Indoxyl sulfate aggravates podocyte damage through the TGF-ß1/Smad/ROS signaling pathway.

INTRODUCTION: Hyperglycaemia induces the production of a large quantity of reactive oxygen species (ROS) and activates the transforming growth factor ß1(TGF-ß1)/Smad signalling pathway, which is the main initiating factor in the formation of diabetic nephropathy. Indoxyl sulfate (IS) is a protein-binding gut-derived uraemic toxin that localizes to podocytes, induces oxidative stress and inflames podocytes. The involvement of podocyte damage in diabetic nephropathy through the TGF-ß1/) signalling pathway is still unclear. METHODS: In this study, we cultured differentiated rat podocytes in vitro and measured the expression levels of nephrin, synaptopodin, CD2AP, SRGAP2a and α-SMA by quantitative real-time PCR (qRT‒PCR) and western blotting after siRNA-mediated TGF-ß1 silencing, TGF-ß1 overexpression and the presence of the ROS inhibitor acetylcysteine. We detected the expression levels of nephrin, synaptopodin, CD2AP, SRGAP2a, SRGAP2a in the Smad2/3, phosphorylated-Smad2/3 (p-Smad2/3), Smad7, NADPH oxidase 4 (NOX4), and ROS levels under high glucose (HG) and IS conditions. RESULTS: The results indicated that nephrin, synaptopodin, CD2AP and SRGAP2a expressions were significantly upregulated and α-SMA expression was significantly downregulated in the presence of HG under siRNA-mediated TGF-ß1 silencing or after the addition of acetylcysteine. However, in the presence of HG, the expressions of nephrin, synaptopodin, CD2AP and SRGAP2a were significantly downregulated, and the expression of α-SMA was significantly upregulated with the overexpression of TGF-ß1. IS supplementation under HG conditions further significantly reduced the expressions of nephrin, synaptopodin, CD2AP and SRGAP2a; altered the expressions of Smad2/3, p-Smad2/3, Smad7 and NOX4; and increased ROS production in podocytes. CONCLUSIONS: This study suggests that IS may modulate the expression of nephrin, synaptopodin, CD2AP and SRGAP2a by regulating the ROS and TGF-ß1/Smad signalling pathways, providing new theoretical support for the treatment of diabetic nephropathy.

Effects of Aviation Mutagenesis on Soil Chemical Indexes, Enzyme Activities, and Metabolites of Dahongpao (Camellia sinensis) Tea Trees.

Aviation mutagenesis is a breeding method for the rapid selection of superior plant varieties. In this study, rhizosphere soil chemical indexes, soil enzyme activities, and soil metabolites were measured in Dahongpao tea trees with aviation mutagenesis (TM) and without aviation mutagenesis (CK). The main soil metabolites distinguishing TM and CK and their relationships with soil chemical indexes and soil enzyme activities were analyzed and obtained. The results showed that there was no significant change in the rhizosphere soils' pH of TM tea trees compared to CK (p = 0.91), while all other chemical indexes of TM were significantly higher than CK (p < 0.05). In addition, the activities of enzymes related to soil nutrient cycling such as urease, protease, sucrase, acid phosphatase and cellulase, and enzymes related to soil antioxidants such as superoxide dismutase, catalase, peroxidase, and polyphenol oxidase were significantly increased (p < 0.05) in the rhizosphere soils of TM tea trees compared to CK. Soil metabolite analysis showed that the main soil metabolites distinguishing CK from TM were carbohydrates, nitrogen compounds, and amines. Of these, carbohydrates and nitrogen compounds were significantly positively correlated with soil chemical indexes and soil enzymes, whereas amine was significantly negatively correlated with soil chemical indexes such as organic matter, total nitrogen, total potassium, available nitrogen, available phosphorus; amine showed significant negative correlation with soil enzymes such as catalase, peroxidase, polyphenol oxidase, and urease. It can be seen that aviation mutagenesis is conducive to improving the ability of tea tree rhizosphere aggregation and transformation of soil nutrients, increasing the total amount of soil nutrients and the content of available nutrients, which is more conducive to promoting the uptake of nutrients by the tea tree, and thus promoting the growth of the tea tree.

Tea Quality of the Mysterious "Dahongpao Mother Tree" (Camellia sinensis).

The quality of the Dahongpao mother tree (Camellia sinensis) remains a mystery to this day. In this study, for the first time, the differences between the Dahongpao mother tree (MD) and Dahongpao cuttings (PD), in terms of odor characteristics and taste characteristics were analyzed by metabomics. The results showed that MD had stronger floral, fruity, green, and woody odor characteristics than PD, and that the contributions were mainly from dihydromyrcenol, methyl salicylate, 2-isobutylpyrazine, 1,6-dihydrocarveol, gamma-terpineol, and linalyl acetate. Further, fresh and brisk taste and mellowness taste characteristics of MD were significantly higher than PD, with contributions mainly from amino acids and derivatives and organic acids. Secondly, bitterness taste characteristics of PD were significantly higher than MD, with contributions from phenolic acids, flavones, and flavonols. This study preliminarily unraveled the legend of the superior quality of the Dahongpao mother tree, and also provided an important reference for the breeding of tea-tree cuttings.

Aviation Mutagenesis Alters the Content of Volatile Compounds in Dahongpao (Camellia sinensis) Leaves and Improves Tea Quality.

Aviation mutagenesis is a fast and efficient breeding method. In this study, we analyzed the effect of aviation mutagenesis on volatile compounds and odor characteristics in Dahongpao fresh leaves and gross tea for the first time. The results showed that aviation mutagenesis significantly increased the total volatile compounds of Dahongpao fresh leaves and gross tea. Aviation mutagenesis most critically significantly increased the content of beta-myrcene in Dahongpao fresh leaves, prompting its conversion to beta-pinene, cubebol, beta-phellandrene, zingiberene, (Z,Z)-3,6-nonadienal, and 6-pentyloxan-2-one after processing, which in turn enhanced the fruity, green, spicy, and woody odor characteristics of the gross tea. This study provided a reference for further exploration of aviation mutagenic breeding of Camellia sinensis.

Deficiency of ASGR1 promotes liver injury by increasing GP73-mediated hepatic endoplasmic reticulum stress.

Liver injury is a core pathological process in the majority of liver diseases, yet the genetic factors predisposing individuals to its initiation and progression remain poorly understood. Here we show that asialoglycoprotein receptor 1 (ASGR1), a lectin specifically expressed in the liver, is downregulated in patients with liver fibrosis or cirrhosis and male mice with liver injury. ASGR1 deficiency exacerbates while its overexpression mitigates acetaminophen-induced acute and CCl4-induced chronic liver injuries in male mice. Mechanistically, ASGR1 binds to an endoplasmic reticulum stress mediator GP73 and facilitates its lysosomal degradation. ASGR1 depletion increases circulating GP73 levels and promotes the interaction between GP73 and BIP to activate endoplasmic reticulum stress, leading to liver injury. Neutralization of GP73 not only attenuates ASGR1 deficiency-induced liver injuries but also improves survival in mice received a lethal dose of acetaminophen. Collectively, these findings identify ASGR1 as a potential genetic determinant of susceptibility to liver injury and propose it as a therapeutic target for the treatment of liver injury.

Genistein prevents the production of hypospadias induced by Di-(2-ethylhexyl) phthalate through androgen signaling and antioxidant response in rats.

Environmental estrogen exposure has increased dramatically over the past 50 years. In particular, prenatal exposure to estrogen causes many congenital diseases, among which reproductive system development disorders are extremely serious. In this study, the molecular mechanism of hypospadias and the therapeutic effect of genistein (GEN) were investigated through in vivo models prepared by Di-(2-ethylhexyl) phthalate (DEHP) exposure between 12 and 19 days of gestation. With increased DEHP concentrations, the incidence of hypospadias increased gradually. DEHP inhibited the key enzymes involved in steroid synthesis, resulting in decreasing testosterone synthesis. At the same time, DEHP increased reactive oxygen species (ROS) and produced inflammatory factors via NADPH oxidase-1 (NOX1) and NADPH oxidase-4 (NOX4) pathways. It also inhibited Steroid 5 α Reductase 2 (Srd5α2) and decreased dihydrotestosterone (DHT) synthesis. Additionally, DEHP inhibited the androgen receptor (AR), resulting in reduced DHT binding to the AR that ultimately retarded the development of the external reproductive system. GEN, a phytoestrogen, competes with DEHP for binding to estrogen receptor ß (ERß). This competition, along with GEN's antiestrogen and antioxidant properties, could potentially reverse impairments. The findings of this study provide valuable insights into the role of phytoestrogens in alleviating environmental estrogen-induced congenital diseases.

Cannulation via the external jugular vein--An alternative to conventional peripherally inserted central catheterisation for paediatric patients.

PURPOSE: This study aimed to describe a peripherally inserted central catheterisation (PICC) for paediatric patients with inaccessible access and a high risk of general anaesthesia (GA). METHODS: This was a retrospective observational study involving all paediatric inpatients who performed the PICC via an EJV approach without GA between September 2014 and September 2021 in a provincial key clinical speciality. RESULTS: A total of 290 EJV line placement attempts were performed, and 29 were excluded due to missing placement results, resulting in a sample size of 261. The anatomical localisation, punctures, and catheterisation success rates for this practice were 100%, 100%, and 90.04%, respectively. The placement success rate in children younger than one year was 93.75% (45/48). The median line duration of use was 19 days, with a median length of catheter insertion of 13 cm. The most common complications were catheter malposition (n = 20) and dislodgement (n = 7). CONCLUSION: The PICC via an EJV approach without GA is a feasible and safe practice with acceptable success and complication rates, and low costs. It might be an attractive alternative for obtaining central vascular access for paediatric patients.

Identification and Validation of CXCL2 as a Key Gene for Childhood Obesity.

This study aims to identify the key genes and their regulatory networks by bioinformatics, increasing understanding of childhood obesity. The data comes from the GEO and Immport database. The immune microenvironment was explored in GSE104815. Key genes were identified by intersection of DEGs with the immune gene set. Enrichment analysis revealed gene-related functions and correlation analysis explored the relationship. Regulatory networks were constructed based on miRcode, TarBase and TargetScan databases. GSE29718 was used to validate our findings. Intercellular communication and cell differentiation trends were further explored using single-cell data from GSE153643. Based on our research, the immune microenvironment in the obese group showed higher immune infiltration. We found 962 DEGs and CXCL2 was identified as the key gene. The co-regulatory network of lncRNA-miRNA-mRNA suggested that obtaining TM4SF19-AS1, GUSBP11, AC105020.1, LINC00189, COL4A2-AS2, VIPR1-AS1 and LINC00242 may regulate CXCL2 (r > 0.9 and P < 0.01). Differential expression of CXCL2 was validated in GSE29718 (P < 0.05) and CXCL2 was identified as a biomarker for childhood obesity (AUC = 0.885). GSVA enrichment analysis revealed many pathways of high group obtaining the TNF-α signaling via NF-κB pathway and interferon γ response pathway. In GSE153643, 11 cell types were identified and CXCL2 was highly expressed in monocyte, macrophage, endothelial cell and pericyte. In CXCL2 high expressing macrophages, there was a tendency for cells to polarize toward M1 macrophages (P < 0.05). In summary, we identified CXCL2 as a potential biomarker of childhood obesity. The development of childhood obesity may be associated with the activation of immune infiltration of macrophage M1 polarization by CXCL2 expression.

ZnS/CoS@C Derived from ZIF-8/67 Rhombohedral Dodecahedron Dispersed on Graphene as High-Performance Anode for Sodium-Ion Batteries.

Metal sulfides are highly promising anode materials for sodium-ion batteries due to their high theoretical capacity and ease of designing morphology and structure. In this study, a metal-organic framework (ZIF-8/67 dodecahedron) was used as a precursor due to its large specific surface area, adjustable pore structure, morphology, composition, and multiple active sites in electrochemical reactions. The ZIF-8/67/GO was synthesized using a water bath method by introducing graphene; the dispersibility of ZIF-8/67 was improved, the conductivity increased, and the volume expansion phenomenon that occurs during the electrochemical deintercalation of sodium was prevented. Furthermore, vulcanization was carried out to obtain ZnS/CoS@C/rGO composite materials, which were tested for their electrochemical properties. The results showed that the ZnS/CoS@C/rGO composite was successfully synthesized, with dodecahedrons dispersed in large graphene layers. It maintained a capacity of 414.8 mAh g-1 after cycling at a current density of 200 mA g-1 for 70 times, exhibiting stable rate performance with a reversible capacity of 308.0 mAh g-1 at a high current of 2 A g-1. The excellent rate performance of the composite is attributed to its partial pseudocapacitive contribution. The calculation of the diffusion coefficient of Na+ indicates that the rapid sodium ion migration rate of this composite material is also one of the reasons for its excellent performance. This study highlights the broad application prospects of metal-organic framework-derived metal sulfides as anode materials for sodium-ion batteries.

The potential effects and mechanism of echinacoside powder in the treatment of Hirschsprung's Disease.

Possible complications, such as intestinal obstruction and inflammation of the intestinal tract, can have a detrimental effect on the prognosis after surgery for Hirschsprung disease. The aim of this study was to investigate the potential targets and mechanisms of action of echinacoside to improve the prognosis of Hirschsprung disease. Genes related to the disease were obtained through analysis of the GSE96854 dataset and four databases: OMIM, DisGeNET, Genecard and NCBI. The targets of echinacoside were obtained from three databases: PharmMapper, Drugbank and TargetNet. The intersection of disease genes and drug targets was validated by molecular docking. The valid docked targets were further explored for their expression by using immunohistochemistry. In this study, enrichment analysis was used to explore the mechanistic pathways involved in the genes. Finally, we identified CA1, CA2, CA9, CA12, DNMT1, RIMS2, RPGRIP1L and ZEB2 as the core targets. Except for ZEB2, which is predominantly expressed in brain tissue, the remaining seven genes show tissue specificity and high expression in the gastrointestinal tract. RIMS2 possesses a high mutation phenomenon in pan-cancer, while a validated ceRNA network of eight genes was constructed. The core genes are involved in several signaling pathways, including the one-carbon metabolic process, carbonate dehydratase activity and others. This study may help us to further understand the pharmacological mechanisms of echinacoside and provide new guidance and ideas to guide the treatment of Hirschsprung disease.

Application of New COF Materials in Secondary Battery Anode Materials.

Covalent organic framework materials (COFs), as a new type of organic porous material, not only have the characteristics of flexible structure, abundant resources, environmental friendliness, etc., but also have the characteristics of a regular structure and uniform pore channels, so they have broad application prospects in secondary batteries. Their functional group structure, type, and number of active sites play a crucial role in the performance of different kinds of batteries. Therefore, this article starts from these aspects, summarizes the application and research progress of the COF anode materials used in lithium-ion batteries, sodium-ion batteries, and potassium-ion batteries in recent years, discusses the energy storage mechanism of COF materials, and expounds the application prospects of COF electrodes in the field of energy storage.

Synchronous multiple primary malignant neoplasms in breast, kidney, and bilateral thyroid: A case report.

BACKGROUND: Multiple primary malignant neoplasms (MPMNs) are rare, while synchronous MPMNs (SMPMNs) are even less common. Owing to the progression of medical technology and the extension of life expectancy, its incidence is gradually increasing. CASE SUMMARY: Although reports of breast and thyroid dual cancers are common, cases of an additional diagnosis of kidney primary cancer within the same individual are rare. CONCLUSION: We present a case of simultaneous MPMN of three endocrine organs, reviewing the relevant literature to enhance our understanding of SMPMNs while emphasizing the increasingly important need for accurate diagnosis and multidisciplinary management whenever this challenging situation arises.

Development of a self-help cognitive behavioral therapy programme for reducing the stigma of stroke survivors: a modified delphi study.

BACKGROUND: Stigma is a common psychological consequence for stroke survivors that aggravates their physical and psychological burden and hinders their rehabilitation. Currently, there are few interventions targeted at the stigma of stroke survivors. OBJECTIVES: This study reports on the development of a self-help cognitive behavioral therapy (CBT) programme driven by a logical model of stigma in stroke survivors, CBT and the advice of multidomain experts. METHODS: A logical model of stigma in stroke survivors was derived from a systematic search of the literature and semistructured interviews with 21 patients to identify factors influencing stigma. The item content of the programme was generated based on this logical model in combination with CBT. A modified Delphi process with an expert panel of multidomain experts was used to evaluate and refine the content of the programme. SPSS 20.0 was used for data analysis. RESULTS: Seventeen experts accepted the invitation to participate, and all completed two rounds of the Delphi survey. Six sections and 26 items were identified. Consensus was reached among experts that the self-help CBT programme included the following six sections: health education, understanding stigma, cognition change, skills training and self-care, self-acceptance and relapse prevention. CONCLUSIONS: The self-help CBT programme includes health education and psychological education. This study extends the limited body of research on stroke-related stigma interventions, and the next step is to evaluate its efficacy in trials.

Molecular regulation of immunity in tea plants.

Tea, which is mainly produced using the young leaves and buds of tea plants (Camellia sinensis (L.) O. Kuntze), is one of the most common non-alcoholic beverages consumed in the world. The standard of tea mostly depends on the variety and quality of tea plants, which generally grow in subtropical areas, where the warm and humid conditions are also conducive to the occurrence of diseases. In fighting against pathogens, plants rely on their sophisticated innate immune systems which has been extensively studied in model plants. Many components involved in pathogen associated molecular patterns (PAMPs) triggered immunity (PTI) and effector triggered immunity (ETI) have been found. Nevertheless, the molecular regulating network against pathogens (e.g., Pseudopestalotiopsis sp., Colletotrichum sp. and Exobasidium vexans) causing widespread disease (such as grey blight disease, anthracnose, and blister blight) in tea plants is still unclear. With the recent release of the genome data of tea plants, numerous genes involved in tea plant immunity have been identified, and the molecular mechanisms behind tea plant immunity is being studied. Therefore, the recent achievements in identifying and cloning functional genes/gene families, in finding crucial components of tea immunity signaling pathways, and in understanding the role of secondary metabolites have been summarized and the opportunities and challenges in the future studies of tea immunity are highlighted in this review.

Assessment of urinary podocalyxin as an alternative marker for urinary albumin creatinine ratio in early stage of diabetic kidney disease in older patients.

This study's objective is to evaluate the correlation relationship between Podocalyxin (PCX), an urinary marker of podocytes, urinary albumin-creatinine ratio (ACR) and the predictive value of PCX in the routine screen of early diabetic kidney disease (DKD) among older people. We also aimed to explore its prediction value despite of other metabolic factor and how PCX alters in the predictive power for early stage of diabetic nephropathy. In retrospective, 320 cases of older patients diagnosed with type 2 diabetes mellitus who met both inclusion and exclusion criteria were collected and divided with levels of urinary albumin, that is, normal albuminuria group, microalbuminuria group and healthy group. The correlation coefficient between PCX and ACR, and the odds ratio of PCX were gauged in the study. Area under the receiver operating characteristic (ROC) curve was also calculated. There were 188 patients in the normal group with urine ACR<30mg/g, and 132 patients in the microproteinuria group with urine ACR 30-300mg/g. 132 cases of DKD diagnosed with ACR, among them, 104 cases of DKD were predicted by PCX. The percentage correction value was 78.8%. The following parameters such as gender, age, course of disease, glycated hemoglobin, triglyceride, total cholesterol, BMI, blood pressure, uric acid, and eGFR were used as variables for adjustment to establish the prediction model of urine PCX and ACR. Multiple logistic regression test was carried out to evaluate against the predictive ability of the model. The area under the ROC curve corresponding to the regression model after adjustment is 0.952. Although factors such as the course of disease, HbA1C, UA, and eGFR could influence on the predictive ability of PCX, PCX still has a good ability to predict early DKD in older patients. Therefore, it could be used as a diagnostic indicator for early-stage DKD in older patients.

Fibrinogen-to-albumin ratio is related to the severity of coronary artery disease in chronic kidney disease patients undergoing coronary angiography.

OBJECTIVES: This study was to explore the potential relationship between the fibrinogen-to-albumin ratio (FAR) and the presence and severity of coronary artery disease (CAD) in stage 3-5 predialysis chronic kidney disease (CKD) patients. DESIGN: This study included 978 patients undergoing coronary angiography (CAG). CAD was defined as the presence of obstructive stenosis>50% of the lumen diameter in any of the four main coronary arteries. Gensini scores (GSs), left main coronary artery (LMCA) and three-vessel coronary artery disease (TVD) were used to elevate the severity of CAD. RESULTS: The adjusted odds ratios of CAD were 3.059 (95% CI: 1.859-5.032) and 2.670 (95% CI: 1.605-4.441) in the third and fourth quartiles of FAR compared with the first quartile, respectively. Among 759 patients diagnosed with CAD, multivariate logistic regression analysis showed that FAR (at the 0.01 level) was significantly positively associated with the presence of LMCA (adjusted OR=1.177, 95% CI 1.067-1.299, P=0.001) or TVD (adjusted OR=1.154, 95% CI 1.076-1.238, P<0.001), and a higher GS (adjusted OR=1.152, 95% CI 1.073-1.238, P<0.001). CONCLUSIONS: FAR levels were independently associated with the presence and severity of CAD in stage 3-5 predialysis CKD patients.

Acute MPTP treatment decreases dendritic spine density of striatal medium spiny neurons via SNK-SPAR pathway in C57BL/6 mice.

Parkinson's disease (PD) is a well-known neurodegenerative disorder associated with a high risk in middle-aged and elderly individuals, severely impacting the patient's quality of life. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is frequently used to establish PD in animals. Dendritic spines are dendritic processes that form the foundation of learning and memory. Reportedly, dendritic spine density of striatal medium spiny neurons (MSNs) declines in PD, and this decline has been associated with PD progression; however, the underlying mechanism remains elusive. Herein, we used the MPTP animal model to examine whether serum-induced kinase (SNK) and spine-associated Rap guanosine triphosphatase (SPAR) contribute to decreased dendritic spine density in striatal MSNs. MPTP was used to establish the animal model, which exhibits motor function impairment and dopaminergic cell loss. To assess spine density, Golgi staining was performed to count striatal dendritic spines, which were reduced in the MPTP group when compared with those in the normal control group. Immunohistochemistry was performed to analyze changes in SNK and SPAR expression. MPTP treatment significantly increased the expression of SNK in striatal MSNs, whereas that of SPAR was significantly decreased when compared with the normal control group. These findings offer clues to further explore the mechanism of declining dendritic spine density in patients with PD and provide evidence for potential target identification in PD.

Polypyrrole Modified MoS2 Nanorod Composites as Durable Pseudocapacitive Anode Materials for Sodium-Ion Batteries.

As a typical two-dimensional layered metal sulfide, MoS2 has a high theoretical capacity and large layer spacing, which is beneficial for ion transport. Herein, a facile polymerization method is employed to synthesize polypyrrole (PPy) nanotubes, followed by a hydrothermal method to obtain flower-rod-shaped MoS2/PPy (FR-MoS2/PPy) composites. The FR-MoS2/PPy achieves outstanding electrochemical performance as a sodium-ion battery anode. After 60 cycles under 100 mA g-1, the FR-MoS2/PPy can maintain a capacity of 431.9 mAh g-1. As for rate performance, when the current densities range from 0.1 to 2 A g-1, the capacities only reduce from 489.7 to 363.2 mAh g-1. The excellent performance comes from a high specific surface area provided by the unique structure and the synergistic effect between the components. Additionally, the introduction of conductive PPy improves the conductivity of the material and the internal hollow structure relieves the volume expansion. In addition, kinetic calculations show that the composite material has a high sodium-ion transmission rate, and the external pseudocapacitance behavior can also significantly improve its electrochemical performance. This method provides a new idea for the development of advanced high-capacity anode materials for sodium-ion batteries.

Impact of klotho on the expression of SRGAP2a in podocytes in diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is the major cause of kidney failure, and glomerular podocytes play critical roles in the pathogenesis of DN by maintaining the glomerular structure and filtration barrier. Klotho and Slit-Robo GTP activating protein 2a (SRGAP2a) have been indicated to play protective roles in reducing kidney injury, but whether there is an internal relationship between these two factors is unclear. METHODS: In this study, we cultured differentiated rat podocytes in vitro and measured the SRGAP2a expressions by immunofluorescence staining, quantitative real-time PCR (qRT-PCR) and western blotting, after siRNA-mediated transforming growth factor ß1 (TGF-ß1) silencing, TGF-ß1 overexpression and in the presence of a reactive oxygen species (ROS) inhibitor. And we detected the expressions of SRGAP2a, small mother against decapentaplegic (Smad)2/3, phosphorylated-Smad2/3 (p-Smad2/3), Smad7, and NAD(P)H oxidase 4 (NOX4), ROS levels and podocyte cytoskeletal remodelling under high glucose (HG) and exogenous klotho conditions. In addition, we performed haematoxylin-eosin (HE) staining and immunohistochemistry with diabetic rat models to confirm the in vitro results. RESULTS: The results indicated that SRGAP2a expression was significantly upregulated under siRNA-mediated TGF-ß1 silencing conditions or after adding a ROS inhibitor, but significantly downregulated with TGF-ß1 overexpression, in the presence of HG. The supplementation of exogenous klotho under HG conditions significantly increased the SRGAP2a expression, remodelled the actin cytoskeleton and altered the expressions of Smad2/3, p-Smad2/3, Smad7 and NOX4 and reduced the ROS generation in podocytes. Moreover, klotho administration protected kidney injury in DN rats. CONCLUSIONS: This study indicated that klotho may modulate the expression of SRGAP2a by regulating the ROS and TGF-ß1 signalling pathways and provided theoretical support for klotho protein as a novel therapeutic strategy for treating DN patients.

Inhibition of PI3K/AKT/mTOR Signalling Pathway Activates Autophagy and Suppresses Peritoneal Fibrosis in the Process of Peritoneal Dialysis.

Peritoneal dialysis (PD) is an important part of replacement therapy for kidney failure. However, long-term PD treatment can cause peritoneal fibrosis. Autophagy may be involved in the pathological mechanism of peritoneal fibrosis (PF). Although autophagy is currently known to be involved in course of PF, its specific effects still lack in-depth research. In this experiment, a high-glucose (HG)-induced peritoneal fibrosis rat model was successfully established via intraperitoneal injection of HG peritoneal dialysate, and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and the mechanistic target of rapamycin (mTOR) inhibitor rapamycin were used to treat peritoneal fibrosis rats. In addition, in vitro studies of high glucose-induced peritoneal fibrosis were performed using rat peritoneal mesothelial cells (PMCs). In vivo and in vitro experiments showed that LY294002 and rapamycin effectively inhibited the process of PF induced by high glucose. In addition, LY294002 and rapamycin were found to alleviate fibrosis by eliminating intracellular reactive oxygen species (ROS) levels, promoting the expression of the epithelial mesenchymal transdifferentiation proteins zonula occludens-1 (ZO-1) and E-cadherin, and inhibiting the expression of p-PI3K, PI3K, p-mTOR, mTOR, the fibroblast-specific proteins ferroptosis suppressor protein 1 (FSP1), and alpha-smooth muscle actin (α-SMA). Moreover, LY294002 and rapamycin promoted expression of autophagy-related proteins LC3-II/I, p62, and beclin-1. The current data indicated that inhibition of PI3K/AKT/mTOR signalling pathway activated autophagy and suppressed PF in the process of PD. Therefore, intervention in this signalling pathway may become a research goal for the prevention and treatment of PF, which has important clinical significance.