Ameliorative effect of total ginsenosides from heat-treated fresh ginseng against cyclophosphamide-induced liver injury in mice.

This study evaluated the effect of heat treatment on the conversion of ginsenoside and the ameliorative effect of heat-treated total ginsenoside (HG) from fresh ginseng on cyclophosphamide (CTX)-induced liver injury. LC-MS analysis revealed that the content of rare ginsenosides increased markedly after heat treatment. HG significantly attenuated CTX-induced hepatic histopathological injury in mice. Western blotting analysis showed that untreated total ginsenoside (UG) and HG regulated the Nrf2/HO-1 and TLR4/MAPK pathways. Importantly, these results may be relevant to the modulation of the intestinal flora. UG and HG significantly increased the short-chain fatty acids (SCFAs)-producing bacteria Lactobacillus and reduced the LPS-producing bacteria Bacteroides and Parabacteroides. These changes in intestinal flora affected the levels of TNF-α, LPS and SCFAs. In short, UG and HG alleviated CTX-induced liver injury by regulating the intestinal flora and the LPS-TLR4-MAPK pathway, and HG was more effective. HG has the potential to be a functional food that can alleviate chemical liver injury.

Efficacy and safety of adjunctive perampanel treatment in pediatric patients with epilepsy aged 4-12 years: a real-world study.

OBJECTIVE: To determine the efficacy and safety of perampanel (PER) as an adjunctive therapy in children aged 4-12 years with epilepsy. METHODS: We performed a non-randomized, open-label, placebo-uncontrolled, real-world self-controlled study that included 216 young children (aged 4-12 years) with epilepsy who received PER as adjunctive therapy at the children's hospital affiliated with Chongqing Medical University from July 4, 2020, to September 20, 2023. RESULTS: (1) The efficacy rates of adjunctive PER therapy at 3, 6, 9, and 12 months were 62.8%, 67.8%, 65.3%, and 61.2%, respectively. PER showed efficacy in alleviating focal seizures, generalized tonic-clonic seizures, myoclonic seizures, and absence seizures. The efficacy rates for variants of self-limited epilepsy with centrotemporal spikes (SeLECTS) and Lennox-Gastaut syndrome (LGS) were 89.5% and 66.7%, respectively. (2) Focal non-motor onset seizures with or without impaired awareness, focal to bilateral tonic-clonic seizures (FBTCS), LGS, variants of SeLECTS, the number of concomitant antiseizure medications (ASMs), a family history of epilepsy, and focal lesions on cranial magnetic resonance imaging were independent factors affecting efficacy. The order of PER addition did not affect efficacy. The retention rates at 3, 6, 9, and 12 months were 90.7%, 84.7%, 74.7%, 64.9%, respectively. (3) Adverse reactions occurred in 45 patients (45/216, 20.8%), with irritability/aggressive behavior (18/216, 8.3%) and somnolence (14/216, 6.5%) being the most common. Twelve patients (12/216, 5.6%) withdrew from the study because of adverse reactions. CONCLUSION: In young Chinese children with epilepsy, PER is effective, safe, and well-tolerated as an adjunctive therapy, making it a viable option for use with broad-spectrum ASMs.

The effects of the predictability of acclimatory temperature on the growth and thermal tolerance of juvenile Spinibarbus sinensis.

Heated effluent injection, cold hypolimnetic water inputs from dams, and extreme weather events can lead to unpredictable temperature fluctuations in natural waters, impacting fish performance and fitness. We hypothesized that fish exposed to such unpredictable fluctuations would exhibit weaker growth and enhanced thermal tolerance compared to predictable conditions. Qingbo (Spinibarbus sinensis) was selected as the experimental subject in this study. The qingbo were divided into a constant temperature group (C, 22 ± 0.5 °C), a predictable temperature fluctuation group (PF, 22 ± 4 °C, first warming, then cooling within a day) and an unpredictable temperature fluctuation group (UF, 22 ± 4 °C, the order of warming or cooling is random). After 40 days of temperature acclimation, the growth, metabolic rate, spontaneous activity, thermal tolerance, plasma cortisol concentration and liver hsp70 level of the fish were measured. Unexpectedly, neither the PF nor the UF group showed decreased growth compared to the C group. This could be attributed to the fact that temperature variation did not lead to a substantial increase in basic energy expenditure. Furthermore, feeding rates increased due to temperature fluctuations, although the difference was not significant. Both the PF and UF groups exhibited increased upper thermal tolerance, but only the UF group exhibited improved lower thermal tolerance and higher liver hsp70 levels compared to the C group. The qingbo that experienced unpredictable temperature fluctuations had the best thermal tolerance among the 3 groups, which might have occurred because they had the highest level of hsp70 expression. This may safeguard fish against the potential lethal consequences of extreme temperatures in the future. These findings suggested that qingbo exhibited excellent adaptability to both predictable and unpredictable temperature fluctuations, which may be associated with frequent temperature fluctuations in its natural habitat.

Precise and automated lung cancer cell classification using deep neural network with multiscale features and model distillation.

Lung diseases globally impose a significant pathological burden and mortality rate, particularly the differential diagnosis between adenocarcinoma, squamous cell carcinoma, and small cell lung carcinoma, which is paramount in determining optimal treatment strategies and improving clinical prognoses. Faced with the challenge of improving diagnostic precision and stability, this study has developed an innovative deep learning-based model. This model employs a Feature Pyramid Network (FPN) and Squeeze-and-Excitation (SE) modules combined with a Residual Network (ResNet18), to enhance the processing capabilities for complex images and conduct multi-scale analysis of each channel's importance in classifying lung cancer. Moreover, the performance of the model is further enhanced by employing knowledge distillation from larger teacher models to more compact student models. Subjected to rigorous five-fold cross-validation, our model outperforms existing models on all performance metrics, exhibiting exceptional diagnostic accuracy. Ablation studies on various model components have verified that each addition effectively improves model performance, achieving an average accuracy of 98.84% and a Matthews Correlation Coefficient (MCC) of 98.83%. Collectively, the results indicate that our model significantly improves the accuracy of disease diagnosis, providing physicians with more precise clinical decision-making support.

The role of SRPK1-mediated phosphorylation of SR proteins in the chromatin configuration transition of mouse germinal vesicle oocytes.

Meiotic resumption in mammalian oocytes involves nucleus and organelle structural changes, notably chromatin configuration transitioning from non-surrounding nucleolus (NSN) to surrounding nucleolus (SN) in germinal vesicle (GV) oocytes. Our study found that nuclear speckles, a subnuclear structure mainly composed of serine-arginine (SR) proteins, changed from a diffuse spotted distribution in mouse NSN oocytes to an aggregation pattern in SN oocytes. We further discovered that SRPK1, an enzyme phosphorylating SR proteins, co-localized with NS at SN stage and NSN oocytes failed to convert into SN oocytes after inhibiting the activity of SRPK1. Furthermore, the typical structure of chromatin ring around the nucleolus in SN oocytes collapsed after inhibitor treatment. To explore the underlying mechanism, phosphorylated SR proteins were confirmed to be associated with chromatin by salt extraction experiment, and in situ DNase I assay showed that the accessibility of chromatin enhanced in SN oocytes with SRPK1 inhibited, accompanied by decreased repressive modification on histone and abnormal recurrence of transcriptional signal. In conclusion, our results indicated that SRPK1-regulated phosphorylation on SR proteins was involved in the NSN to SN transition and played an important role in maintaining the condensation nucleus of SN oocytes via interacting with chromatin.

Targeting the Ferroptosis and Endoplasmic Reticulum Stress Signaling Pathways by CBX7 in Myocardial Ischemia/reperfusion Injury.

Ferroptosis and endoplasmic reticulum stress (ERS) are common events in the process of myocardial ischemia/reperfusion injury (IRI). The suppression of chromobox7 (CBX7) has been reported to protect against ischemia/reperfusion injury, This research is purposed to expose the impacts and mechanism of CBX7 in myocardial IRI. CBX7 expression was detected using RT-qPCR and western blotting analysis. CCK-8 assay detected cell viability. Inflammatory response and oxidative stress were detected by ELISA, DCFH-DA probe and related assay kits. Flow cytometry analysis and caspase3 activity assay were used to detect cell apoptosis. C11-BODIPY 581/591 staining and ferro-orange staining were used to detect lipid reactive oxygen species (ROS) and Fe2+ level, respectively. Western blotting was used to detect the expression of proteins associated with apoptosis, ferroptosis and ERS. In the hypoxia/reoxygenation (H/R) model of rat cardiomyocytes H9c2, CBX7 was highly expressed. CBX7 interference significantly protected against inflammatory response, oxidative stress, apoptosis, ferroptosis and ERS induced by H/R in H9c2 cells. Moreover, after the pretreatment with ferroptosis activator erastin or ERS agonist Tunicamycin (TM), the protective effects of CBX7 knockdown on the inflammation, oxidative stress and apoptosis in H/R-induced H9c2 cells was partially abolished. To summarize, CBX7 down-regulation may exert anti-ferroptosis and anti-ERS activities to alleviate H/R-stimulated myocardial injury.

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies.

The sirtuin (SIRT) family is well-known as a group of deacetylase enzymes that rely on nicotinamide adenine dinucleotide (NAD+). Among them, mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) are deacetylases located in mitochondria that regulate the acetylation levels of several key proteins to maintain mitochondrial function and redox homeostasis. Mitochondrial SIRTs are reported to have the Janus role in tumorigenesis, either tumor suppressive or oncogenic functions. Although the multi-faceted roles of mitochondrial SIRTs with tumor-type specificity in tumorigenesis, their critical functions have aroused a rising interest in discovering some small-molecule compounds, including inhibitors and activators for cancer therapy. Herein, we describe the molecular structures of mitochondrial SIRTs, focusing on elucidating their regulatory mechanisms in carcinogenesis, and further discuss the recent advances in developing their targeted small-molecule compounds for cancer therapy. Together, these findings provide a comprehensive understanding of the crucial roles of mitochondrial SIRTs in cancer and potential new therapeutic strategies.

Cyanomethylquinolones as a New Class of Potential Multitargeting Broad-Spectrum Antibacterial Agents.

This work identified a class of cyanomethylquinolones (CQs) and their carboxyl analogues as potential multitargeting antibacterial candidates. Most of the prepared compounds showed high antibacterial activities against most of the tested bacteria, exhibiting lower MIC values (0.125-2 µg/mL) than those of clinical norfloxacin, ciprofloxacin, and clinafloxacin. The low hemolysis, drug resistance, and cytotoxicity, as well as good predictive pharmacokinetics of active CQs and carboxyl analogues revealed their development potential. Furthermore, they could eradicate the established biofilm, facilitating bacterial exposure to these antibacterial candidates. These active compounds could induce bacterial death through multitargeting effects, including intercalating into DNA, up-regulating reactive oxygen species, damaging membranes directly, and impeding metabolism. Moreover, the highly active cyclopropyl CQ 15 exhibited more effective in vivo anti-MRSA potency than ciprofloxacin. These findings highlight the potential of CQs and their carboxyl analogues as multitargeting broad-spectrum antibacterial candidates for treating intractable bacterial infections.

LiCl in situ decorated metal-organic framework (MOF)-derived porous carbon for efficient solar-driven atmospheric water harvesting.

Solar-powered sorption-based atmospheric water harvesting (AWH) technology is a promising solution to the freshwater scarcity in arid regions. Existing adsorbent materials still face challenges in aspects such as cycling stability and adsorption kinetics and require further development. Herein, we presented a strategy for the in situ fabrication of high-performance adsorbents, lithium chloride (LiCl)-decorated metal-organic framework (MOF)-derived porous carbon sorbents (PCl), via high-temperature pyrolysis and hydrogen chloride (HCl) vapor treatment. The sorbents display high adsorption capacity across a wide range of humidity water adsorption capacities in a wide humidity range with the maximum adsorption capacity of 7.87 g g-1, and rapid response to the solar-driven process and excellent cyclic stability. The LiCl nanocrystals in PCl can be utilized efficiently and decorated within the porous framework stably, and demonstrate water adsorption at 20%, 40%, 60% and 80% RH, of 1.34, 1.69, 2.56 and 4.23 gH2O·gLiCl-1, respectively, and significantly higher water uptake and release rates than bulk LiCl. This may provide new guides for designing efficient solar-driven AWH.

Quercetin-Loaded Bioglass Injectable Hydrogel Promotes m6A Alteration of Per1 to Alleviate Oxidative Stress for Periodontal Bone Defects.

Periodontal disease ranks third among noncommunicable illnesses, behind cancer and cardiovascular disease, and is closely related to the occurrence and progression of various systemic diseases. However, elucidating the processes of periodontal disease and promoting periodontal bone regeneration remains a challenge. Here, quercetin is demonstrated to reduce the oxidative stress state of orofacial mesenchymal stem cells (OMSCs) in vitro and to affect the osteogenic growth of OMSCs through molecular mechanisms that mediate the m6A change in Per1. Nevertheless, the limited therapeutic efficacy of systemic medication and the limitations of local medication resulting from the small, moist, and highly dynamic periodontal environment make it challenging to treat periodontal tissues with medication. Herein, a biosafe injectable hydrogel drug-controlled delivery system is constructed as a bone-enhancing factory and loaded with quercetin to treat oxidative stress injury in periodontal tissues. This drug-carrying system made up of nanoscale bioglass microspheres and a light-cured injectable hydrogel, allows effective drug particle loading and cementation in the dynamic and moist periodontal environment. Furthermore, the system demonstrates the ability to stimulate OMSCs osteogenic differentiation in a Per1-dependent manner, which ultimately promotes periodontal bone repair, suggesting that this system has potential for clinical periodontal therapy.

Deep magnetic resonance fingerprinting based on Local and Global Vision Transformer.

To mitigate systematic errors in magnetic resonance fingerprinting (MRF), the precomputed dictionary is usually computed with minimal granularity across the entire range of tissue parameters. However, the dictionary grows exponentially with the number of parameters increase, posing significant challenges to the computational efficiency and matching accuracy of pattern-matching algorithms. Existing works, primarily based on convolutional neural networks (CNN), focus solely on local information to reconstruct multiple parameter maps, lacking in-depth investigations on the MRF mechanism. These methods may not exploit long-distance redundancies and the contextual information within voxel fingerprints introduced by the Bloch equation dynamics, leading to limited reconstruction speed and accuracy. To overcome these limitations, we propose a novel end-to-end neural network called the Local and Global Vision Transformer (LG-ViT) for MRF parameter reconstruction. Our proposed LG-ViT employs a multi-stage architecture that effectively reduces the computational overhead associated with the high-dimensional MRF data and the transformer model. Specifically, a local Transformer encoder is proposed to capture contextual information embedded within voxel fingerprints and local correlations introduced by the interconnected human tissues. Additionally, a global Transformer encoder is proposed to leverage long-distance dependencies arising from shared characteristics among different tissues across various spatial regions. By incorporating MRF physics-based data priors and effectively capturing local and global correlations, our proposed LG-ViT can achieve fast and accurate MRF parameter reconstruction. Experiments on both simulation and in vivo data demonstrate that the proposed method enables faster and more accurate MRF parameter reconstruction compared to state-of-the-art deep learning-based methods.

Characterization of differences in physicochemical properties, volatile organic compounds and non-volatile metabolites of prune wine by inoculation of different lactic acid bacteria during malolactic fermentation.

To investigate the effects of inoculating with three strains of lactic acid bacteria on prune wine quality during malolactic fermentation, this study determined its antioxidant activity, phenolic compounds, organic acids, and volatile/non-volatile metabolites. The results showed that inoculation with Lactobacillus paracasei SMN-LBK improved the antioxidant activity and phenolic compounds of prune wine. 73 VOCs were detected in prune wine by HS-SPME-GC-MS, and VOC content increased by 4.3% and 9.1% in MLFS and MLFB, respectively. Lactobacillus delbrueckii subsp. Bulgaricus showed better potential for winemaking, and citral and 5-nonanol, were detected in the MLF samples. 39 shared differential metabolites were screened and their metabolic pathways were investigated based on nontargeted metabolomics. Differences in amino acid and flavonoid content between strains reflected their specificity in flavonoid biosynthesis and amino acid biosynthesis. These findings will provide useful information for the biochemical study and processing of prune wine.

A hybrid deep learning approach to predict hourly riverine nitrate concentrations using routine monitored data.

With high-frequency data of nitrate (NO3-N) concentrations in waters becoming increasingly important for understanding of watershed system behaviors and ecosystem managements, the accurate and economic acquisition of high-frequency NO3-N concentration data has become a key point. This study attempted to use coupled deep learning neural networks and routine monitored data to predict hourly NO3-N concentrations in a river. The hourly NO3-N concentration at the outlet of the Oyster River watershed in New Hampshire, USA, was predicted through neural networks with a hybrid model architecture coupling the Convolutional Neural Networks and the Long Short-Term Memory model (CNN-LSTM). The routine monitored data (the river depth, water temperature, air temperature, precipitation, specific conductivity, pH and dissolved oxygen concentrations) for model training were collected from a nested high-frequency monitoring network, while the high-frequency NO3-N concentration data obtained at the outlet were not included as inputs. The whole dataset was separated into training, validation, and testing processes according to the ratio of 5:3:2, respectively. The hybrid CNN-LSTM model with different input lengths (1d, 3d, 7d, 15d, 30d) displayed comparable even better performance than other studies with lower frequencies, showing mean values of the Nash-Sutcliffe Efficiency 0.60-0.83. Models with shorter input lengths demonstrated both the higher modeling accuracy and stability. The water level, water temperature and pH values at monitoring sites were main controlling factors for forecasting performances. This study provided a new insight of using deep learning networks with a coupled architecture and routine monitored data for high-frequency riverine NO3-N concentration forecasting and suggestions about strategies about variable and input length selection during preprocessing of input data.

Endoscopic closure of large gastric defects with a novel through-the-scope closing device in a porcine model (with videos).

BACKGROUND AND AIM: After endoscopic full-thickness resection (EFTR), defects require a reliable and sustained closure. We present a novel, through-the-scope "bow-tie" (TTS-BT) closing device enabling direct defect closure without scope withdrawal. This preclinical study aimed to evaluate the feasibility and safety of this device for large defect closure after EFTR in a porcine model. METHODS: Exposed EFTR was performed for virtual lesions > 2 cm in the stomach of twelve pigs. Subsequently, TTS-BT closing devices were used for defect closure. Conventional metal clips were used to close any remaining defects. Gastroscopy was performed for 8 weeks to examine the wound sites and the pigs were subsequently sacrificed. After sacrificing the pigs, the wound healing was histologically verified by hematoxylin-eosin (HE) staining. The primary outcome was a successful closure rate, while the secondary outcomes were complete healing rate, closure time, and incidence of adverse events. RESULTS: The median long and short diameters of perforations were 4.0 (3.0-6.0) cm and 3.0 (2.0-4.0) cm, respectively. Defect closure using novel TTS-BT closure devices and conventional metal clips was successfully performed in all pigs. Complete healing was achieved in the defects of 12 pigs. The median closure time was 13 (9-38) minutes. No serious adverse events occurred during the 8-week follow-up. CONCLUSIONS: The novel TTS-BT closure device is feasible and safe for closing large gastric perforations and could be a promising tool for clinical practice.

Effective Underwater Drag Reduction: A Butterfly Wing Scale-Inspired Superhydrophobic Surface.

The microstructured superhydrophobic surface serves as an alternative strategy to decrease resistance of underwater vehicles, but the sustainment of an entrapped air layer and the stability of the corresponding gas-liquid interface within textures in flow shear or high pressure are still a great challenge. Inspired by the scales of Parantica melaneus wings, we propose a biomimetic surface with a hierarchical structure featuring longitudinal ridges and regular cavities that firmly pin the gas-liquid interface. The drag reduction rate of the Butterfly Wing Scale-Like Surface (BWSLS) demonstrates a noticeable rise over the single-scale textured mainstream biomimetic surfaces at moderate Reynolds numbers. The superior drag reduction mechanism is revealed as the synergistic effect of a thicker gas film and a more pronounced secondary vortex within the hierarchical textures. The former reduces the velocity gradient near the surface, while the latter decreases the vorticity and energy dissipation. In a high hydrostatic pressure environment, the proposed surface also demonstrates significant stability of the gas-liquid interface, with a gas coverage rate of over 67% during the cyclic loading, surpassing single-structured surfaces. Our study suggests promising surface designs for optimal drag reduction by mimicking and leveraging diverse surfaces of organisms adapted to oceanic climates.

St. Louis Enhancing Engagement and Retention in HIV/AIDS Care (STEER): a participatory intersectional needs assessment for intervention and implementation planning.

Background Missouri is one of seven priority states identified by the Ending the HIV Epidemic Initiative, and St. Louis contains almost half of the people living with HIV (PLWH) in Missouri. As St. Louis has a marked history of structural racism and economic inequities, we utilized the Intersectionality Based Policy Analysis (IBPA) framework to guide a participatory needs assessment for planning and program development. Methods The planning team included researchers, the lead implementer from our community partner, and two community representatives, and had biweekly 60-90 minute meetings for 18 months. The planning team discussed and approved all research materials, reviewed and interpreted results, and made decisions about outreach, recruitment, conduct of the needs assessment and development of the planned intervention. The needs assessment integrated information from existing data, (1) interviews with (a) PLWH (n=12), (b) community leaders (n=5), (c) clinical leaders (n=4), and (d) community health workers (CHWs) (n=3) and (e) CHW supervisors (n=3) who participated in a Boston University-led demonstration project on CHWs in the context of HIV and (2) focus groups (2 FG, 12 participants) with front line health workers such as peer specialists, health coaches and outreach workers. A rapid qualitative analysis approach was used for all interviews and focus groups. Results The IBPA was used to guide team discussions of team values, definition and framing of the problem, questions and topics in the key informant interviews, and implementation strategies. Applying the IBPA framework contributed to a focus on intersectional drivers of inequities in HIV services. The effective management of HIV faces significant challenges from high provider turnover, insufficient integration of CHWs into care teams, and organizational limitations in tailoring treatment plans. Increasing use of CHWs for HIV treatment and prevention also faces challenges. People living with HIV (PLWH) encounter multiple barriers such as stigma, lack of social support, co-morbidities, medication side effects and difficulties in meeting basic needs. Conclusions Addressing intersectional drivers of health inequities may require multi-level, structural approaches. We see the IBPA as a valuable tool for participatory planning while integrating community engagement principles in program and implementation design for improving HIV outcomes.

Tea saponin co-ball milled commercial micro zero-valent iron for boosting Cr(VI) removal.

Tea saponins (TS), a natural biosurfactant extracted from tea trees, were co-ball milled with commercial micro zero-valent iron (mZVI) to produce TS modified mZVI (TS-BZVI) for efficient hexavalent chromium (Cr(VI)) removal. The findings demonstrated that TS-BZVI could nearly remove 100% of Cr(VI) within 2 h, which was 1.43 times higher than that by ball milled mZVI (BZVI) (70%). Kinetics analysis demonstrated a high degree of compatibility with the pseudo-second-order (PSO), revealing that TS-BZVI exhibited a 2.83 times faster Cr(VI) removal rate involved primarily chemisorption. Further, X-ray photoelectron spectroscopy (XPS) and X-ray absorption near edge structure (XANES) measurements indicated that the TS co-ball milling process improved the exposure of Fe(II) and Fe(0) on mZVI, which further promoted the Cr(VI) reduction process. Impressively, the introduction of TS increased the hydrophobicity of ZVI, effectively inhibiting the H2 evolution by 95%, thus improved electron selectivity for efficient Cr(VI) removal. Ultimately, after operating for 10 days, a simulated permeable reactive barrier (PRB) column experiment revealed that TS-BZVI had a higher Cr(VI) elimination efficiency than BZVI, indicating that TS-BZVI was promising for practical environment remediation.

Immunoglobulin Superfamily Containing Leucine-Rich Repeat (ISLR) Serves as a Redox Sensor That Modulates Antioxidant Capacity by Suppressing Pyruvate Kinase Isozyme M2 Activity.

Cells defend against oxidative stress by enhancing antioxidant capacity, including stress-activated metabolic alterations, but the underlying intracellular signaling mechanisms remain unclear. This paper reports that immunoglobulin superfamily containing leucine-rich repeat (ISLR) functions as a redox sensor that responds to reactive oxygen species (ROS) stimulation and modulates the antioxidant capacity by suppressing pyruvate kinase isozyme M2 (PKM2) activity. Following oxidative stress, ISLR perceives ROS stimulation through its cysteine residue 19, and rapidly degrades in the autophagy-lysosome pathway. The downregulated ISLR enhances the antioxidant capacity by promoting the tetramerization of PKM2, and then enhancing the pyruvate kinase activity, PKM2-mediated glycolysis is crucial to the ISLR-mediated antioxidant capacity. In addition, our results demonstrated that, in triple-negative breast cancer, cisplatin treatment reduced the level of ISLR, and PKM2 inhibition sensitizes tumors to cisplatin by enhancing ROS production; and argued that PKM2 inhibition can synergize with cisplatin to limit tumor growth. Our results demonstrate a molecular mechanism by which cells respond to oxidative stress and modulate the redox balance.

Melatonin Ameliorates Post-Stroke Cognitive Impairment in Mice by Inhibiting Excessive Mitophagy.

Post-stroke cognitive impairment (PSCI) remains the most common consequence of ischemic stroke. In this study, we aimed to investigate the role and mechanisms of melatonin (MT) in improving cognitive dysfunction in stroke mice. We used CoCl2-induced hypoxia-injured SH-SY5Y cells as a cellular model of stroke and photothrombotic-induced ischemic stroke mice as an animal model. We found that the stroke-induced upregulation of mitophagy, apoptosis, and neuronal synaptic plasticity was impaired both in vivo and in vitro. The results of the novel object recognition test and Y-maze showed significant cognitive deficits in the stroke mice, and Nissl staining showed a loss of neurons in the stroke mice. In contrast, MT inhibited excessive mitophagy both in vivo and in vitro and decreased the levels of mitophagy proteins PINK1 and Parkin, and immunofluorescence staining showed reduced co-localization of Tom20 and LC3. A significant inhibition of mitophagy levels could be directly observed under transmission electron microscopy. Furthermore, behavioral experiments and Nissl staining showed that MT ameliorated cognitive deficits and reduced neuronal loss in mice following a stroke. Our results demonstrated that MT inhibits excessive mitophagy and improves PSCI. These findings highlight the potential of MT as a preventive drug for PSCI, offering promising therapeutic implications.

Inhibition of the ATR-DNAPKcs-RB axis drives G1/S-phase transition and sensitizes triple-negative breast cancer (TNBC) to DNA holliday junctions.

Targeting the DNA damage response (DDR) is a promising strategy in oncotherapy, as most tumor cells are sensitive to excess damage due to their repair defects. Ataxia telangiectasia mutated and RAD3-related protein (ATR) is a damage response signal transduction sensor, and its therapeutic potential in tumor cells needs to be precisely investigated. Herein, we identified a new axis that could be targeted by ATR inhibitors to decrease the DNA-dependent protein kinase catalytic subunit (DNAPKcs), downregulate the expression of the retinoblastoma (RB), and drive G1/S-phase transition. Four-way DNA Holliday junctions (FJs) assembled in this process could trigger S-phase arrest and induce lethal chromosome damage in RB-positive triple-negative breast cancer (TNBC) cells. Furthermore, these unrepaired junctions also exerted toxic effects to RB-deficient TNBC cells when the homologous recombination repair (HRR) was inhibited. This study proposes a precise strategy for treating TNBC by targeting the DDR and extends our understanding of ATR and HJ in tumor treatment.