visceral adipocytes, and conversely, IRE1α inhibition restored adiponectin expression. Conclusions Our findings suggest that periodontitis induces ERS in visceral adipocytes leading to hypoadiponectinemia. IRE1α is a key protein regulating adiponectin expression in visceral adipocytes.

The emerging tumor ferroptosis therapy confronts impediments of the tumor microenvironment (TME) with weak intrinsic acidity, inadequate endogenous H2 O2 , and a powerful intracellular redox balance system that eliminates toxic reactive oxygen species (ROS). Herein, a strategy of Fenton reaction cycloacceleration initiated by remodeling the TME for magnetic resonance imaging (MRI)-guided high-performance ferroptosis therapy of tumors is proposed. The synthesized nanocomplex exhibits enhanced accumulation at carbonic anhydrase IX (CAIX)-positive tumors based on the CAIX-mediated active targeting, and increased acidification via the inhibition of CAIX by 4-(2-aminoethyl) benzene sulfonamide (ABS) (remodeling TME). This accumulated H+ and abundant glutathione in TME synergistically trigger biodegradation of the nanocomplex to release the loaded cuprous oxide nanodots (CON), β-lapachon (LAP), Fe3+ , and gallic acid-ferric ions coordination networks (GF). The Fenton and Fenton-like reactions are cycloaccelerated via the catalytic loop of Fe-Cu, and the LAP-triggered and nicotinamide adenine dinucleotide phosphate quinone oxidoreductase1-mediated redox cycle, generating robust ROS and plenitudinous lipid peroxides accumulation for ferroptosis of tumor cells. The detached GF network has improved relaxivities in response to the TME. Therefore, the strategy of Fenton reaction cycloacceleration initiated by remodeling the TME is promising for MRI-guided high-performance ferroptosis therapy of tumors.

Pancreas ductal adenocarcinoma has a highly aggressive phenotype and is one of the most lethal malignancies in the world. Although the use of FOLFIRINOX and abraxane plus gemcitabine chemotherapy regimens have improved patient care, their recurrence rates and long-term survival are still not promising. In this study, PLGA/gemcitabine microspheres were prepared by emulsification–solvent volatilization using gemcitabine as the drug model, and scanning electron microsopy showed that the microspheres had a smooth surface, small size, and large specific surface area. The PLGA microspheres have a high loading capacity and are capable of long-term release. The combination of PLGA/gemcitabine microspheres with chimeric antigen receptor T-cell treatment can regulate MUC1 expression in epithelial cells and reduce the aggressiveness of tumors; thus, it is expected to be applied in the treatment of pancreatic ductal adenocarcinoma.

A prevalent problem of magnetic resonance imaging (MRI) contrast agents (CAs) for drug loading applications is easy aggregation. The major concern of hollow mesoporous organosilica nanoparticles (HMONs) is hard control of untimely drug leakage. To overcome both problems, a new strategy of limited‐space controlled aggregation for generic enhancement of drug loading capability is proposed. Typically, MRI CAs of exceedingly small gadolinium oxide nanoparticle (GO) and Gd poly(acrylic acid) macrochelate (GP) are exploited to load doxorubicin (D) in HMONs hollow core. The GO@D@HMONs and GP@D@HMONs without precipitation formation display much higher drug loading contents (33.0 ± 4.9%, 39.6 ± 4.0%) than GO@D and GP@D with serious precipitation generation (4.7 ± 0.5% and 14.7 ± 3.4%), which can be ascribed to the generation of GO@D and GP@D aggregates with larger sizes in HMONs hollow core than the pore size of HMONs preventing the drug leakage. The tumor microenvironment (TME)‐specific glutathione (GSH)‐triggered degradation of HMONs and the controlled drug release behaviors reinforce the chemotherapeutic efficacy and alleviate side effects on normal cells/tissues. The GSH‐activatable T 1 ‐MRI is favorable to high contrast tumor imaging. Overall, the strategy of limited‐space controlled aggregation is promising for generic enhancement of drug loading capability of MRI CAs, realizing MRI‐guided high‐performance cancer treatments.

To surmount the major concerns of commercial small molecule Gd chelates and reported Gd‐based contrast agents (GBCAs) for magnetic resonance imaging (MRI), a new concept of organogadolinium macrochelates (OGMCs) constructed from the coordination between Gd 3+ and macromolecules is proposed. A library of macromolecules were screened for Gd 3+ coordination, and two candidates [i.e., poly(acrylic acid) (PAA), and poly(aspartic acid) (PASP)] succeeded in OGMC formation. Under optimized synthesis conditions, both Gd‐PAA12 and Gd‐PASP11 OGMCs are outstanding T 1 ‐weighted CAs owing to their super high r 1 values (> 50 m m −1 s −1 , 3.0 T) and ultralow r 2 / r 1 ratios (< 1.6, 3.0 T). The ferromagnetism of OGMCs is completely different from the paramagnetism of commercial and reported GBCAs. The ferromagnetism is very weak (M s < 1.0 emu g −1 ) leading to a low r 2 , which is preferred for T 1 MRI. Gd 3+ is not released from the OGMC Gd‐PAA12 and Gd‐PASP11, ensuring biosafety for in vivo applications. The safety and T 1 ‐weighted MRI efficiencies of the OGMC Gd‐PAA12 and Gd‐PASP11 are tested in cells and mice. The synthesis method of the OGMCs is facile and easy to be scaled up. Consequently, the OGMC Gd‐PAA12 and Gd‐PASP11 are superior T 1 ‐weighted CAs with promising translatability to replace the commercial Gd chelates.

Urethane has little effect on nervous system and is often used in neuroscience studies. However, the effect of urethane in neurons is not thoroughly clear. In this study, we investigated changes in neuron responses to tones in inferior colliculus during urethane anesthesia. As urethane was metabolized, the best and characteristic frequencies did not obviously change, but the minimal threshold (MT) remained relatively stable or was elevated. The frequency tuning bandwidth at 60 dB SPL (BW 60dBSPL ) remained unchanged or decreased, and the average evoked spike of effective frequencies at 60 dB SPL (ES 60dBSPL ) gradually decreased. Although the average evoked spike of effective frequencies at a tone intensity of 20 dB SPL above MT (ES 20dBSPLaboveMT ) decreased, the frequency tuning bandwidth at a tone intensity of 20 dB SPL above MT (BW 20dBSPLaboveMT ) did not change. In addition, the changes in MT, ES 60dBSPL , BW 60dBSPL , and ES 20dBSPLaboveMT increased with the MT in pre-anesthesia awake state (MT pre−anesthesiaawake ). In some neurons, the MT was lower, BW 60dBSPL was broader, and ES 60dBSPL and ES 20dBSPLaboveMT were higher in urethane anesthesia state than in pre-anesthesia awake state. During anesthesia, the inhibitory effect of urethane reduced the ES 20dBSPLaboveMT , but did not change the MT, characteristic frequency, or BW 20dBSPLaboveMT . In the recording session with the strongest neuron response, the first spike latency did not decrease, and the spontaneous spike did not increase. Therefore, we conclude that urethane can reduce/not change the MT, increase the evoked spike, or broaden/not change the frequency tuning range, and eventually improve the response of auditory neurons to tone with or without “pushing down” the tonal receptive field in thresholding model. The improved effect increases with the MT pre−anesthesiaawake of neurons. The changes induced by the inhibitory and improved effects of urethane abide by similar regularities, but the change directions are contrary. The improvement mechanism may be likely due to the increase in the ratio of excitatory/inhibitory postsynaptic inputs to neurons.

The inferior colliculus (IC) is a critical centre for the binaural processing of auditory information. However, previous studies have mainly focused on the central nucleus of the inferior colliculus (ICC), and less is known about the dorsal nucleus of the inferior colliculus (ICD). Here, we first examined the characteristics of the neuronal responses in the mouse ICD and compared them with those in the inferior colliculus under binaural and monaural conditions using in vivo loose-patch recordings. ICD neurons exhibited stronger responses to ipsilateral sound stimulation and better binaural summation than those of ICC neurons, which indicated a role for the ICD in binaural hearing integration. According to the abundant interactions between bilateral ICDs detected using retrograde virus tracing, we further studied the effect of unilateral ICD silencing on the contralateral ICD. After lidocaine was applied, the responses of some ICD neurons (13/26), especially those to ipsilateral auditory stimuli, decreased. Using whole-cell recording and optogenetic methods, we investigated the underlying neuronal circuits and synaptic mechanisms of binaural auditory information processing in the ICD. The unilateral ICD provides both excitatory and inhibitory projections to the opposite ICD, and the advantaged excitatory inputs may be responsible for the enhanced ipsilateral responses and binaural summation of ICD neurons. Based on these results, the contralateral ICD might modulate the ipsilateral responses of the neurons and binaural hearing.