Lutein protects senescent ciliary muscle against oxidative stress through the Keap1/Nrf2/ARE pathway.

BACKGROUND: Aging-induced decline in ciliary muscle function is an important factor in visual accommodative deficits in elderly adults. With this study, we provide an innovative investigation of the interaction between ciliary muscle aging and oxidative stress. METHODS: Tricolor guinea pigs were used for the experiments in vivo and primary guinea pig ciliary smooth muscle cells were used for the experiments in vitro. RESULTS: We enriched for genes associated with muscle-aging-lutein relationship using bioinformatics, including Nuclear factor-erythroid 2-related factor-2 (Nrf2), Glutathione Peroxidase (GPx) gene family, Superoxide Dismutase (SOD) gene family, NAD(P)H: Quinone Oxidoreductase 1 (NQO1) and Heme Oxygenase-1 (HO-1). After gavage to aged guinea pigs, lutein reduced Reactive Oxygen Species (ROS) and P21 levels in senescent ciliary muscle; lutein decreased refractive error and restored accommodation of the eye. In addition, lutein increased GPx, SOD, and Catalase (CAT) levels in serum; lutein increased GPx and CAT levels in ciliary bodies. Lutein regulated the expression of proteins such as Nrf2, Kelch-like ECH-associated protein 1 (Keap1), and downstream proteins in senescent ciliary bodies. Similarly, guinea pig ciliary muscle cell senescence was associated with oxidative stress. In vitro, 100 µM lutein reversed the damage caused by 800 µM H2O2; it reduced Senescence-Associated ß-galactosidase (SA-ß-Gal) and ROS activites, cell apoptosis and cell migration. Also, lutein increased the expression of smooth muscle contractile proteins. Lutein also increased the expression of Nrf2, GPx2, NQO1 and HO-1, decreased the expression of Keap1. A reduction in Nrf2 activity led to a reduction in the ability of lutein to activate antioxidant enzymes in the cells, thus reducing its inhibitory effect on cell senescence. CONCLUSION: lutein improved resistance to oxidative stress in senescent ciliary muscle in vivo and in vitro by regulating the Keap1/Nrf2/Antioxidant Response Element pathway. We have innovatively demonstrated the molecular pharmacological mechanism by which lutein reverse age-related ciliary muscle systolic and diastolic deficits.

Initial dosage optimization of olanzapine in patients with bipolar disorder based on model-informed precision dosing: a study from the real world.

Objectives: Olanzapine is used for treating bipolar disorder (BPD); however, the optimal initial dosing regimen is unclear. The present study aimed to investigate the optimal olanzapine initial dosage in patients with BPD via model-informed precision dosing (MIPD) based on a real-world study. Methods: Thirty-nine patients with BPD from the real-world study were collected to construct the MIPD model. Results: Weight, combined used quetiapine influenced olanzapine clearances in patients with BPD, where the clearance rates were 0.152:1 in patients with or without quetiapine under the same weight. We simulated olanzapine doses once a day or twice a day, of which twice a day was optimal. Without quetiapine, for twice-a-day olanzapine doses, 0.80, 0.70, and 0.60 mg/kg/day were suitable for 40- to 56-kg BPD patients, 56- to 74-kg BPD patients, and 74- to 100-kg BPD patients, respectively. With quetiapine, for twice-a-day olanzapine doses, 0.05 mg/kg/day was suitable for 40- to 100-kg BPD patients. Conclusion: This study was the first to investigate the optimal olanzapine initial dosage in patients with BPD via MIPD based on a real-world study, providing clinical reference for the precision medication of olanzapine in BPD patients.

The initiation and early development of apical-basal polarity in Toxoplasma gondii.

The body plan of the human parasite Toxoplasma gondii has a well-defined polarity. The minus ends of the 22 cortical microtubules are anchored to the apical polar ring, a putative microtubule-organizing center. The basal complex caps and constricts the parasite posterior end, and is critical for cytokinesis. How this apical-basal polarity is initiated was unknown. Here we examined the development of the apical polar ring and the basal complex using expansion microscopy. We found that substructures in the apical polar ring have different sensitivity to perturbations. In addition, apical-basal differentiation is already established upon nucleation of the cortical microtubule array: arc forms of the apical polar ring and basal complex associate with opposite ends of the microtubules. As the nascent daughter framework grows towards the centrioles, the apical and basal arcs co-develop ahead of the microtubule array. Lastly, two apical polar ring components, APR2 and KinesinA, act synergistically. The removal of individual proteins has modest impact on the lytic cycle. However, the loss of both results in abnormalities in the microtubule array and highly reduced plaquing and invasion efficiency.

A dosimetric comparison of brachytherapy sources for endometrial cancer: an electronic brachytherapy and an iridium-192 source with multichannel cylinders and a three-dimensional technique.

BACKGROUND AND PURPOSE: Ir192 vaginal brachytherapy (IBT) is commonly used for patients with postoperative endometrial cancer (EC). We devised a novel multichannel vaginal applicator that could be equipped with an electronic brachytherapy (EBT) device. We aimed to explore the differences in physical parameters between the EBT and IBT. MATERIALS AND METHODS: This retrospective study included 20 EC patients who received adjuvant IBT from March 1, 2023, to May 1, 2023. Multichannel vaginal cylinders were used, and three-dimensional plans were generated. We designed an electronic multichannel vaginal applicator model and simulated a three-dimensional EBT plan. In order to ensure comparability, D90 of the CTV for the EBT plan was normalized to be equivalent to that of the IBT plan for the same patient. RESULTS: Twenty EBT plans were compared with 20 IBT plans. Results showed, the mean D90 value of clinical target volume (CTV) was 536.1 cGy for both treatment plans. For the mean dose of CTV, the EBT was significantly greater (738.3 vs. 684.3 cGy, p = 0.000). There was no significant difference in CTV coverage between the EBT and IBT plans. For high-dose areas (V200% and V150%), the EBTs were significantly greater. There were no significant differences in the maximum doses to the vaginal mucosa between the EBT and IBT, whether at the apex or in the middle segment. For the bladder and rectum, both the low-dose area and high-dose area were significantly lower in the EBT plans. For the conformity index, there was no significant difference between the EBT and IBT plans. For the dose homogeneity index, the EBT value was lower. CONCLUSION: In conclusion, under the premise of a three-dimensional brachytherapy plan, for patients receiving multichannel vaginal applicator brachytherapy, compared with IBT, EBT could reduce the dose to the surrounding organs at risk while maintaining the dose in the target area.

Leveraging phenazine and dihydrophenazine redox dynamics in conjugated microporous polymers for high-efficiency overall photosynthesis of hydrogen peroxide.

Harnessing solar energy for hydrogen peroxide (H2O2) production from water and oxygen is crucial for sustainable solar fuel generation. Conjugated microporous polymers (CMPs), with their vast structural versatility and extended π-conjugation, are promising photocatalysts for solar-driven H2O2 generation, though enhancing their efficiency is challenging. Inspired by the crucial role of phenazine derives in biological redox cycling and electron transfer processes, the redox-active phenazine moiety is rationally integrated into a CMP framework (TPE-PNZ). By leveraging the reversible redox dynamics between phenazine and dihydrophenazine, TPE-PNZ sets a new benchmark for H2O2 production among CMP-based photocatalysts, reaching a production rate of 5142 µmol g-1 h-1 and a solar-to-chemical conversion efficiency of 0.58% without requiring sacrificial agents. This interconversion allows for the storage of photogenerated electrons by phenazine and subsequent conversion into dihydrophenazine, which then reduces O2 to H2O2 while reverting to phenazine, markedly facilitating charge transfer and mitigating charge recombination. Experimental and computational investigations further reveal that this reversible process enhances O2 adsorption and reduction, significantly lowering the energy barrier towards H2O2 formation. This study offers critical insights into designing advanced materials for sustainable energy research.

Improvement of hepatic fibrosis after tenofovir disoproxil fumarate switching to tenofovir alafenamide for three years.

BACKGROUND: Both tenofovir alafenamide (TAF) and tenofovir disoproxil fumarate (TDF) are the first-line treatments for chronic hepatitis B (CHB). We have showed switching from TDF to TAF for 96 weeks resulted in further alanine aminotransferase (ALT) improvement, but data remain lacking on the long-term benefits of TDF switching to TAF on hepatic fibrosis. AIM: To assess the benefits of TDF switching to TAF for 3 years on ALT, aspartate aminotransferase (AST), and hepatic fibrosis improvement in patients with CHB. METHODS: A single center retrospective study on 53 patients with CHB who were initially treated with TDF, then switched to TAF to determine dynamic patterns of ALT, AST, AST to platelet ratio index (APRI), fibrosis-4 (FIB-4) scores, and shear wave elastography (SWE) reading improvement at switching week 144, and the associated factors. RESULTS: The mean age was 55 (28-80); 45.3%, males; 15.1%, clinical cirrhosis; mean baseline ALT, 24.8; AST, 25.7 U/L; APRI, 0.37; and FIB-4, 1.66. After 144 weeks TDF switching to TAF, mean ALT and AST were reduced to 19.7 and 21, respectively. From baseline to switching week 144, the rates of ALT and AST < 35 (male)/25 (female) and < 30 (male)/19 (female) were persistently increased; hepatic fibrosis was also improved by APRI < 0.5, from 79.2% to 96.2%; FIB-4 < 1.45, from 52.8% to 58.5%, respectively; mean APRI was reduced to 0.27; FIB-4, to 1.38; and mean SWE reading, from 7.05 to 6.30 kPa after a mean of 109 weeks switching. The renal function was stable and the frequency of patients with glomerular filtration rate > 60 mL/min was increased from 86.5% at baseline to 88.2% at switching week 144. CONCLUSION: Our data confirmed that switching from TDF to TAF for 3 years results in not only persistent ALT/AST improvement, but also hepatic fibrosis improvement by APRI, FIB-4 scores, as well as SWE reading, the important clinical benefits of long-term hepatitis B virus antiviral treatment with TAF.

Weight, CYP3A5 Genotype, and Voriconazole Co-administration Influence Tacrolimus Initial Dosage in Pediatric Lung Transplantation Recipients with Low Hematocrit based on a Simulation Model.

OBJECTIVE: The method of administering the initial doses of tacrolimus in recipients of pediatric lung transplantation, especially in patients with low hematocrit, is not clear. The present study aims to explore whether weight, CYP3A5 genotype, and voriconazole co-administration influence tacrolimus initial dosage in recipients of pediatric lung transplantation with low hematocrit based on safety and efficacy using a simulation model. METHODS: The present study utilized the tacrolimus population pharmacokinetic model, which was employed in lung transplantation recipients with low hematocrit. RESULTS: For pediatric lung transplantation recipients not carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-13, 13-19, 19-22, 22-35, 35-38, and 38-40 kg are 0.03, 0.04, 0.05, 0.06, 0.07, and 0.08 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and without voriconazole, the recommended tacrolimus doses for weights of 10-18, 18-30, and 30-40 kg are 0.06, 0.08, 0.11 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients not carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20 and 20-40 kg are 0.02 and 0.03 mg/kg/day, which are split into two doses, respectively. For pediatric lung transplantation recipients carrying CYP3A5*1 and with voriconazole, the recommended tacrolimus doses for weights of 10-20, 20-33, and 33-40 kg are 0.03, 0.04, and 0.05 mg/kg/day, which are split into two doses, respectively. CONCLUSION: The present study is the first to recommend the initial dosages of tacrolimus in recipients of pediatric lung transplantation with low hematocrit using a simulation model.

Generation of Isolated Subfemtosecond Electron Bunches by the Diffraction of a Polarization-Tailored Intense Laser Beam.

We propose utilizing a polarization-tailored high-power laser pulse to extract and accelerate electrons from the edge of a solid foil target to produce isolated subfemtosecond electron bunches. The laser pulse consists of two orthogonally polarized components with a time delay comparable to the pulse duration, such that the polarization in the middle of the pulse rapidly rotates over 90° within few optical cycles. Three-dimensional particle-in-cell simulations show that when such a light pulse diffracts at the edge of a plasma foil, a series of isolated relativistic electron bunches are emitted into separated azimuthal angles determined by the varying polarization. In comparison with most other methods that require an ultrashort drive laser, we show the proposed scheme works well with typical multicycle (∼30 fs) pulses from high-power laser facilities. The generated electron bunches have typical durations of a few hundred attoseconds and charges of tens of picocoulombs.

Short-term intermittent hypoxia exposure for dyspnea and fatigue in post-acute sequelae of COVID-19: A randomized controlled study.

BACKGROUND: Post-acute sequelae of COVID-19 (PASC) is incurring a huge health and economic burden worldwide. There is currently no effective treatment or recommended drug for PASC. METHODS: This prospective randomized controlled study was conducted in a hospital in China. The effect of intermittent hypoxia exposure (IHE; 5-min hypoxia alternating with 5-min normal air, repeated five times) on dyspnea and fatigue was investigated in patients meeting the NICE definition of PASC. Patients were computationally randomized to receive normoxia exposure (NE) and routine therapy or IHE and routine therapy. Six-minute walk distance (6MWD) and spirometry were tested before and after the interventions; the Borg Dyspnea Scale (Borg) and the modified Medical Research Council Dyspnea Scale (mMRC) were used to assess dyspnea; and the Fatigue Assessment Scale (FAS) and the Chalder Fatigue Scale-11 (CFQ-11) were used to assess fatigue. The study was registered in the Chinese Clinical Trial Registry (ChiCTR2300070565). FINDINGS: Ninety-five participants (33 males and 62 females) were recruited between March 1, 2023 and December 30, 2023. Forty-seven patients in the IHE group received 10.0 (9.0, 15.0) days of IHE, and 48 patients in NE group received 10.0 (8.0, 12.0) days of NE. 6MWD, forced vital capacity (FVC), FVC %pred, forced expiratory volume in 1 s (FEV1), FEV1 %pred, tidal volume (VT), and dyspnea and fatigue scales markedly improved after IHE (p < 0.05), and improvements were greater than in the NE group (all p < 0.05). Furthermore, participants in IHE group had better subjective improvements in dyspnea and fatigue than those in the NE group (p < 0.05). Compared with <10 days of IHE, ≥10 days of IHE had a greater impact on 6MWD, FVC, FEV1, FEV1 %pred, VT, FAS, and CFQ-11. No severe adverse events were reported. INTERPRETATION: IHE improved spirometry and 6MWD and relieved dyspnea and fatigue in PASC patients. Larger prospective studies are now needed to verify these findings.

Prussian Blue Nanohybridized Multicellular Spheroids as Composite Engraftment for Antioxidant Bone Regeneration and Photoacoustic Tomography.

Regulating the complex microenvironment after tooth extraction to promote alveolar bone regeneration is a pressing challenge for restorative dentistry. In this study, through modulating the mechanical properties of the cellular matrix, we guided various types of cells by self-organizing to form multicellular spheroids (MCSs) and hybridized MCSs with Prussian Blue nanoparticles (PBNPs) in the process. The constructed Prussian Blue nanohybridized multicellular spheroids (PBNPs@MCSs) with empowered antioxidant functions effectively reduced cell apoptosis under peroxidative conditions and exhibited enhanced ability to regulate the microenvironment and promote bone repair both in vitro and in vivo. In addition, the PBNPs@MCSs exhibited enhanced photoacoustic imaging ability to trace low doses of PBNPs. Therefore, the constructed PBNPs@MCSs based on the biomimetic hydrogel can be used as a form of an engraftment building block, with a greater potential for pro-bone repair application in the complex microenvironment of the oral cavity.

Pilocarpine mediated excessive calcium accumulation leads to ciliary muscle cell senescence and apoptosis.

The ciliary muscle constitutes a crucial element in refractive regulation. Investigating the pathophysiological mechanisms within the ciliary muscle during excessive contraction holds significance in treating ciliary muscle dysfunction. A guinea pig model of excessive contraction of the ciliary muscle induced by drops pilocarpine was employed, alongside the primary ciliary muscle cells was employed in in vitro experiments. The results of the ophthalmic examination showed that pilocarpine did not significantly change refraction and axial length during the experiment, but had adverse effects on the regulatory power of the ciliary muscle. The current data reveal notable alterations in the expression profiles of hypoxia inducible factor 1 (HIF-1α), ATP2A2, P53, α-SMA, Caspase-3, and BAX within the ciliary muscle of animals subjected to pilocarpine exposure, alongside corresponding changes observed in cultured cells treated with pilocarpine. Augmented levels of ROS were detected in both tissue specimens and cells, culminating in a significant increase in cell apoptosis in in vivo and in vitro experiments. Further examination revealed that pilocarpine induced an increase in intracellular Ca2+ levels and disrupted MMP, as evidenced by mitochondrial swelling and diminished cristae density compared to control conditions, concomitant with a noteworthy decline in antioxidant enzyme activity. However, subsequent blockade of Ca2+ channels in cells resulted in downregulation of HIF-1α, ATP2A2, P53, α-SMA, Caspase-3, and BAX expression, alongside ameliorated mitochondrial function and morphology. The inhibition of Ca2+ channels presents a viable approach to mitigate ciliary cells damage and sustain proper ciliary muscle function by curtailing the mitochondrial damage induced by excessive contractions.

Association Between Dyadic Coping and Psychosocial Adjustment and the Mediation Effect of Fear of Disease Progression in Patients With Malignancy and Their Caregivers: Based on the Actor-Partner Interdependence Model.

BACKGROUND: Psychosocial adjustment (PSA) in patients exhibits a positive correlation with dyadic coping (DC) and a negative correlation with fear of disease progression (FoP). However, few studies have explored how DC impacts PSA and whether FoP mediates this relationship. OBJECTIVE: To investigate the status of DC, FoP, and PSA in patients with malignancy and their caregivers and to explore the actor-partner and mediating effect of FoP on the association between PSA and DC. METHODS: This study employed a cross-sectional design with convenience sampling to select patients with malignancy and their caregivers from 2 hospitals in China. SPSS and AMOS were used for data analysis. RESULTS: The model showed the mediation effect accounts for 28.30% of the total effect. For the actor effects, patients' and their caregivers' DC influenced their PSA directly (both ß = -.138, P < .05) or through their FoP (ß = -.050 and ß = -.55, both P < .05). As for partner effects, patients' DC influenced the caregivers' PSA directly or through the patients' FoP (ß = -.118 and ß = -.020, both P < .05). Caregivers' DC also influenced patients' PSA directly (ß = -.118, P < .05) or through the patients' or caregivers' FoP (ß = -.098 and ß = -.018, both P < .05). CONCLUSIONS: The model revealed a significant mediating effect of FoP on the association between the PSA and DC of patients with malignancy and their caregivers. IMPLICATIONS FOR PRACTICE: Nurses should adopt a comprehensive perspective that includes caregivers in holistic care to improve their PSA by improving their level of DC or mitigating FoP.

Autophagy-mediated activation of the AIM2 inflammasome enhances M1 polarization of microglia and exacerbates retinal neovascularization.

Retinopathy of prematurity (ROP) is a retinal neovascularization (RNV) disease that is characterized by abnormal blood vessel development in the retina. Importantly, the etiology of ROP remains understudied. We re-analyzed previously published single-cell data and discovered a strong correlation between microglia and RNV diseases, particularly ROP. Subsequently, we found that reactive oxygen species reduced autophagy-dependent protein degradation of absent in melanoma 2 (AIM2) in hypoxic BV2 cells, leading to increased AIM2 protein accumulation. Furthermore, we engineered AIM2 knockout mice and observed that the RNV was significantly reduced compared to wild-type mice. In vitro vascular function assays also demonstrated diminished angiogenic capabilities following AIM2 knockdown in hypoxic BV2 cells. Mechanistically, AIM2 enhanced the M1-type polarization of microglia via the ASC/CASP1/IL-1ß pathway, resulting in RNV. Notably, the administration of recombinant protein IL-1ß exacerbated angiogenesis, while its inhibition ameliorated the condition. Taken together, our study provides a novel therapeutic target for ROP and offers insight into the interaction between pyroptosis and autophagy.

Thyroid dysfunction in the wake of Omicron: understanding its role in COVID-19 severity and mortality.

Purpose: SARS-CoV-2 can invade the thyroid gland. This study was to delineate the risk of thyroid dysfunction amidst the prevalence of the Omicron variant, and to investigate the correlation between thyroid function and Coronavirus disease 2019 (COVID-19) outcomes. The study also aimed to ascertain whether thyroid dysfunction persisted during COVID-19 recovery phase. Methods: This was a retrospective cohort study. COVID-19 patients from the Renmin Hospital of Wuhan University, China during the epidemic of Omicron variants were included, and their thyroid function were analyzed in groups. Results: A history of thyroid disease was not associated with COVID-19 outcomes. COVID-19 can lead to a bimodal distribution of thyroid dysfunction. The severity of COVID-19 was inversely proportional to the levels of thyroid- stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4), leading to a higher prevalence of thyroid dysfunction. Severe COVID-19 was a risk factor for euthyroid sick syndrome (ESS) (OR=22.5, 95% CI, 12.1 - 45.6). Neutrophil to lymphocyte ratio mediated the association between severe COVID-19 and ESS (mediation effect ratio = 41.3%, p < 0.001). ESS and decreased indicators of thyroid function were associated with COVID-19 mortality, while high levels of FT3 and FT4 exhibited a protective effect against death. This effect was more significant in women (p < 0.05). During the recovery period, hyperthyroidism was quite uncommon, while a small percentage of individuals (7.7%) continued to exhibit hypothyroidism. Conclusion: COVID-19 severity was linked to thyroid dysfunction. Severe COVID-19 increased the risk of ESS, which was associated with COVID-19 mortality. Post-recovery, hyperthyroidism was rare, but some individuals continued to have hypothyroidism.

A pilot randomized controlled trial of major ozone autohemotherapy for patients with post-acute sequelae of COVID-19.

This prospective, randomized, controlled clinical trial assessed the therapeutic effects of major ozone autohemotherapy (O3-MAH) in patients with post-acute sequelae of COVID-19 (PASC). Seventy-three eligible participants were randomly assigned to an O3-MAH plus conventional therapy group (n = 35) or a conventional therapy alone group (n = 38). Symptom score, pulmonary function, 6-minute walk distance (6MWD), and hematological, biochemical, and immunological parameters were evaluated before and after the interventions. Both groups demonstrated improvements in various parameters post-intervention, but efficacy was greater in the O3-MAH group than the conventional treatment group; with intervention effectiveness defined as a ≥ 50 % reduction in symptom score, 25 of 35 patients (71 %) responded to O3-MAH, while 17/38 patients (45 %) responded to conventional treatment alone (P = 0.0325). Significant improvements in symptom scores (P = 0.0478), tidal volume (P = 0.0374), predicted 6MWD (P = 0.0032), and coagulation and inflammatory indicators were noted in the O3-MAH group compared with the conventional treatment group. O3-MAH was more likely to be effective in patients with elevated CRP levels. Furthermore, O3-MAH markedly improved cellular immunity, and this improvement became more pronounced with extended treatment duration. In summary, combining O3-MAH with conventional treatment was more effective than conventional therapy alone in improving symptoms, pulmonary function, inflammation, coagulation, and cellular immunity in patients with PASC. Further research is now warranted to validate these findings and individualize the regimen.

Dexamethasone-loaded ROS stimuli-responsive nanogels for topical ocular therapy of corneal neovascularization.

Dexamethasone (DEX) has been demonstrated to inhibit the inflammatory corneal neovascularization (CNV). However, the therapeutic efficacy of DEX is limited by the poor bioavailability of conventional eye drops and the increased risk of hormonal glaucoma and cataract associated with prolonged and frequent usage. To address these limitations, we have developed a novel DEX-loaded, reactive oxygen species (ROS)-responsive, controlled-release nanogel, termed DEX@INHANGs. This advanced nanogel system is constructed by the formation of supramolecular host-guest complexes by cyclodextrin (CD) and adamantane (ADA) as a cross-linking force. The introduction of the ROS-responsive material, thioketal (TK), ensures the controlled release of DEX in response to oxidative stress, a characteristic of CNV. Furthermore, the nanogel's prolonged retention on the corneal surface for over 8 h is achieved through covalent binding of the integrin ß1 fusion protein, which enhances its bioavailability. Cytotoxicity assays demonstrated that DEX@INHANGs was not notably toxic to human corneal epithelial cells (HCECs). Furthermore, DEX@INHANGs has been demonstrated to effectively inhibit angiogenesis in vitro. In a rabbit model with chemically burned eyes, the once-daily topical application of DEX@INHANGs was observed to effectively suppress CNV. These results collectively indicate that the nanomedicine formulation of DEX@INHANGs may offer a promising treatment option for CNV, offering significant advantages such as reduced dosing frequency and enhanced patient compliance.

An acid-activatable fluorouracil prodrug for colorectal cancer synergistic therapy.

5-Fluorouracil has demonstrated certain efficiency in patients with colorectal cancer. However, significant side effects of use by injection are common. To address this issue defects, a reengineered 5'-deoxy-5-fluorocytidine (DFCR) based drug delivery system (POACa) is developed as a prominent tumor-selective nano-activator. Investigations demonstrate that the constructed nano-activator exhibits good biocompatibility and high therapeutic efficiency in mice with subcutaneous and orthotopic SW-480 colorectal tumors, as its activity is strictly dependent on the tumor-associated acid environment and thymidine phosphorylase. These strategies diminish the off-target toxicity and improve the specificity and sensitivity of human colorectal cancer cells to 5-Fu, obtaining potent efficiency by the combination of H2O2 mediated oxidative stress, calcium overload and 5-Fu-induced chemotherapy (the combination index is 0.11). Overall, the engineered nano-activator exhibits a high therapeutic index in vitro and in vivo. STATEMENT OF SIGNIFICANCE: In this study, we designed and prepared a pH-responsive polymer to synchronously deliver DFCR (5'-deoxy-5-fluorocytidine, a prodrug of 5-Fu), Ca2+ and H2O2. The constructed nano-activator was denoted as POACa. (1) To address the problem of premature leakage of cargo by physical embedding, our research modified the inactive prodrug DFCR through chemical bonding. (2) The activation of the prepared nano-activator was strictly dependent on the tumor-associated acid environment and thymidine phosphorylase, providing the drug delivery system with inherent safety. (3) A distinctly low combination index value (0.11) of CaO2 and DFCR indicated that POACa has a prominent tumor suppression effect by tumor calcium overload sensitized chemotherapy and H2O2 mediated cytotoxicity.

Bioluminescence-optogenetics-mediated gene therapy in a sleep-disordered breathing mouse model.

Obstructive sleep apnea (OSA) incurs a huge individual, societal, and economic burden. Specific and selective targeting of hypoglossal motor neurons could be an effective means to treat OSA. Bioluminescent-optogenetics (BL-OG) is a novel genetic regulatory approach in which luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels, increase neuronal excitability when exposed to a suitable substrate. Here we develop and validate the feasibility of BL-OG for sleep-disordered breathing (SDB). Upon confirming that diet-induced obese mice represent an excellent SDB model, we employed a method of targeting the hypoglossal nucleus (12 N) by peripherally injecting retrogradely transported rAAV2/Retro. With AAV transduction, the eLMO3 protein is expressed in hypoglossal motor neurons (HMN); administration of CTZ results in production of bioluminescence that in turn activates the tethered channelrhodopsin, leading to an increase in the firing of HMN and a 2.7 ± 0.8-fold increase in phasic activity of the genioglossus muscle, a 7.6 ± 1.8-fold increase in tonic activity, and improvements in hypoventilation and apnea index without impacting sleep structure. This is therefore the first study to leverage the rAAV2/Retro vector to execute the BL-OG approach in SDB, which amplified genioglossus muscle discharge activity and increased airflow in mice after activation. This study marks the pioneering utilization of BL-OG in SDB research.

Palladium nanocrystals regulates scleral extracellular matrix remodeling in myopic progression by modulating the hypoxia signaling pathway Nrf-2/Ho-1.

Myopia represents a widespread global public health concern influenced by a combination of environmental and genetic factors. The prevailing theory explaining myopia development revolves around scleral extracellular matrix (ECM) remodeling, characterized by diminished Type I collagen (Col-1) synthesis and increased degradation, resulting in scleral thinning and eye axis elongation. Existing studies underscore the pivotal role of scleral hypoxia in myopic scleral remodeling. This study investigates the peroxidase-like activity and catalytic performance of octahedral Palladium (Pd) nanocrystals, recognized as nanozymes with antioxidative properties. We explore their potential in reducing oxidative stress and alleviating hypoxia in human scleral fibroblasts (HSF) and examine the associated molecular mechanisms. Our results demonstrate the significant peroxidase-like activity of Pd nanocrystals. Furthermore, we observe a substantial reduction in oxidative stress in HSF under hypoxia, mitigating cellular damage. These effects are linked to alterations in Nrf-2/Ho-1 expression, a pathway associated with hypoxic stress. Importantly, our findings indicate that Pd nanocrystals contribute to attenuated scleral matrix remodeling in myopic guinea pigs, effectively slowing myopia progression. This supports the hypothesis that Pd nanocrystals regulate myopia development by controlling oxidative stress associated with hypoxia. Based on these results, we propose that Pd nanocrystals represent a novel and potential treatment avenue for myopia through the modulation of scleral matrix remodeling. This study introduces innovative ideas and directions for the treatment and prevention of myopia.

Species-specific metabolism of triphenyl phosphate and its mono-hydroxylated product by human and rat CYP2E1 and the carp ortholog.

Organophosphorus flame retardants (PFRs) are a class of flame retardants and environmental pollutants with various biological effects. Recentstudies have evidenced activation of some PFRs by human CYP enzymes (including CYP2E1) for genotoxic effects. However, the activity of CYPs in fish species toward PFR metabolism remains unclear. This study was aimed on comparing the metabolism of triphenyl phosphate (TPHP) and 4-OH-TPHP in human, rat, and common carp, and the involvement of human CYP2E1 and its orthologs in the metabolism, by using fomepizole (4-MP, CYP2E1 inhibitor) as a modulator, in silico molecular docking and dynamics analyses. The rate of TPHP metabolism was apparently faster with human and rat, microsomes than with fish microsomes, the major metabolites were phosphodiester and hydroxylated phosphate, with 30-80 % of TPHP forming unidentified metabolites in the system of each species. 4-OH-TPHP was readily metabolized by both human and rat microsomes, whereas it was hardly metabolized in carp assays. Meanwhile, with 4-MP the transformation of TPHP to 4-OH-TPHP was enhanced in the human/rat systems while suppressed in the carp system. Moreover, the formation of unidentified metabolites in human and rat systems was mostly inhibited by 4-MP. Through molecular dynamics analysis TPHP and its primary metabolites showed high affinity for human and rat CYP2E1, as well as the carp ortholog (CYP2G1-like enzyme), however, the 4-OH-TPHP bond to the latter was too far from the heme to permit a biochemical reaction. This study suggests that the metabolism/activation of TPHP might be favored in mammals rather than carp, a fish species.