Berberine inhibits the malignant cell phenotype by inactivating PI3K/AKT/mTOR signaling in laryngeal squamous cell carcinoma.

BACKGROUND: Berberine is an active compound found in different herbs used in Chinese medicine and is well-known for its potential anticancer properties. The study aimed to figure out the role of berberine in regulating the malignant behavior of laryngeal squamous cell carcinoma (LSCC) cells. METHODS: LSCC cell lines (SNU-899 and AMC-HN-8) were treated with different concentrations of berberine (0-200 µM) to determine its cytotoxicity. The migration, invasion, and apoptosis of LSCC cells were measured by wound healing assays, Transwell assays, and flow cytometry. Western blot was performed for the quantification of proteins involved in PI3K/AKT/mTOR signaling. RESULTS: The viability of LSCC cells was dose-dependently reduced by berberine. Berberine dampened LSCC cell migration and invasion while augmenting cell apoptosis, as evidenced by a reduced wound closure rate, a decrease in invaded cell number, and a surge in cell apoptosis in the context of berberine stimulation. Importantly, the effects of berberine on the cancer cell process were enhanced by LY294002 (an inhibitor for PI3K) treatment. Moreover, the protein levels of phosphorylated PI3K, AKT, and mTOR were markedly reduced in response to berberine treatment. CONCLUSION: Berberine inhibits cell viability, migration, and invasion but augments cell apoptosis by inactivating PI3K/AKT/mTOR signaling in LSCC.

Evaluation of sex differences in the receipt of concomitant atrial fibrillation procedures during non-mitral cardiac surgery.

OBJECTIVE: Females are less likely to receive guideline-recommended cardiovascular care, but evaluation of sex-based disparities in cardiac surgical procedures is limited. Receipt of concomitant atrial fibrillation (AF) procedures during non-mitral cardiac surgery was compared by sex for patients with preoperative AF. METHODS: Patients with preoperative AF undergoing coronary artery bypass grafting and/or aortic valve replacement at any of the 33 hospitals in Michigan from 2014-2022 were included. Patients with prior cardiac surgery, transcatheter AF procedure, or emergent/salvage status were excluded. Hierarchical logistic regression identified predictors of concomitant AF procedures, account for hospital and surgeon as random effects. RESULTS: Of 5,460 patients with preoperative AF undergoing non-mitral cardiac surgery, 24% (n=1,291) were female with a mean age of 71. Females were more likely to have paroxysmal (versus persistent) AF than males (80% vs 72%, p<0.001) and had a higher mean predicted risk of mortality (5% vs 3%, p<0.001). The unadjusted rate of concomitant AF procedure was 59% for females and 67% for males(p<0.001). After risk adjustment, females had 26% lower adjusted odds of concomitant AF procedure than males (ORadj:0.74, (95%CI 0.64-0.86), p<0.001). Female sex was the risk factor associated with the lowest odds of concomitant AF procedure. CONCLUSIONS: Females are less likely to receive guideline recommended concomitant AF procedure during non-mitral surgery. Identification of barriers to concomitant AF procedure in females may improve treatment of AF.

Nomograms Predict PFS and OS for SCLC Patients After Standardized Treatment: A Real-World Study.

Purpose: This study aims to investigate the process of small cell lung cancer (SCLC) patients from achieving optimal efficacy to experiencing disease progression until death. It examines the predictive value of the treatment response on progression free survival (PFS) and overall survival (OS) of SCLC patients. Patients and Methods: We conducted a retrospective analysis on 136 SCLC patients diagnosed from 1992 to 2018. Important prognostic factors were identified to construct nomogram models. The predictive performance of the models was evaluated using the receiver operating characteristic curves and calibration curves. Survival differences between groups were compared using Kaplan-Meier survival curves. Subsequently, an independent cohort consisting of 106 SCLC patients diagnosed from 2014 to 2021 was used for validation. Results: We constructed two nomograms to predict first-line PFS (PFS1) and OS of SCLC. The area under the receiver operating characteristic curves for the PFS1 nomogram predicting PFS at 3-, 6-, and 12-months were 0.919 (95% CI: 0.867-0.970), 0.908 (95% CI: 0.860-0.956) and 0.878 (95% CI: 0.798-0.958), and for the OS nomogram predicting OS at 6-, 12-, and 24-months were 0.814 (95% CI: 0.736-0.892), 0.819 (95% CI: 0.749-0.889) and 0.809 (95% CI: 0.678-0.941), indicating those two models with a high discriminative ability. The calibration curves demonstrated the models had a high degree of consistency between predicted and observed values. According to the risk scores, patients were divided into high-risk and low-risk groups, showing a significant difference in survival rate. And these findings were validated in another independent validation cohort. Conclusion: Based on the patients' treatment response after standardized treatment, we developed and validated two nomogram models to predict PFS1 and OS of SCLC. The models demonstrated good accuracy, reliability and clinical applicability by validating in an independent cohort.

Sc-Modified C3N4 Nanotubes for High-Capacity Hydrogen Storage: A Theoretical Prediction.

Utilizing hydrogen as a viable substitute for fossil fuels requires the exploration of hydrogen storage materials with high capacity, high quality, and effective reversibility at room temperature. In this study, the stability and capacity for hydrogen storage in the Sc-modified C3N4 nanotube are thoroughly examined through the application of density functional theory (DFT). Our finding indicates that a strong coupling between the Sc-3d orbitals and N-2p orbitals stabilizes the Sc-modified C3N4 nanotube at a high temperature (500 K), and the high migration barrier (5.10 eV) between adjacent Sc atoms prevents the creation of metal clusters. Particularly, it has been found that each Sc-modified C3N4 nanotube is capable of adsorbing up to nine H2 molecules, and the gravimetric hydrogen storage density is calculated to be 7.29 wt%. It reveals an average adsorption energy of -0.20 eV, with an estimated average desorption temperature of 258 K. This shows that a Sc-modified C3N4 nanotube can store hydrogen at low temperatures and harness it at room temperature, which will reduce energy consumption and protect the system from high desorption temperatures. Moreover, charge donation and reverse transfer from the Sc-3d orbital to the H-1s orbital suggest the presence of the Kubas effect between the Sc-modified C3N4 nanotube and H2 molecules. We draw the conclusion that a Sc-modified C3N4 nanotube exhibits exceptional potential as a stable and efficient hydrogen storage substrate.

MSC-derived small extracellular vesicles mitigate diabetic retinopathy by stabilizing Nrf2 through miR-143-3p-mediated inhibition of neddylation.

Diabetic retinopathy (DR) is a highly hazardous and widespread complication of diabetes mellitus (DM). The accumulated reactive oxygen species (ROS) play a central role in DR development. The aim of this research was to examine the impact and mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEV) on regulating ROS and retinal damage in DR. Intravitreal injection of sEV inhibited Cullin3 neddylation, stabilized Nrf2, decreased ROS, reduced retinal inflammation, suppressed Müller gliosis, and mitigated DR. Based on MSC-sEV miRNA sequencing, bioinformatics software, and dual-luciferase reporter assay, miR-143-3p was identified to be the key effector for MSC-sEV's role in regulating neural precursor cell expressed developmentally down-regulated 8 (NEDD8)-mediated neddylation. sEV were able to be internalized by Müller cells. Compared to advanced glycation end-products (AGEs)-induced Müller cells, sEV coculture decreased Cullin3 neddylation, activated Nrf2 signal pathway to combat ROS-induced inflammation. The barrier function of endothelial cells was impaired when endothelial cells were treated with the supernatant of AGEs-induced Müller cells, but was restored when treated with supernatant of AGEs-induced Müller cells cocultured with sEV. The protective effect of sEV was, however, compromised when miR-143-3p was inhibited in sEV. Moreover, the protective efficacy of sEV was diminished when NEDD8 was overexpressed in Müller cells. These findings showed MSC-sEV delivered miR-143-3p to inhibit Cullin3 neddylation, stabilizing Nrf2 to counteract ROS-induced inflammation and reducing vascular leakage. Our findings suggest that MSC-sEV may be a potential nanotherapeutic agent for DR, and that Cullin3 neddylation could be a new target for DR therapy.

SLC7A11-ROS/αKG-AMPK axis regulates liver inflammation through mitophagy and impairs liver fibrosis and NASH progression.

The changes of inflammation and metabolism are two features in nonalcoholic steatohepatitis (NASH). However, how they interact to regulate NASH progression remains largely unknown. Our works have demonstrated the importance of solute carrier family 7 member 11 (SLC7A11) in inflammation and metabolism. Nevertheless, whether SLC7A11 regulates NASH progression through mediating inflammation and metabolism is unclear. In this study, we found that SLC7A11 expression was increased in liver samples from patients with NASH. Upregulated SLC7A11 level was also detected in two murine NASH models. Functional studies showed that SLC7A11 knockdown or knockout had augmented steatohepatitis with suppression of inflammatory markers in mice. However, overexpression of SLC7A11 dramatically alleviated diet-induced NASH pathogenesis. Mechanically, SLC7A11 decreased reactive oxygen species (ROS) level and promoted α-ketoglutarate (αKG)/prolyl hydroxylase (PHD) activity, which activated AMPK pathway. Furthermore, SLC7A11 impaired expression of NLRP3 inflammasome components through AMPK-mitophagy axis. IL-1ß release through NLRP3 inflammasome recruited myeloid cells and promoted hepatic stellate cells (HSCs) activation, which contributed to the progression of liver injury and fibrosis. Anti-IL-1ß and anakinra might attenuate the hepatic inflammatory response evoked by SLC7A11 knockdown. Moreover, the upregulation of SLC7A11 in NASH was contributed by lipid overload-induced JNK-c-Jun pathway. In conclusions, SLC7A11 acts as a protective factor in controlling the development of NASH. Upregulation of SLC7A11 is protective by regulating oxidation, αKG and energy metabolism, decreasing inflammation and fibrosis.

Development and validation of a clinical-radiomics model for prediction of prostate cancer: a multicenter study.

PURPOSE: To develop an early diagnosis model of prostate cancer based on clinical-radiomics to improve the accuracy of imaging diagnosis of prostate cancer. METHODS: The multicenter study enrolled a total of 449 patients with prostate cancer from December 2017 to January 2022. We retrospectively collected information from 342 patients who underwent prostate biopsy at Minhang Hospital. We extracted T2WI images through 3D-Slice, and used mask tools to mark the prostate area manually. The radiomics features were extracted by Python using the "Pyradiomics" module. Least Absolute Shrinkage and Selection Operator (LASSO) regression was used for data dimensionality reduction and feature selection, and the radiomics score was calculated according to the correlation coefficients. Multivariate logistic regression analysis was used to develop predictive models. We incorporated the radiomics score, PI-RADS, and clinical features, and this was presented as a nomogram. The model was validated using a cohort of 107 patients from the Xuhui Hospital. RESULTS: In total, 110 effective radiomics features were extracted. Finally, 9 features were significantly associated with the diagnosis of prostate cancer, from which we calculated the radiomics score. The predictors contained in the individualized prediction nomogram included age, fPSA/tPSA, PI-RADS, and radiomics score. The clinical-radiomics model showed good discrimination in the validation cohort (C-index = 0.88). CONCLUSION: This study presents a clinical-radiomics model that incorporates age, fPSA/PSA, PI-RADS, and radiomics score, which can be conveniently used to facilitate individualized prediction of prostate cancer before prostate biopsy.

The efferocytosis process in aging: Supporting evidence, mechanisms, and therapeutic prospects for age-related diseases.

BACKGROUND: Aging is characterized by an ongoing struggle between the buildup of damage caused by a combination of external and internal factors. Aging has different effects on phagocytes, including impaired efferocytosis. A deficiency in efferocytosis can cause chronic inflammation, aging, and several other clinical disorders. AIM OF REVIEW: Our review underscores the possible feasibility and extensive scope of employing dual targets in various age-related diseases to reduce the occurrence and progression of age-related diseases, ultimately fostering healthy aging and increasing lifespan. Key scientific concepts of review Hence, the concurrent implementation of strategies aimed at augmenting efferocytic mechanisms and anti-aging treatments has the potential to serve as a potent intervention for extending the duration of a healthy lifespan. In this review, we comprehensively discuss the concept and physiological effects of efferocytosis. Subsequently, we investigated the association between efferocytosis and the hallmarks of aging. Finally, we discuss growing evidence regarding therapeutic interventions for age-related disorders, focusing on the physiological processes of aging and efferocytosis.

Modeling and Simulation of Graphene-Based Transducers in NEMS Accelerometers.

The mechanical characteristics of graphene ribbons with an attached proof mass that can be used as NEMS transducers have been minimally studied, which hinders the development of graphene-based NEMS devices. Here, we simulated the mechanical characteristics of graphene ribbons with an attached proof mass using the finite element method. We studied the impact of force, residual stress, and geometrical size on displacement, strain, resonant frequency, and fracture strength of graphene ribbons with an attached proof mass. The results show that the increase of width and thickness of graphene ribbons would result in a decrease of the displacement and strain but also an increase of resonant frequency. The increase of the length of graphene ribbons has an insignificant impact on the strain, but it could increase the displacement and decrease the resonant frequency. The increase of residual stress in the graphene ribbons decreases its strain and displacement. The estimated fracture strength of graphene shows limited dependence on its thickness, with an estimated value of around 148 GPa. These findings contribute to the understanding of the mechanical characteristics of graphene ribbons with an attached proof mass and lay the solid foundation for the design and manufacture of high-performance graphene-based NEMS devices such as accelerometers.

Spatial distribution and ecological risk assessment of short and medium chain chlorinated paraffins in water and sediments of river Ravi, Pakistan.

Short (SCCPs) and medium (MCCPs) chain chlorinated paraffins being the emerging organic pollutants have raised serious concerns due to their widespread use and related human health risks. However, their occurrence in aquatic bodies like rivers and associated damage to ecological integrity is yet unknown in some regions of the world. The current study is the first ever assessment of SCCPs and MCCPs in sediment and water of river Ravi, Pakistan. Spatial occurrence and associated ecological risks were investigated from sediments (n = 16) and composite water samples (n = 8) collected at eight locations along the stretch of river Ravi. The concentrations of SCCPs and MCCPs varied from below limit of detection (

Association of sodium-glucose cotransporter 2 inhibitors with risk of major adverse cardiovascular events in type 2 diabetes patients with acute coronary syndrome: a propensity score­matched analysis.

BACKGROUND: This study aimed to investigate the association of sodium-glucose cotransporter 2 inhibitors (SGLT2i) use with cardiovascular (CV) clinical outcomes in type 2 diabetes (T2D) patients with acute coronary syndrome (ACS). METHODS: Data of T2D patients hospitalized for ACS at Civil Aviation General Hospital from January 2019 to December 2022 were collected. Based on SGLT2i use or not, patients were stratified as SGLT2i group and SGLT2i-free group. A 1:1 nearest-neighbor propensity score-matched (PSM) was performed to adjust for the confounding factors and facilitate the robust comparisons between groups. The first occurrence of major adverse cardiovascular events (MACE) with 1 year follow-up, which consisted of CV death, all cause death, non-fatal myocardial infarction or stroke, coronary revascularization or heart failure readmission, was assessed. Kaplan-Meier analysis and Cox regressions were conducted to evaluate the prognostic significance of SGLT2i use. Subgroup analyses were performed to assess the interaction between subgroups and SGLT2i use. RESULTS: A total of 925 patients were included, and the SGLT2i use increased from 9.9% in 2019 to 43.8% in 2022. 226 pairs were finally matched using the PSM model. During 1 year follow-up period, a total of 110 patients experienced MACE in the matched cohort, with a rate of 24.3%. Survival analyses showed cumulative incidence of MACE, CV death, and heart failure readmission in the SGLT2i group were significantly lower than the SGLT2i-free group. Additionally, the adjusted Cox analyses demonstrated that SGLT2i was associated with a 34.1% lower risk of MACE (HR 0.659, 95% CI 0.487-0.892, P = 0.007), which was primarily driven by a decrease in the risk of CV death by 12.0% (HR 0.880, 95% CI 0.7830.990, P = 0.033), and heart failure readmission by 45.5% (HR 0.545, 95% CI 0.332-0.893, P = 0.016). This MACE preventive benefit was consistent across different subgroups (P interaction > 0.05 for all comparisons). CONCLUSIONS: In T2D patients with ACS, there was a clear increasing trend in SGLT2i use. SGLT2i was associated with a significantly lower risk of MACE, driven by the decrease in the risk of CV death, and heart failure readmission. Our study confirmed real-world use and efficacy of SGLT2i in a general T2D population with ACS.

Customizing catalyst surface/interface structures for electrochemical CO2 reduction.

Electrochemical CO2 reduction reaction (CO2RR) provides a promising route to converting CO2 into value-added chemicals and to neutralizing the greenhouse gas emission. For the industrial application of CO2RR, high-performance electrocatalysts featuring high activities and selectivities are essential. It has been demonstrated that customizing the catalyst surface/interface structures allows for high-precision control over the microenvironment for catalysis as well as the adsorption/desorption behaviors of key reaction intermediates in CO2RR, thereby elevating the activity, selectivity and stability of the electrocatalysts. In this paper, we review the progress in customizing the surface/interface structures for CO2RR electrocatalysts (including atomic-site catalysts, metal catalysts, and metal/oxide catalysts). From the perspectives of coordination engineering, atomic interface design, surface modification, and hetero-interface construction, we delineate the resulting specific alterations in surface/interface structures, and their effect on the CO2RR process. At the end of this review, we present a brief discussion and outlook on the current challenges and future directions for achieving high-efficiency CO2RR via surface/interface engineering.

NCF4 regulates antigen presentation of cysteine peptides by intracellular oxidative response and restricts activation of autoreactive and arthritogenic T cells.

Autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematous, are regulated by polymorphisms in genes contributing to the NOX2 complex. Mutations in both Ncf1 and Ncf4 affect development of arthritis in experimental models of RA, but the different regulatory pathways mediated by NOX2-derived reactive oxygen species (ROS) have not yet been clarified. Here we address the possibility that intracellular ROS, regulated by the NCF4 protein (earlier often denoted p40phox) which interacts with endosomal membranes, could play an important role in the oxidation of cysteine peptides in mononuclear phagocytic cells, thereby regulating antigen presentation and activation of arthritogenic T cells. To study the role of NCF4 we used mice with an amino acid replacing mutation (NCF4R58A), which is known to affect interaction with endosomal membranes, leading to decreased intracellular ROS production. To study the impact of NCF4 on T cell activation, we used the glucose phosphate isomerase peptide GPI325-339, which contains two cysteine residues (325-339c-c). Macrophages from mice with the NCF458A mutation efficiently presented the peptide when the two cysteines were intact and not crosslinked, leading to a strong arthritogenic T cell response. T cell priming occurred in the draining lymph nodes (LNs) within 8 days after immunization. Clodronate treatment, which depletes antigen-presenting mononuclear phagocytes, ameliorated arthritis severity, whereas treatment with FYT720, which traps activated T cells in LNs, prohibited arthritis. We conclude that NCF4-dependent intracellular ROS maintains cysteine peptides in an oxidized crosslinked state, which prevents presentation of peptides recognized by non-tolerized T cells and thereby protects against autoimmune arthritis.

Metabolic heterogeneity in clear cell renal cell carcinoma revealed by single-cell RNA sequencing and spatial transcriptomics.

BACKGROUND: Clear cell renal cell carcinoma is a prototypical tumor characterized by metabolic reprogramming, which extends beyond tumor cells to encompass diverse cell types within the tumor microenvironment. Nonetheless, current research on metabolic reprogramming in renal cell carcinoma mostly focuses on either tumor cells alone or conducts analyses of all cells within the tumor microenvironment as a mixture, thereby failing to precisely identify metabolic changes in different cell types within the tumor microenvironment. METHODS: Gathering 9 major single-cell RNA sequencing databases of clear cell renal cell carcinoma, encompassing 195 samples. Spatial transcriptomics data were selected to conduct metabolic activity analysis with spatial localization. Developing scMet program to convert RNA-seq data into scRNA-seq data for downstream analysis. RESULTS: Diverse cellular entities within the tumor microenvironment exhibit distinct infiltration preferences across varying histological grades and tissue origins. Higher-grade tumors manifest pronounced immunosuppressive traits. The identification of tumor cells in the RNA splicing state reveals an association between the enrichment of this particular cellular population and an unfavorable prognostic outcome. The energy metabolism of CD8+ T cells is pivotal not only for their cytotoxic effector functions but also as a marker of impending cellular exhaustion. Sphingolipid metabolism evinces a correlation with diverse macrophage-specific traits, particularly M2 polarization. The tumor epicenter is characterized by heightened metabolic activity, prominently marked by elevated tricarboxylic acid cycle and glycolysis while the pericapsular milieu showcases a conspicuous enrichment of attributes associated with vasculogenesis, inflammatory responses, and epithelial-mesenchymal transition. The scMet facilitates the transformation of RNA sequencing datasets sourced from TCGA into scRNA sequencing data, maintaining a substantial degree of correlation. CONCLUSIONS: The tumor microenvironment of clear cell renal cell carcinoma demonstrates significant metabolic heterogeneity across various cell types and spatial dimensions. scMet exhibits a notable capability to transform RNA sequencing data into scRNA sequencing data with a high degree of correlation.

Refractive stability and timing of spectacle prescription following cataract surgery in myopic eyes.

PURPOSE: To investigate the post-operative refractive stabilisation time and provide evidence for the optimal timing of a spectacle prescription in myopic post-cataract surgery patients. METHODS: A total of 116 consecutive myopic cataract patients were recruited from the Zhongshan Ophthalmic Center in this prospective study. Post-operative subjective refraction was assessed after 1 week and 1 month (4-6 weeks), with the interval for the new spectacle acquisition being recorded. Visual Function Index-14 (VF-14) questionnaires were used to assess the vision-related quality of life. RESULTS: There was no significant difference in spherical (p = 0.33), cylindrical (p = 0.65) or spherical equivalent refractions (p = 0.45) obtained 1 week and 1 month post-operatively, indicating that subjects achieved refractive stability within 1 week. In subgroups having differing age and axial lengths, there were also no significant differences between the 1 week and 1 month findings. The spherical equivalent refractive shift between 1 week and 1 month was significantly correlated with the post-operative prediction error (R = 0.35; p < 0.001). Only five (4.3%) out of 116 patients obtained new spectacles 1 week post-surgery. The VF-14 values improved from 85.77 ± 7.24 to 90.45 ± 5.39 after acquiring new spectacles (p < 0.01). CONCLUSIONS: The stabilisation of subjective refraction occurred within 1 week in myopic cataract patients. Shortening the interval before prescribing a new spectacle prescription is recommended for myopic patients following cataract surgery to improve their vision-related quality of life.

A rapid and efficient Agrobacterium-mediated transient transformation system in grape berries.

Transient transformation is extremely useful for rapid in vivo assessment of gene function, especially for fruit-related genes. Grape berry, while an important fruit crop, is recalcitrant to transient transformation, due to the high turgor pressure in its mesocarp cells that limits the ability of Agrobacterium to penetrate into the tissue. It is urgent to establish a simple transient transformation system for rapid analysis of gene function. In this study, different injection methods, grape genotypes, and developmental stages were tested in order to develop a rapid and efficient Agrobacterium-mediated transient transformation methodology for grape berries. Two injection methods, namely punch injection and direct injection, were evaluated using the ß-glucuronidase (GUS) gene and by x-gluc tissue staining and 4-methylumbelliferyl-ß-D-glucuronide fluorescence analysis. The results indicated that there were no significant differences on transformation effects between the two methods, but the latter was more suitable because of its simplicity and convenience. Six grape cultivars ('Hanxiangmi', 'Moldova', 'Zijixin', 'Jumeigui', 'Shine-Muscat', and 'A17') were tested for transient transformation. 'Hanxiangmi', 'Moldova', and 'Zijixin' grape berries were not suitable for agroinfiltration due to frequently fruit cracking, browning, and formation of scar skin. The fruit integrity rates of 'Jumeigui', 'Shine-Muscat', and 'A17' berries were all above 80%, and GUS activity was detected in the berries of the three cultivars 3-14 days after injection with the Agrobacterium culture, while higher GUS activities were observed in the 'Jumeigui' berries. The levels of GUS activity in injected berries at 7-8 weeks after full blooming (WAFB) were more than twice at 6 WAFB. In subsequent assays, the over-expression of MYB transcription factor VvMYB44 via transient transformation accelerated the anthocyanin accumulation and fruit coloring through raising the expression levels of VvLAR1, VvUFGT, VvLDOX, VvANS, and VvDFR, which verified the effectiveness of this transformation system. These experiments finally identified the reliable grape cultivars and suitable operational approach for transient transformation and further indicated that this Agrobacterium-mediated transient transformation system was efficient and suitable for the elucidation of gene function in grape berries.

A landscape of gene expression regulation for synovium in arthritis.

The synovium is an important component of any synovial joint and is the major target tissue of inflammatory arthritis. However, the multi-omics landscape of synovium required for functional inference is absent from large-scale resources. Here we integrate genomics with transcriptomics and chromatin accessibility features of human synovium in up to 245 arthritic patients, to characterize the landscape of genetic regulation on gene expression and the regulatory mechanisms mediating arthritic diseases predisposition. We identify 4765 independent primary and 616 secondary cis-expression quantitative trait loci (cis-eQTLs) in the synovium and find that the eQTLs with multiple independent signals have stronger effects and heritability than single independent eQTLs. Integration of genome-wide association studies (GWASs) and eQTLs identifies 84 arthritis related genes, revealing 38 novel genes which have not been reported by previous studies using eQTL data from the GTEx project or immune cells. We further develop a method called eQTac to identify variants that could affect gene expression by affecting chromatin accessibility and identify 1517 regions with potential regulatory function of chromatin accessibility. Altogether, our study provides a comprehensive synovium multi-omics resource for arthritic diseases and gains new insights into the regulation of gene expression.

Novel 18-norspirostane steroidal saponins: Extending lifespan and mitigating neurodegeneration through promotion of mitophagy and mitochondrial biogenesis in Caenorhabditis elegans.

Pharmacological strategies to delay aging and combat age-related diseases are increasingly promising. This study explores the anti-aging and therapeutic effects of two novel 18-norspirostane steroidal saponins from Trillium tschonoskii Maxim, namely deoxytrillenoside CA (DTCA) and epitrillenoside CA (ETCA), using Caenorhabditis elegans (C. elegans). Both DTCA and ETCA significantly extended the lifespan of wild-type N2 worms and improved various age-related phenotypes, including muscle health, motility, pumping rate, and lipofuscin accumulation. Furthermore, these compounds exhibited notable alleviation of pathology associated with Parkinson's disease (PD) and Huntington's disease (HD), such as the reduction of α-synuclein and poly40 aggregates, improvement in motor deficits, and mitigation of neuronal damage. Meanwhile, DTCA and ETCA improved the lifespan and healthspan of PD- and HD-like C. elegans models. Additionally, DTCA and ETCA enhanced the resilience of C. elegans against heat and oxidative stress challenges. Mechanistic studies elucidated that DTCA and ETCA induced mitophagy and promoted mitochondrial biogenesis in C. elegans, while genetic mutations or RNAi knockdown affecting mitophagy and mitochondrial biogenesis effectively eliminated their capacity to extend lifespan and reduce pathological protein aggregates. Together, these compelling findings highlight the potential of DTCA and ETCA as promising therapeutic interventions for delaying aging and preventing age-related diseases.

Effective treatment of optic neuropathies by intraocular delivery of MSC-sEVs through augmenting the G-CSF-macrophage pathway.

Optic neuropathies, characterized by injury of retinal ganglion cell (RGC) axons of the optic nerve, cause incurable blindness worldwide. Mesenchymal stem cell-derived small extracellular vesicles (MSC-sEVs) represent a promising "cell-free" therapy for regenerative medicine; however, the therapeutic effect on neural restoration fluctuates, and the underlying mechanism is poorly understood. Here, we illustrated that intraocular administration of MSC-sEVs promoted both RGC survival and axon regeneration in an optic nerve crush mouse model. Mechanistically, MSC-sEVs primarily targeted retinal mural cells to release high levels of colony-stimulating factor 3 (G-CSF) that recruited a neural restorative population of Ly6Clow monocytes/monocyte-derived macrophages (Mo/MΦ). Intravitreal administration of G-CSF, a clinically proven agent for treating neutropenia, or donor Ly6Clow Mo/MΦ markedly improved neurological outcomes in vivo. Together, our data define a unique mechanism of MSC-sEV-induced G-CSF-to-Ly6Clow Mo/MΦ signaling in repairing optic nerve injury and highlight local delivery of MSC-sEVs, G-CSF, and Ly6Clow Mo/MΦ as therapeutic paradigms for the treatment of optic neuropathies.

Electrospun fibers based anisotropic silk fibroin film with photodynamic antibacterial therapy for S. aureus infected wound healing.

Bacterial infection has been regarded as a life-threatening problem in clinic. In addition to screening of new antibiotics, it is important to develop highly effective antibacterial materials against antibiotic resistance with capacities on modulating chronic inflammation. Herein, aligned Chlorin e6 (Ce6) conjugated silk fibroin electrospun fibers were successfully fabricated on silk fibroin based film via electrospining to achieve effective photodynamic antibacterial activities under near infrared (NIR) irradiation. The aligned electrospun fiber based film composite (SFCF@Film) exhibited good mechanical properties and desirable hemocompatibility. SFCF@Film provided a promising guidance cue for directing cell orientation and promoting cell growth. Significantly, SFCF@Film effectively generated ROS under NIR irradiation to kill S. aureus for treating wound infections within 10 min and promoted M2 polarization of macrophages for wound healing at later stage. Therefore, we believed that this engineered bioscaffold can be a powerful strategy for handling wound infection.