Nrf2/FSP1/CoQ10 axis-mediated ferroptosis is involved in sodium aescinate-induced nephrotoxicity.

Sodium aescinate (SA), an active compound found in horse chestnut seeds, is widely used in clinical practice. Recently, the incidence of SA-induced adverse events, particularly renal impairment, has increased. Our previous work demonstrated that SA causes severe nephrotoxicity via nephrocyte ferroptosis; however, the underlying mechanism remains to be fully elucidated. In the current study, we investigated additional molecular pathways involved in SA-induced nephrotoxicity. Our results showed that SA inhibited cell viability, disrupted cellular membrane integrity, and enhanced reactive oxygen species (ROS), ferrous iron (Fe2+), and malondialdehyde (MDA) levels, as well as lipid peroxidation in rat proximal renal tubular epithelial cell line (NRK-52E) cells. SA also depleted coenzyme Q10 (CoQ10, ubiquinone) and nicotinamide adenine dinucleotide (NADH) and reduced ferroptosis suppressor protein 1 (FSP1) and polyprenyltransferase (coenzyme Q2, COQ2) activity, triggering lipid peroxidation and ROS accumulation in mouse kidneys and NRK-52E cells. The overexpression of COQ2, FSP1, or CoQ10 (ubiquinone) supplementation effectively attenuated SA-induced ferroptosis, whereas iFSP1 or 4-formylbenzoic acid (4-CBA) pretreatment exacerbated SA-induced nephrotoxicity. Additionally, SA decreased nuclear factor-erythroid-2-related factor 2 (Nrf2) levels and inhibited Nrf2 binding to the -1170/-1180 bp ARE site in FSP1 promoter, resulting in FSP1 suppression. Overexpression of Nrf2 or its agonist dimethyl fumarate (DMF) promoted FSP1 expression, thereby improving cellular antioxidant capacity and alleviating SA-induced ferroptosis. These results suggest that SA-triggers renal injury through oxidative stress and ferroptosis, driven by the suppression of the Nrf2/FSP1/CoQ10 axis.

Efficient fabrication of bioinspired soft, ridged-slippery surfaces with large-range anisotropic wettability for droplet manipulation.

The droplet lossless directional motion control on slippery surfaces holds immense promise for applications in microfluidic chips, hazardous substance detection, chemical dispensing, etc. However, a significant challenge in this domain lies in efficiently developing soft, slippery surfaces with large-range anisotropic wettability and compatibility for curved scenarios. This study addressed this challenge through a quick 3D printing-assisted method to produce soft, ridged-slippery surfaces (SRSSs) as the droplet manipulation platform. The SRSSs demonstrated substantial anisotropic rolling resistances, measuring 116.9 µN in the perpendicular direction and 7.7 µN in the parallel direction, exhibiting a ratio of 15.2. Combining several extents of anisotropic wettability on a soft substrate could realize diverse reagent manipulation functions. Furthermore, these SRSSs showcased high compatibility with various droplet constituents, impressive liquid impact resistance, self-repair capability, and mechanical durability and thermal durability, ensuring exceptional applicability. As proofs of concept, the SRSSs were successfully applied in droplet control and classification for heavy metal ion detection, mechanical arm-based droplet grab and release, and cross-species transport, showcasing their remarkable versatility, compatibility, and practicality in advanced droplet microfluidic chips and water harvesting applications.

[Experimental study on treatment of retinitis pigmentosa by inducing Müller cell reprogramming with Lycii Fructus and Salviae Miltiorrhizae Radix et Rhizoma].

This study aims to explore the effect of Lycii Fructus and Salviae Miltiorrhizae Radix et Rhizoma(LFSMR), a drug pair possesses the function of nourishing Yin, promoting blood circulation, and brightening the eyes, in treating retinitis pigmentosa(RP)by inhibiting the gliosis of Müller cells(MCs) and inducing their reprogramming and differentiation into various types of retinal nerve cells. Twelve C57 mice were used as the normal control group, and 48 transgenic RP(rd10) mice were randomly divided into the model group, positive control group, and low and high dose LFSMR groups, with 12 mice in each group. HE staining was used to detect pathological changes in the retina, and an electroretinogram was used to detect retinal function. Retinal optical coherence tomography was used to detect retinal thickness and perform fundus photography, and laser speckle perfusion imaging was used to detect local retinal blood flow. Digital PCR was used to detect gene expression related to retinal nerve cells, and immunofluorescence was used to detect protein expression related to retinal nerve cells. LFSMR could significantly improve the pathological changes, increase the amplitude of a and b waves, increase the retinal thickness, restore retinal damage, and increase retinal blood flow in mice with RP lesions. LFSMR could also significantly inhibit the m RNA expression of the glial fibrillary acidic protein( GFAP) during the pathogenesis of RP and upregulate m RNA expression of sex determining region Y box protein 2(SOX2), paired box protein 6(Pax6),rhodopsin, protein kinase C-α(PKCα), syntaxin, and thymic cell antigen 1. 1(Thy1. 1). LFSMR could significantly inhibit GFAP protein expression and enhance protein expression of SOX2, Pax6, rhodopsin, PKCα, syntaxin, and Thy1. 1. It could also reverse the pathological changes in the retina of rd10 mice, improve retinal function and fundus performance, increase retinal thickness, enhance local retinal blood flow, and exert therapeutic effects on RP. The mechanism of action of LFSMR may be related to inhibiting the gliosis of MCs and promoting their reprogramming and differentiation into various types of retinal nerve cells.

Sodium aescinate induces renal toxicity by promoting Nrf2/GPX4-mediated ferroptosis.

Sodium aescinate (SA) is extracted from Aesculus wilsonii Rehd seeds and was first marketed as a medicament in German. With the wide application of SA in clinical practice, reports of adverse drug reactions and adverse events have gradually increased, including renal impairment. However, the pathogenic mechanisms of SA have not yet been fully elucidated. The toxic effects and underlying mechanisms of SA were explored in this study. Our data showed that SA significantly elevated the levels of blood urea nitrogen (BUN), serum creatinine (Scr) and Kidney injury molecule 1 (Kim-1), accompanied by pathologically significant changes in renal tissue. SA induced NRK-52E cell death and disrupted the integrity of the cell membrane. Moreover, SA caused significant reductions in FTH, Nrf2, xCT, GPX4, and FSP1 levels, but increased TFR1 and ACSL4 levels. SA decreased glutathione peroxidase (GPx), glutathione (GSH) and cysteine (Cys) levels, but improved Fe2+, malondialdehyde (MDA), reactive oxygen species (ROS) and lipid peroxidation levels, ultimately leading to the induction of ferroptosis. Importantly, inhibition of ferroptosis or activation of the Nrf2/GPX4 pathway prevented SA-induced nephrotoxicity. These findings indicated that SA induced oxidative damage and ferroptosis-mediated kidney injury by suppressing the Nrf2/GPX4 axis activity.

Quercetin inhibits hypertonicity-induced inflammatory injury in human corneal epithelial cells via the PTEN/PI3K/AKT pathway.

Dry eye is a prevalent ophthalmic disease. Ocular surface inflammation in the hyperosmolar environment of the tear film is critical in dry eye progression. Quercetin has strong anti-inflammatory effects; however, its exact mechanism of action in dry eye is not fully understood. Therefore, this study investigated whether quercetin could inhibit the damage sustained to human corneal epithelial cells (HCECs) in a hyperosmolar environment through its anti-inflammatory effects. HCECs were cultured in a complete medium and were divided into four groups: normal, model, quercetin, and inhibitor. The proliferation of HCECs was detected by Ki67 staining; the expression levels of PTEN, p-PI3K and p-AKT were detected by Western blotting and immunofluorescence staining; the relative mRNA expression levels of PTEN, PI3K, AKT, IL-6 and TNF-ɑ were detected by quantitative real-time PCR; the relative expression levels of IL-6 and TNF-α were detected by enzyme-linked immunosorbent assay. In this study, the proliferation of HCECs in the model group was found to be significantly inhibited compared with that in the normal group; however, quercetin was effective in improving the proliferation of HCECs, decreasing the relative expression of p-PI3K, p-AKT, IL-6, TNF-ɑ as well as increasing PTEN. In conclusion, this study demonstrated that quercetin could promote the proliferation of HCECs and reduce the expression of inflammatory factors by inhibiting the PTEN/PI3K/AKT pathway in the hyperosmolarity-induced HCECs model.

PCa-RadHop: A transparent and lightweight feed-forward method for clinically significant prostate cancer segmentation.

Prostate Cancer is one of the most frequently occurring cancers in men, with a low survival rate if not early diagnosed. PI-RADS reading has a high false positive rate, thus increasing the diagnostic incurred costs and patient discomfort. Deep learning (DL) models achieve a high segmentation performance, although require a large model size and complexity. Also, DL models lack of feature interpretability and are perceived as "black-boxes" in the medical field. PCa-RadHop pipeline is proposed in this work, aiming to provide a more transparent feature extraction process using a linear model. It adopts the recently introduced Green Learning (GL) paradigm, which offers a small model size and low complexity. PCa-RadHop consists of two stages: Stage-1 extracts data-driven radiomics features from the bi-parametric Magnetic Resonance Imaging (bp-MRI) input and predicts an initial heatmap. To reduce the false positive rate, a subsequent stage-2 is introduced to refine the predictions by including more contextual information and radiomics features from each already detected Region of Interest (ROI). Experiments on the largest publicly available dataset, PI-CAI, show a competitive performance standing of the proposed method among other deep DL models, achieving an area under the curve (AUC) of 0.807 among a cohort of 1,000 patients. Moreover, PCa-RadHop maintains orders of magnitude smaller model size and complexity.

HHO optimized support vector machine classifier for traditional Chinese medicine syndrome differentiation of diabetic retinopathy.

AIM: To develop a classifier for traditional Chinese medicine (TCM) syndrome differentiation of diabetic retinopathy (DR), using optimized machine learning algorithms, which can provide the basis for TCM objective and intelligent syndrome differentiation. METHODS: Collated data on real-world DR cases were collected. A variety of machine learning methods were used to construct TCM syndrome classification model, and the best performance was selected as the basic model. Genetic Algorithm (GA) was used for feature selection to obtain the optimal feature combination. Harris Hawk Optimization (HHO) was used for parameter optimization, and a classification model based on feature selection and parameter optimization was constructed. The performance of the model was compared with other optimization algorithms. The models were evaluated with accuracy, precision, recall, and F1 score as indicators. RESULTS: Data on 970 cases that met screening requirements were collected. Support Vector Machine (SVM) was the best basic classification model. The accuracy rate of the model was 82.05%, the precision rate was 82.34%, the recall rate was 81.81%, and the F1 value was 81.76%. After GA screening, the optimal feature combination contained 37 feature values, which was consistent with TCM clinical practice. The model based on optimal combination and SVM (GA_SVM) had an accuracy improvement of 1.92% compared to the basic classifier. SVM model based on HHO and GA optimization (HHO_GA_SVM) had the best performance and convergence speed compared with other optimization algorithms. Compared with the basic classification model, the accuracy was improved by 3.51%. CONCLUSION: HHO and GA optimization can improve the model performance of SVM in TCM syndrome differentiation of DR. It provides a new method and research idea for TCM intelligent assisted syndrome differentiation.

Effectiveness of acupuncture combined with artificial tears in managing dry eye syndrome: A systematic review and meta-analysis.

BACKGROUND: Dry eye syndrome is an ocular surface disease with high incidence. Acupuncture combined with artificial tears is effective for treating dry eye syndrome. This study aimed to evaluate the evidence for the efficacy of acupuncture combined with artificial tears in dry eye syndrome by conducting a systematic review and meta-analysis. METHODS: A systematic online search was performed from the date of database establishment to July 1, 2023. The study groups that addressed acupuncture combined with artificial tears for patients with dry eye syndrome (DES) and the control groups that addressed artificial tears were analyzed. The main outcomes were tear breakup time (BUT) and Schirmer I test (SIT), assessed as previously described. RESULTS: Sixteen randomized or controlled trials met the selection criteria, and 1383 patients with DES were included in this study. The analysis results showed that BUT [Standard mean difference (SMD) = 1.25, 95% confidence interval (CI) (1.14, 1.37), P < .0001], SIT [SMD = 1.55, 95% CI (1.08, 2.02), P < .0001], and corneal fluorescein staining [SMD = -2.08, 95% CI (-2.96, -1.20), P < .00001] significantly improved in the trial groups compared with the control groups. The acupuncture treatment was more effective in reducing the levels of IL-6 (P < .0001) and TNF-α (P < .00001). The overall efficacy rate was better in the trial group than in the control group [odds ratio = 4.09, 95% CI (3.04, 5.51), P < .00001]. However, no significant difference was observed in the ocular surface disease index (P = .15) between the trial and control groups. CONCLUSION: The results of this study indicated that acupuncture combined with artificial tears could be considered safe, effective to patients with DES.

Characteristics of different Mandarin pronunciation element perception: evidence based on a multifeature paradigm for recording MMN and P3a components of phonemic changes in speech sounds.

Background: As a tonal language, Mandarin Chinese has the following pronunciation elements for each syllable: the vowel, consonant, tone, duration, and intensity. Revealing the characteristics of auditory-related cortical processing of these different pronunciation elements is interesting. Methods: A Mandarin pronunciation multifeature paradigm was designed, during which a standard stimulus and five different phonemic deviant stimuli were presented. The electroencephalogram (EEG) data were recorded with 256-electrode high-density EEG equipment. Time-domain and source localization analyses were conducted to demonstrate waveform characteristics and locate the sources of the cortical processing of mismatch negativity (MMN) and P3a components following different stimuli. Results: Vowel and consonant differences elicited distinct MMN and P3a components, but tone and duration differences did not. Intensity differences elicited distinct MMN components but not P3a components. For MMN and P3a components, the activated cortical areas were mainly in the frontal-temporal lobe. However, the regions and intensities of the cortical activation were significantly different among the components for the various deviant stimuli. The activated cortical areas of the MMN and P3a components elicited by vowels and consonants seemed to be larger and show more intense activation. Conclusion: The auditory processing centers use different auditory-related cognitive resources when processing different Mandarin pronunciation elements. Vowels and consonants carry more information for speech comprehension; moreover, more neurons in the cortex may be involved in the recognition and cognitive processing of these elements.