Simultaneous Cu(II)-EDTA decomplexation and Cu(II) recovery using integrated contact-electro-catalysis and capacitive deionization from electroplating wastewater.

The complex of heavy metals and organic acids leads to high difficulty in heavy metals separation by traditional technologies. Meanwhile, alkaline precipitation commonly used in industry causes the great consumption of resources and extra pollution. Herein, the effective decomplexation of Cu(Ⅱ)-EDTA and synchronous recycling of Cu2+ were realized by contact-electro-catalysis (CEC) coupled with capacitive deionization (CDI) innovatively. In particular, fluorinated ethylene propylene (FEP) as dielectric powders could generate reactive oxygen species under ultrasonic stimulation, realizing continuous deaminization and decarboxylation of Cu(Ⅱ)-EDTA and accelerating the totally breakage of Cu-O and Cu-N bonds. Additionally, the degradation pathway and intermediates evolution of Cu(Ⅱ)-EDTA were investigated using various characterization methods. It was confirmed that decarboxylation predominantly governed the degradation process of Cu(Ⅱ)-EDTA in CEC. During the course of treatment, the degradation ratio of Cu(Ⅱ)-EDTA reached 86.4 % within 150 min. Impressively, this strategy had satisfactory applicability to other metal combinations and excellent cycle stability. Subsequently, the released Cu ions were captured by CuSe cathode electrode through CDI. This research elucidated the degradation mechanism of persistent organic pollutant during CEC, and provided a novel approach for efficiently treating industrial wastewater containing metal complexes and advancing the exploitation and utilization of new technologies for metal recovery.

Targeted blocking of EGFR and GLUT1 by compound H reveals a new strategy for treatment of triple-negative breast cancer and nasopharyngeal carcinoma.

BACKGROUND: Cytoplasmic epidermal growth factor receptor (EGFR) is overexpressed in both nasopharyngeal carcinoma (NPC) and triple-negative breast cancer (TNBC), while clinical outcome and prognosis vary greatly among patients treated with gefitinib, and all patients eventually develop resistance to this agent. Therefore, we propose a new concept for synthesizing multitarget compounds and reveal new therapeutic strategies for NPC and TNBC expressing EGFR. METHODS: Compound H was synthesized in our previous study. Molecular docking, and cell thermal shift assays (CETSAs) and drug affinity responsive target stability(DARTS) were used to confirm the binding of compound H to EGFR and GLUT1. Methylthiazolyldiphenyl-tetrazolium bromide(MTT), annexin V-PE assays, mitochondrial membrane potential (MMP) assays, and animal models were used to evaluate the inhibitory effect of compound H on TNBC cell lines. Energy metabolism tests, Western blotting, and immunofluorescence staining were performed to evaluate the synergistic effects on EGFR- and glucose transporter type 1(GLUT1)-mediated energy metabolism. RESULTS: Compound H can simultaneously act on the EGFR tyrosine kinase ATP-binding site and inhibit GLUT1-mediated energy metabolism, resulting in reductions in ATP, MMP, intra-cellular lactic acid, and EGFR nuclear transfer. The anti-tumor activity of compound H is significantly superior to the combination of GLUT1 inhibitor BAY876 and EGFR inhibitor gefitinib. Compound H has remarkable anti-proliferative effects on TNBC MDA-MB231 cells, and importantly, no obvious toxicity effects of compound H were found in vivo. CONCLUSIONS: Synergistic effects of inhibition of EGFR- and GLUT1-mediated energy metabolism by compound H may present a new strategy for the treatment of TNBC and NPC.

A Current Understanding of FXR in NAFLD: The multifaceted regulatory role of FXR and novel lead discovery for drug development.

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. The incidence of NAFLD-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. However, there are currently no US Food and Drug Administration-approved drugs for NAFLD. Increasing evidence underscores the close association between NAFLD and bile acid metabolism disorder, highlighting the feasibility of targeting the bile acid signaling pathway for NAFLD treatment. The farnesoid X receptor (FXR) is an endogenous receptor for bile acids that exhibits favorable effects in ameliorating the metabolic imbalance of bile acids, lipid disorders, and disruption of intestinal homeostasis, all of which are key characteristics of NAFLD, making FXR a promising therapeutic target for NAFLD. The present review provides a comprehensive overview of the diverse mechanisms through which FXR improves NAFLD, with particular emphasis on its involvement in regulating bile acid homeostasis and the recent advancements in drug development targeting FXR for NAFLD treatment.

Role of Quercetin in DNA Repair: Possible Target to Combat Drug Resistance in Diabetes.

Diabetes Mellitus (DM) is referred to as hyperglycemia in either fasting or postprandial phases. Oxidative stress, which is defined by an excessive amount of reactive oxygen species (ROS) production, increased exposure to external stress, and an excessive amount of the cellular defense system against them, results in cellular damage. Increased DNA damage is one of the main causes of genomic instability, and genetic changes are an underlying factor in the emergence of cancer. Through covalent connections with DNA and proteins, quercetin has been demonstrated to offer protection against the creation of oxidative DNA damage. It has been found that quercetin shields DNA from possible oxidative stress-related harm by reducing the production of ROS. Therefore, Quercetin helps to lessen DNA damage and improve the ability of DNA repair mechanisms. This review mainly focuses on the role of quercetin in repairing DNA damage and compensating for drug resistance in diabetic patients. Data on the target topic was obtained from major scientific databases, including SpringerLink, Web of Science, Google Scholar, Medline Plus, PubMed, Science Direct, and Elsevier. In preclinical studies, quercetin guards against DNA deterioration by regulating the degree of lipid peroxidation and enhancing the antioxidant defense system. By reactivating antioxidant enzymes, decreasing ROS levels, and decreasing the levels of 8-hydroxydeoxyguanosine, Quercetin protects DNA from oxidative damage. In clinical studies, it was found that quercetin supplementation was related to increased antioxidant capacity and decreased risk of type 2 diabetes mellitus in the experimental group as compared to the placebo group. It is concluded that quercetin has a significant role in DNA repair in order to overcome drug resistance in diabetes.

Gentisic acid prevents colorectal cancer metastasis via blocking GPR81-mediated DEPDC5 degradation.

BACKGROUND: Metastasis driven by epithelial-mesenchymal transition (EMT) remains a significant contributor to the poor prognosis of colorectal cancer (CRC), and requires more effective interventions. GPR81 signaling has been linked to tumor metastasis, while lacks an efficient specific inhibitor. PURPOSE: Our study aimed to investigate the effect and mechanism of Gentisic acid on colorectal cancer (CRC) metastasis. STUDY DESIGN: A lung metastasis mouse model induced by tail vein injection and a subcutaneous graft tumor model were used. Gentisic acid (GA) was administered by an intraperitoneal injection. HCT116 was treated with lactate to establish an in vitro model. METHODS: MC38 cells with mCherry fluorescent protein were injected into tail vein to investigate lung metastasis ability in vivo. GA was administered by intraperitoneal injection for 3 weeks. The therapeutic effect was evaluated by survival rates, histochemical analysis, RT-qPCR and live imaging. The mechanism was explored using small interfering RNA (siRNA), Western blotting, RT-qPCR and immunofluorescence. RESULTS: GA had a therapeutic effect on CRC metastasis and improved survival rates and pathological changes in dose-dependent manner. GA emerged as an GPR81 inhibitor, effectively suppressed EMT and mTOR signaling in CRC induced by lactate both in vivo and in vitro. Mechanistically, GA halted lactate-induce degradation of DEPDC5 through impeding the activation of Chaperone-mediated autophagy (CMA). CONCLUSION: CMA-mediated DEPDC5 degradation is crucial for lactate/GPR81-induced CRC metastasis, and GA may be a promising candidate for metastasis by inhibiting GPR81 signaling.

Carbapenem-resistant Gram-negative bacteria (CR-GNB) in ICUs: resistance genes, therapeutics, and prevention - a comprehensive review.

Intensive care units (ICUs) are specialized environments dedicated to the management of critically ill patients, who are particularly susceptible to drug-resistant bacteria. Among these, carbapenem-resistant Gram-negative bacteria (CR-GNB) pose a significant threat endangering the lives of ICU patients. Carbapenemase production is a key resistance mechanism in CR-GNB, with the transfer of resistance genes contributing to the extensive emergence of antimicrobial resistance (AMR). CR-GNB infections are widespread in ICUs, highlighting an urgent need for prevention and control measures to reduce mortality rates associated with CR-GNB transmission or infection. This review provides an overview of key aspects surrounding CR-GNB within ICUs. We examine the mechanisms of bacterial drug resistance, the resistance genes that frequently occur with CR-GNB infections in ICU, and the therapeutic options against carbapenemase genotypes. Additionally, we highlight crucial preventive measures to impede the transmission and spread of CR-GNB within ICUs, along with reviewing the advances made in the field of clinical predictive modeling research, which hold excellent potential for practical application.

Impact of transcranial electrical stimulation on serum neurotrophic factors and language function in patients with speech disorders.

BACKGROUND: Speech disorders have a substantial impact on communication abilities and quality of life. Traditional treatments such as speech and psychological therapies frequently demonstrate limited effectiveness and patient compliance. Transcranial electrical stimulation (TES) has emerged as a promising non-invasive treatment to improve neurological functions. However, its effectiveness in enhancing language functions and serum neurofactor levels in individuals with speech disorders requires further investigation. AIM: To investigate the impact of TES in conjunction with standard therapies on serum neurotrophic factor levels and language function in patients with speech disorders. METHODS: In a controlled study spanning from March 2019 to November 2021, 81 patients with speech disorders were divided into a control group (n = 40) receiving standard speech stimulation and psychological intervention, and an observation group (n = 41) receiving additional TES. The study assessed serum levels of ciliary neurotrophic factor (CNTF), glial cell-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF), as well as evaluations of motor function, language function, and development quotient scores. RESULTS: After 3 wk of intervention, the observation group exhibited significantly higher serum levels of CNTF, GDNF, BDNF, and NGF compared to the control group. Moreover, improvements were noted in motor function, cognitive function, language skills, physical abilities, and overall development quotient scores. It is worth mentioning that the observation group also displayed superior performance in language-specific tasks such as writing, reading comprehension, retelling, and fluency. CONCLUSION: This retrospective study concluded that TES combined with traditional speech and psychotherapy can effectively increase the levels of neurokines in the blood and enhance language function in patients with speech disorders. These results provide a promising avenue for integrating TES into standard treatment methods for speech disorders.

[Clinical and Mechanism Research Progress in Amelioration of Mild Cognitive Impairment via Meditation].

Mild cognitive impairment(MCI)has a high risk of progressing to dementia,with no recommended therapies.Recent studies have shown that meditation has huge potential to improve the cognitive function,with low cost and high safety,being suitable to be applied in the treatment of neurological and psychotic disorders.This paper reviews the application and prospects of meditation in treating MCI from the concept,clinical efficacy,and mechanism of meditation,aiming to provide reference for future clinical studies.

Sex differences in the association of the uric acid to high-density lipoprotein cholesterol ratio with coronary artery disease risk among Chinese nondialysis patients with CKD stages 3-5.

BACKGROUND AND AIMS: Evidence has indicated that serum uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) are positively and negatively associated with coronary artery disease (CAD). The UA to HDL-C ratio (UHR) has recently drawn attention as a new predictor for metabolic syndrome, inflammation and atherosclerosis. However, the association between the UHR and CAD in nondialysis chronic kidney disease (CKD) patients is still unclear. METHODS AND RESULTS: We retrospectively analysed 733 733 nondialysis patients with CKD stage 3-5 who received their first coronary artery angiography (CAG), including 510 participants with CAD. All laboratory indicators were collected within one week before CAG. The median UHR of CAD and non-CAD patients was 15.52% and 12.29%, respectively. In multivariate analysis, female patients with a high UHR were 4.7 times more at risk of CAD than those with a lower UHR. Meanwhile, the positive association of the UHR with the severity of coronary artery stenosis (CAS) persisted significantly in female CAD subjects but not in males. In addition, receiver operating characteristic (ROC) curves were constructed for CAD and severe CAS. The area under the curve (AUC) for the UHR was higher than that for UA and HDL-C alone in female patients [UHR (AUC): 0.715 for CAD and 0.716 for severe CAS]. CONCLUSIONS: An elevated UHR was independently related to an increased CAD risk and the severity of CAS in nondialysis female patients with CKD stage 3-5, and was more predictive of the onset of CAD and the severity of CAS than UA or HDL-C alone.

Vanillic acid restores homeostasis of intestinal epithelium in colitis through inhibiting CA9/STIM1-mediated ferroptosis.

The damage of integrated epithelial epithelium is a key pathogenic factor and closely associated with the recurrence of ulcerative colitis (UC). Here, we reported that vanillic acid (VA) exerted potent therapeutic effects on DSS-induced colitis by restoring intestinal epithelium homeostasis via the inhibition of ferroptosis. By the CETSA assay and DARTS assay, we identified carbonic anhydrase IX (CAIX, CA9) as the direct target of VA. The binding of VA to CA9 causes insulin-induced gene-2 (INSIG2) to interact with stromal interaction molecule 1 (STIM1), rather than SREBP cleavage-activating protein (SCAP), leading to the translocation of SCAP-SREBP1 from the endoplasmic reticulum (ER) to the Golgi apparatus for cleavage into mature SREBP1. The activation of SREBP1 induced by VA then significantly facilitated the transcription of stearoyl-CoA desaturase 1 (SCD1) to exert an inhibitory effect on ferroptosis. By inhibiting the excessive death of intestinal epithelial cells caused by ferroptosis, VA effectively preserved the integrity of intestinal barrier and prevented the progression of unresolved inflammation. In conclusion, our study demonstrated that VA could alleviate colitis by restoring intestinal epithelium homeostasis through CA9/STIM1-mediated inhibition of ferroptosis, providing a promising therapeutic candidate for UC.

Development strategy of early childhood music education industry: An IFS-AHP-SWOT analysis based on dynamic social network.

Early childhood music education has garnered recognition for its unique contribution to cognitive, emotional, and social development in children. Nevertheless, the industry grapples with numerous challenges, including a struggle to adapt traditional educational paradigms to new curriculum reforms, and an excessive emphasis on skill training at the expense of nurturing a love for music and aesthetics in children. To navigate these challenges and explore growth strategies for the early childhood music education industry, we initiated a comprehensive approach that involved distributing surveys to practitioners and parents and engaging experts for insightful discussions. Consequently, we proposed an analytical method based on dynamic social networks in conjunction with Intuitionistic Fuzzy Sets (IFS), Analytic Hierarchy Process (AHP), and Strengths, Weaknesses, Opportunities, and Threats (SWOT) analysis, collectively referred to as IFS-AHP-SWOT. This integrated methodology synergizes the capabilities of dynamic social networks, IFS, AHP, and SWOT analysis to offer a nuanced perspective on industry development strategies. The findings underscore that institutions within the early childhood music education industry need to adopt a development strategy that leverages their strengths and opportunities to foster sustainable growth. Ultimately, this research aims to provide critical decision-making support for industry practitioners, policymakers, and researchers, contributing significantly to the ongoing discourse on strategic development in the early childhood music education industry.

UHPLC-MS/MS Assay for Quantification of Legubicin, a Novel Doxorubicin-Based Legumain-Activated Prodrug, and Its Application to Pharmacokinetic and Tissue Distribution Studies.

Legubicin, a novel prodrug based on doxorubicin, has both albumin-binding and legumain-activating properties. The aim of this study was to develop and validate a UHPLC-MS/MS method for investigating the in vivo pharmacokinetics and tissue distribution profiles of legubicin in rats and tumor-bearing mice following intravenous administration, and to compare this prodrug with the positive control drug doxorubicin. The study employed a UHLC-MS/MS method to determine the levels of albumin-bound of legubicin and two metabolites (free Leu-DOX and DOX) in plasma, tumor, and tissue samples. This method was validated for good selectivity, high sensitivity, excellent extraction recovery, and short run time. The results showed that legubicin was present in the circulation in vivo mainly in a protein-bound form with larger AUC values and lower clearance and distribution, and essentially released small amounts of doxorubicin. Compared to administration of equimolar doses of doxorubicin, legubicin showed increased exposure of the active drug in the tumor and decreased the level of the active drug in the heart and kidney. This study provides valuable information on the pharmacokinetics and tissue distribution of legubicin, implicating its potential as a novel and effective drug candidate for anti-cancer therapies.

Attention gate and dilation U-shaped network (GDUNet): an efficient breast ultrasound image segmentation network with multiscale information extraction.

Background: In recent years, computer-aided diagnosis (CAD) systems have played an important role in breast cancer screening and diagnosis. The image segmentation task is the key step in a CAD system for the rapid identification of lesions. Therefore, an efficient breast image segmentation network is necessary for improving the diagnostic accuracy in breast cancer screening. However, due to the characteristics of blurred boundaries, low contrast, and speckle noise in breast ultrasound images, breast lesion segmentation is challenging. In addition, many of the proposed breast tumor segmentation networks are too complex to be applied in practice. Methods: We developed the attention gate and dilation U-shaped network (GDUNet), a lightweight, breast lesion segmentation model. This model improves the inverted bottleneck, integrating it with tokenized multilayer perceptron (MLP) to construct the encoder. Additionally, we introduce the lightweight attention gate (AG) within the skip connection, which effectively filters noise in low-level semantic information across spatial and channel dimensions, thus attenuating irrelevant features. To further improve performance, we innovated the AG dilation (AGDT) block and embedded it between the encoder and decoder in order to capture critical multiscale contextual information. Results: We conducted experiments on two breast cancer datasets. The experiment's results show that compared to UNet, GDUNet could reduce the number of parameters by 10 times and the computational complexity by 58 times while providing a double of the inference speed. Moreover, the GDUNet achieved a better segmentation performance than did the state-of-the-art medical image segmentation architecture. Conclusions: Our proposed GDUNet method can achieve advanced segmentation performance on different breast ultrasound image datasets with high efficiency.

S-adenosylmethionine attenuates angiotensin II-induced aortic dissection formation by inhibiting vascular smooth muscle cell phenotypic switch and autophagy.

It is well known that aortic dissection (AD) is a very aggressive class of vascular diseases. S-adenosylmethionine (SAM) is an autophagy inhibitor with anti-inflammatory and anti-oxidative stress effects; however, the role of SAM in AD is unknown. In this study, we constructed an animal model of AD using subcutaneous minipump continuous infusion of AngII-induced ApoE-/-mice and a cytopathic model using AngII-induced primary vascular smooth muscle cells (VSMCs) to investigate the possible role of SAM in AD. The results showed that mice in the AngII + SAM group had significantly lower AD incidence, significantly prolonged survival, and reduced vascular elastic fiber disruption compared with mice in the AngII group. In addition, SAM significantly inhibited autophagy in vivo and in vitro. Meanwhile, SAM also inhibited the cellular phenotypic switch, mainly by up regulating the expression levels of contractile marker proteins [α-smooth muscle actin (α-SMA) and smooth muscle 22α (SM22α)] and down regulating the expression levels of synthetic marker proteins [osteoblast protein (OPN), matrix metalloproteinase-2 (MMP2), and matrix metalloproteinase-9 (MMP9)]. Molecularly, SAM inhibited AD formation mainly by activating the PI3K/AKT/mTOR signaling pathway. Using a PI3K inhibitor (LY294002) significantly reversed the protective effect of SAM in AngII-induced mice and VSMCs.Our study demonstrates the protective effect of SAM on mice under AngII-induced AD for the first time. SAM prevented AD formation mainly by inhibiting cellular phenotypic switch and autophagy, and activation of the PI3K/AKT/mTOR signaling pathway is a possible molecular mechanism. Thus, SAM may be a novel strategy for the treatment of AD.

Endoplasmic reticulum stress in skin aging induced by UVB.

Aging is a normal and complex biological process. Skin is located in the most superficial layer of the body, and its degree of aging directly reflects the aging level of the body. Endoplasmic reticulum stress refers to the aggregation of unfolded or misfolded proteins in the endoplasmic reticulum and the disruption of the calcium ion balance when cells are stimulated by external stimuli. Mild endoplasmic reticulum stress can cause a series of protective mechanisms, including the unfolded protein response, while sustained high intensity stimulation leads to endoplasmic reticulum stress and eventually apoptosis. Photoaging caused by ultraviolet radiation is an important stimulus in skin aging. Many studies have focused on oxidative stress, but increasing evidence shows that endoplasmic reticulum stress plays an important role in photoaging. This paper reviews the development and mechanism of endoplasmic reticulum stress (ERS) in skin photoaging, and provides research directions for targeting the ERS pathway to slow aging.

Indoor Localization System Based on RSSI-APIT Algorithm.

An indoor localization system based on the RSSI-APIT algorithm is designed in this study. Integrated RSSI (received signal strength indication) and non-ranging APIT (approximate perfect point-in-triangulation test) localization methods are fused with machine learning in order to improve the accuracy of the indoor localization system. The system focuses on the improvement of preprocessing and localization algorithms. The primary objective of the system is to enhance the preprocessing of the acquired RSSI data and optimize the localization algorithm in order to enhance the precision of the coordinates in the indoor localization system. In order to mitigate the issue of significant fluctuations in RSSI, a technique including the integration of Gaussian filtering and an artificial neural network (ANN) is employed. This approach aims to preprocess the acquired RSSI data, thus reducing the impact of multipath effects. In order to address the issue of low localization accuracy encountered by the conventional APIT localization algorithm during wide-area localization, the RSSI ranging function is incorporated into the APIT localization algorithm. This addition serves to further narrow down the localization area. Consequently, the resulting localization algorithm is referred to as the RSSI-APIT positioning algorithm. Experimental results have demonstrated the successful reduction of inherent localization errors within the system by employing the RSSI-APIT positioning algorithm. The present study aims to investigate the impact of the localization scene and the number of anchors on the RSSI-APIT localization algorithm, with the objective of enhancing the performance of the indoor localization system. The conducted experiments demonstrated that the enhanced system exhibits several advantages. Firstly, it successfully decreased the frequency of anchor calls, resulting in a reduction in the overall operating cost of the system. Additionally, it effectively enhanced the accuracy and stability of the system's localization capabilities. In a complex environment of 100 m2 in size, compared with the traditional trilateral localization method and the APIT localization algorithm, the RSSI-APIT localization algorithm reduced the localization error by about 2.9 m and 1.8 m, respectively, and the overall error was controlled within 1.55 m.

Generation of locomotor­like activity using monopolar intraspinal electrical microstimulation in rats.

Severe spinal cord injury (SCI) affects the ability of functional standing and walking. As the locomotor central pattern generator (CPG) in the lumbosacral spinal cord can generate a regulatory signal for movement, it is feasible to activate CPG neural network using intra-spinal micro-stimulation (ISMS) to induce alternating patterns. The present study identified two special sites with the ability to activate the CPG neural network that are symmetrical about the posterior median sulcus in the lumbosacral spinal cord by ISMS in adult rats. A reversal of flexion and extension can occur in an attempt to generate a stepping movement of the bilateral hindlimb by either reversing the pulse polarity of the stimulus or changing the special site. Therefore, locomotor-like activity can be restored with monopolar intraspinal electrical stimulation on either special site. To verify the motor function regeneration of the paralyzed hindlimbs, a four-week locomotor training with ISMS applied to the special site in the SCI + ISMS group (n=12) was performed. Evaluations of motor function recovery using behavior, kinematics and physiological analyses, were used to assess hindlimb function and the results showed the stimulation at one special site can promote significant functional recovery of the bilateral hindlimbs (P<0.05). The present study suggested that motor function of paralyzed bilateral hindlimbs can be restored with monopolar ISMS.

Circ-KATNAL1 Knockdown Reduces Neuronal Apoptosis and Alleviates Spinal Cord Injury Through the miR-98-5p/PRDM5 Regulatory Axis.

Spinal cord injury (SCI) is a common disease of the central nervous system. circRNAs play a crucial role in neurological disease. The purpose of this study was to investigate the role of circ-KATNAL1 in SCI and its regulatory mechanism. T9-L10 spinal segment of Sprague Dawley rats was compressed or contused after T10 laminectomy to establish the SCI rat model. Then, rats were divided into SCI group, si-NC group, si-circ-KATNAL1 group, si-circ-KATNAL1 + antagomir NC group, si-circ-KATNAL1 + miR-98-5p antagomir group, si-circ-KATNAL1 + oe-NC group, and si-circ-KATNAL1 + oe-PRDM5 group, with 6 rats in each group. There was another sham operation group that received no treatment. Basso, Beattie, and Bresnahan (BBB) scores were used to evaluate the neural function of rats. In addition to that, the pathological changes of spinal cord tissue, neuronal apoptosis, and inflammatory responses were correspondingly observed and analyzed. Quantitative measurements of circ-KATNAL1, miR-98-5p, and PRDM5 levels were conducted, as well as analyses of their interrelationship. Circ-KATNAL1 was up-regulated in the spinal cord tissue of SCI rats, and circ-KATNAL1 knockdown could improve neural function, alleviate pathological changes of spinal cord tissue, and inhibit neuronal apoptosis and inflammatory responses in SCI rats. For miR-98-5p, circ-KATNAL1 was an upstream factor, while PRDM5 was a downstream actor. miR-98-5p deficiency or PRDM5 restoration impaired the remission effect of circ-KATNAL1 knockdown on SCI. Circ-KATNAL1 knockdown reduces neuronal apoptosis and alleviates SCI through miR-98-5p/PRDM5 regulatory axis.

Chitosan nanoparticles encapsulated with BEZ235 prevent acute rejection in mouse heart transplantation.

Acute rejection may manifest following heart transplantation, despite the implementation of relatively well-established immunosuppression protocols. The significance of the mTOR signaling pathway in rejection is widely acknowledged. BEZ235, a second-generation mTOR inhibitor with dual inhibitory effects on PI3K and mTOR, holds promise for clinical applications. This study developed a nanodelivery system, BEZ235@NP, to facilitate the intracellular delivery of BEZ235, which enhances efficacy and reduces adverse effects by improving the poor solubility of BEZ235. In the complete MHCII-mismatched model, BEZ235@NP significantly prolonged cardiac allografts survival compared to free BEZ235, which was attributed to more effective suppression of effector T cell activation and promotion of greater expansion of Tregs. These nanoparticles demonstrated excellent biosafety and exhibited no short-term biotoxicity upon investigation. To elucidate the mechanism, primary T cells were isolated from the spleen and it was observed that BEZ235@NP treatment resulted in the arrest of these cells in the G0/G1 phase. As indicated by Western blot analysis, BEZ235@NP substantially reduced mTOR phosphorylation. This, in turn, suppressed downstream pathways and ultimately exerted an anti-proliferative and anti-activating effect on cells. Furthermore, it was observed that inhibition of the mTOR pathway stimulated T-cell autophagy. In conclusion, the strategy of intracellular delivery of BEZ235 presents promising applications for the treatment of acute rejection.

Inhibiting sorting nexin 10 promotes mucosal healing through SREBP2-mediated stemness restoration of intestinal stem cells.

Intestinal stem cell (ISC) is a promising therapeutic target for inflammatory bowel disease. Cholesterol availability is critical for ISC stemness. Low plasma cholesterol is a typical feature of Crohn's disease (CD); however, its impact on mucosal healing remains unclear. Here, we identified an essential role of sorting nexin 10 (SNX10) in maintaining the stemness of ISCs. SNX10 expression in intestinal tissues positively correlates with the severity of human CD and mouse colitis. Conditional SNX10 knockout in intestinal epithelial cells or ISCs promotes intestinal mucosal repair by maintaining the ISC population associated with increased intracellular cholesterol synthesis. Disassociation of ERLIN2 with SCAP by SNX10 deletion enhances the activation of SREBP2, resulting in increased cholesterol biosynthesis. DC-SX029, a small-molecule inhibitor of SNX10, was used to verify the druggable potential of SNX10 for the treatment of patients with CD. Our study provides a strategy for mucosal healing through SREBP2-mediated stemness restoration of ISCs.